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1
Wander, Seth A. "p27 and Metastatic Progression: Molecular Mechanisms Underlying Bone Metastasis." Scholarly Repository, 2011. http://scholarlyrepository.miami.edu/oa_dissertations/690.
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The complex PI3K/mTOR pathway regulates tumor progression via effects on cellular proliferation, apoptosis, autophagy, and motility. New drugs that inhibit the catalytic site of both PI3K and mTOR have shown promise in clinical trials. Here, we report the first use of a novel, dual PI3K/mTOR catalytic site inhibitor (PF-04691502, PF1502) in a xenograft model of breast cancer metastasis to bone. Metastatic MDA-MB-1833 cells showed PI3K/mTOR activation relative to parental MDA-MB-231. Low-dose PF1502 significantly impaired tumor cell motility and invasion in vitro without causing cell cycle arrest, apoptosis, or reduced proliferation. Pre-treatment of tumor cells at this dose reduced bone metastatic outgrowth in vivo. The atypical tumor suppressor, p27KIP1, is phosphorylated in its C-terminal region by multiple AGC kinases downstream of PI3K/mTOR. These phosphorylation events promote cytoplasmic mislocalzation of p27 which, in turn, facilitates inhibition of the RhoA cytoskeletal regulatory protein. The resulting turnover of the actin cytoskeleton is thought to underlie the increased cellular motility attributed to cytoplasmic p27. In MDA-MB-1833 cells, PI3K/mTOR inhibition reduced p27 C-terminal phosphorylation at T157 and T198 and reduced cytoplasmic p27 levels. Overexpression of a p27T157D/T198D phospho-mimetic mutant conferred resistance to the anti-motility effects of PF1502 in vitro. MDA-MB-1833 cells demonstrate p27-dependent inhibition of RhoA-ROCK signaling, as well as p27-dependent motility and invasion in vitro, however, RhoA knockdown did not confer resistance to the anti-motility effects of PF1502. p27shRNA dramatically impaired the bone metastatic outgrowth of MDA-MB-1833 in vivo. In an effort to explore potentially novel RhoA-independent mechanisms whereby cytoplasmic p27 might drive tumor cell motility and metastasis, we turned to the process known as epithelial-to-mesenchymal transition (EMT). The EMT program has been implicated as a critical driver of tumor metastasis in a variety of cancer models. PI3K/mTOR inhibition and shRNA p27 treatment both reversed expression of EMT markers in MDA-MB-1833. Thus, PI3K/mTOR appears to drive p27-dependent motility and metastasis at least in part by induction of an EMT-like phenotype, a novel mechanism through which p27 might act to promote tumor progression. These results provide an important new clinical rationale supporting the use of PI3K/mTOR inhibitors as anticancer agents via their inhibition of tumor invasion and metastasis.
2
Li, Carman Man-Chung. "Transcriptional regulation of metastatic progression in lung adenocarcinoma." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/98545.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2015.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references.
Lung cancer is the most prevalent cancer type, leading to more than one million deaths per year worldwide. The vast majority of these mortalities were attributed to metastasis, which is the dissemination of tumor cells from the lungs to other organs. The molecular mechanisms for metastasis is complex and not well understood. In this thesis, I investigated the gene expression changes in tumor cells that contribute to metastasis of lung adenocarcinoma, the major subtype of lung cancer. Using a genetically-engineered mouse model and derivative cell lines, we showed that metastatic lung adenocarcinoma cells are capable of forming proteolytic membrane protrusions known as invadopodia to degrade the extracellular matrix. The formation and function of invadopodia are dependent on an isoform switch of the adaptor protein Tks5. The Tks5long isoform, which is upregulated in metastatic cells, is capable of localizing to the cell membrane and activating invadopodia formation. In contrast, the Tks5short isoform, which is transcribed from a promoter independent of Tks5long, is the predominant isoform in non-metastatic cells, and functions to inhibit invadopodia-mediated matrix degradation by destabilizing these protrusions. We demonstrated that an increased ratio of Tks5long-to- Tks5short promoted invadopodia activity in vitro and metastasis in vivo. Furthermore, a high Tks5long-to-Tks5short ratio in human tumors correlated with advanced stage and worse survival. These data strongly suggest that a balance between Tks5long and Tks5short expression is critical for metastasis. In addition, we found that the expression of the pro-metastatic Tks5long isoform is synergistically inhibited by three transcription factors - Nkx2-1, Foxa2, and Cdx2. These three factors were highly expressed in non-metastatic cells, and downregulated in metastatic cells. Altered expression of these factors led to commensurate changes in Tks5long levels. Finally, we demonstrated that Nkx2-1, Foxa2, and Cdx2 function cooperatively to inhibit metastasis by suppressing a network of target genes. Silencing of all three factors in non-metastatic cells activated a program of metastasis-related genes, and increased metastasis in a transplantation model. Furthermore, the expression patterns of these factors strongly correlated with tumor progression in an autochthonous model of lung adenocarcinoma, and were closely associated with disease stage and survival outcomes of human patients. Collectively, these findings strongly argue that Nkx2-1, Foxa2, and Cdx2 synergize to restrain metastatic progression. Taken together, this study provides insights on some of the key molecular regulators of lung cancer metastasis. Our findings contribute to a better understanding of metastasis, and potentially to the development of better therapeutic strategies in the future.
by Carman Man-Chung Li.
Ph. D.
3
Donald, Carlton Dewitt. "Metastatic characteristics of tumor progression in Prostate Cancer." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 1995. http://digitalcommons.auctr.edu/dissertations/3299.
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Tumor biologist have long appreciated that both cell to
cell and cell to extracellular matrix (ECM) interactions are
involved in the invasive and metastatic events that are
characteristic of malignancy. Cancer cell attachment to and
invasion of an ECM has been associated with metastatic
potential of cell lines of the Dunning rat prostate model.
It was postulated that differences observed in the
metastatic potential of four Dunning cell lines may
correlate with cell-matrix interactions. Four cell lines,
highly metastatic ML, MLL, AT-3 and non-metastatic AT-1 were
studied. The adhesive, invasive and chemoinvasive
capability of each cell line was compared. Cell adhesion
was examined by plating the cells on plastic dishes coated
with various components of the ECM (fibronectin, laminin and
collagen) as well as EHS Natrix (a natural ECM) . Invasion
was determined by examining cells ability to traverse a
matrigel barrier. Correlations were found between the
cells' adhesive and invasive abilities in response to the
ECM. These observations suggest that ECM components are
highly involved in prostate cancer cell activities and loss
may contribute to tumor progression and metastasis.
4
Gooding, Alex Joseph. "Characterizing a Role for the lncRNA BORG during Breast Cancer Progression and Metastasis." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1528462540265762.
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Usmani, Badar Alam. "Genomic instability and the metastatic potential of B16 murine melanomas." Thesis, University of Newcastle Upon Tyne, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238763.
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Mian, Shahid A. "Tissue transglutaminase and its relationship to cell cycle kinetics, apoptosis and tumour progression." Thesis, Nottingham Trent University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360772.
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7
Fiore, Leann S. "A Novel Link Between Abl Family Kinases and NM23-H1 During Metastatic Progression." UKnowledge, 2014. http://uknowledge.uky.edu/pharmacol_etds/5.
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Cancer patient mortality is caused by the ability of tumor cells to invade the extracellular matrix and metastasize. Our lab was the first to identify the role of Abl family of non-receptor tyrosine kinases (c-Abl and Arg) in the progression of solid tumor cancers. In our previous studies, we showed that high c-Abl/Arg activity promotes proliferation, invasion, and metastasis in melanoma and breast cancer cells lines. Here, we demonstrate that our previous findings are clinically relevant by showing increased c-Abl/Arg kinase activity in primary melanoma tumor tissue in comparison to low activity as compared to benign nevi. Additionally, in breast cancer tissue, we found aggressive tumor subtypes (triple-negative and high-grade breast cancer) had increased c-Abl/Arg activity as compared to less aggressive subtypes. To define the mechanism by which c-Abl and Arg promote melanoma and breast cancer metastasis, we searched for novel pathways by which c-Abl and Arg promote invasion, a key step in metastasis. Significantly, we found that c-Abl and Arg decrease the expression of non-metastatic protein, NM23-H1, a metastasis suppressor that is lost during metastatic progression. We demonstrate that NM23-H1 is localized and degraded within the lysosome via proteases, cathepsins L and B. Moreover, we show that c-Abl and Arg upregulate cathepsin mRNA levels and activate the cathepsins, which in-turn degrade NM23-H1. We demonstrate that this pathway is functionally significant as c-Abl and Arg require the downregulation of NM23-H1 to promote invasion in melanoma and breast cancer cell lines. We show that the pathway is clinically significant as c-Abl/Arg activity is inversely correlated with NM23-H1 expression in mouse lung metastases, as well as in human primary melanoma and primary breast cancer tissue. In summary, we are the first to demonstrate novel crosstalk between oncogenic and metastasis suppressor signaling pathways, and provide evidence that pharmacological inhibition of Abl family kinases in melanoma and breast cancer patients may prevent metastatic progression by stabilizing a metastasis suppressor.
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Fishel, Ben-Kenan Rotem. "Anatomic Patterns of Relapse and Progression Following Treatment with 131I-MIBG in Metastatic Neuroblastoma." Thesis, The University of Arizona, 2018. http://hdl.handle.net/10150/627159.
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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.Purpose and Background: Neuroblastomais the most common pediatric extracranialsolid tumor •50% of patients present with metastatic disease typically involving bone and bone marrow •Despite intensive multimodality therapy, 40% of patients with high-risk neuroblastomawill experience relapse •131I-MIBG is an active salvage agent for relapsed and refractory MIBG-avid disease •It is unknown whether disease progression following 131I-MIBG treatment occurs in previously involved vs. new sites of disease •A better understanding of this pattern may inform the use of consolidative focal therapies following 131I-MIBG administration
9
Jones, Robert John. "A study of Src kinase in the regulation of metastatic progression in colorectal cancer." Thesis, University of Glasgow, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269495.
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Alcock, Helen Elizabeth. "The analysis of genetic change associated with metastatic progression in colorectal and other adenocarcinomas." Thesis, University of Sheffield, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392718.
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Hyler, Alexandra Rochelle. "Evaluating the Effects of Fluid Shear Stress on Ovarian Cancer Progression and Metastatic Potential." Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/94135.
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Most women die of ovarian metastasis rather than the effects of the primary tumor. However, little is known about the factors that support the survival and secondary outgrowth of exfoliated ovarian cancer cells. In addition to genetic and molecular factors, the unique environment of the peritoneal cavity exposes ovarian cells to biophysical forces, particularly fluid shear stress (FSS). These biomechanical forces, only recently identified as a hallmark of cancer, induce rapid signaling events in attached and aggregated cells, a process termed mechanotransduction. The cellular responses to these forces and their impact on tumor initiation, progression, and metastasis are not understood. In order to delineate these phenomena, dynamic and syngeneic cell models are needed that represent the development of the disease and can be used in relevant engineered testing platforms. Thus, in an interdisciplinary approach, this work bridges molecular and cancer biology, device engineering, fluid mechanics, and biophysics strategies.
The results demonstrated that even a low level of continual FSS significantly and differentially affected the viability of epithelial ovarian cancer cells of various stages of progression over time, and enhanced their aggregation, adhesion, and cellular architecture, traits of more aggressive disease. Furthermore, benign cells that survived FSS displayed phenotypic and genotypic changes resembling more aggressive stages of the disease, suggesting an impact of FSS on early stages of tumor development.
After identifying a biological affect, we designed an in vitro testing platform for controlled FSS investigations, and we modeled the system fluid mechanics to understand the platform's performance capability. A cylindrical platform divided into annular sections with lid-driven flow was selected to allow continuous experiments sustainable for long durations. Tuning of the lid speed or fluid height resulted in a wide range of FSS magnitudes (0- 20 N/m2) as confirmed by analytical and numerical modeling. Further, detailed numerical modeling uncovered that FSS magnitudes experienced by cell aggregates were larger than previously observed, suggesting an even larger role of FSS in ovarian cancer. Finally, we built and engineered the designed platform to investigate changes in benign and cancer cells as a function of time and FSS magnitude. Device precision was balanced with biological consistency needs, and a novel platform was built for controlled FSS investigations. This work provides a foundational understanding of the physical environment and its potential links to ovarian cancer progression and metastatic potential.Ph. D.
12
Mathsyaraja, Haritha. "CSF1 DRIVEN TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL ALTERATIONS IN MYELOID CELLS PROMOTE METASTATIC TUMOR PROGRESSION." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1396965183.
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Donald, Carlton Dewitt. "Cytoskeletal Dynamics and cellular differentiation influence tumor progression and metastatic potential in Prostate Adenocarcinoma." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 1997. http://digitalcommons.auctr.edu/dissertations/3298.
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Cancer cell attachment to and invasion of an extracellular matrix has been associated with metastatic potential. Recently it has become apparent that the extracellular matrix may influence several phenotype properties of metastatic cancer cells. The mechanisms which regulate prostate cancer growth and metastasis may be particularly relevant to the development of clinical strategies for better understanding and ultimate treatment and control of the disease.
Cell-matrix interactions of prostate tumor cells were investigated by comparing the invasive ability through and attachment to reconstructed extracellular matrix components. A correlation was found between metastatic potential and adhesive ability. Non-metastatic AT-1 cells possessed a higher adhesive potential to extracellular matrix components than the highly metastatic cells (Mat-Lu, Mat-LyLu and AT-3) which had higher invasive potentials.
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Flores, Roberto Ettore. "Mycoplasma arginini increases activation, energetic deregulation, and tumor progression of VM-M3 metastatic macrophage cells." Thesis, Boston College, 2014. http://hdl.handle.net/2345/bc-ir:104072.
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Thesis advisor: Thomas N. SeyfriedMycoplasmas are the smallest, self-replicating free-living prokaryotes, and have been associated with carcinogenesis. Mycoplasmas can be detected in a high percentage of a wide variety of primary human cancers. Some mycoplasma species such as M. fermentans and M. hyorhinis can transform normal murine and human cell lines into tumorigenic cells. Mycoplasma infection can activate oncogenes as well as inactivate tumor suppressor genes. These observations suggest that mycoplasmas can be both carcinogenic and or onco-modulatory. I found that the metastatic macrophage VM-M3 cell line (referred to as M3+) was infected with mycoplasmas. Mycoplasmal16S rDNA sequencing showed M3+ cells were infected by the mycoplasma species M. arginini. Antibiotic was used to eradicate M. arginini from M3+ cells (referred to as M3- cells). The energetics of the infected M3+ cells and the non-infected M3- cells was studied by measuring respiration (oxygen consumption) and fermentation (lactate production). Respiration was enhanced and fermentation was reduced in the M3- cells compared to the M3+ cells. Glucose enhanced the fermentation and reduced the respiration of both the M3+ and the M3- cells. The M3+ cells produced higher quantities of metabolites indicative of immunological activation (itaconic acid, succinate, and citrulline) compared to M3- cells. In addition, in-vitro proliferation was higher in the M3+ cells than in the M3- cells at high cell densities. Primary subcutaneous tumor growth and metastasis was less in mice inoculated with the M3- cells than with the M3+ cells. The survival of a VM mouse was longer when inoculated with the M3- cells compared to the M3+ cells. Altogether these data indicates that M. arginini is an onco-modulator associated with activation, deregulated energetics and enhanced tumor progression of VM-M3 metastatic macrophage cells
Thesis (MS) — Boston College, 2014
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Biology
15
Singhal, Mahak [Verfasser], and Ana [Akademischer Betreuer] Martin-Villalba. "Angio-regulation of liver neovascularization and lung metastatic progression / Mahak Singhal ; Betreuer: Ana Martin-Villalba." Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://d-nb.info/1236403088/34.
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De, Pitta Cristiano. "microRNAs and breast cancer: a genomic study reveals miR-148b as a major coordinator of tumor progression." Doctoral thesis, Università degli studi di Padova, 2013. http://hdl.handle.net/11577/3422987.
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Breast cancer is a multistep disease controlled by a wide spectrum of genetic and epigenetic changes occurring within a cell as well as environmental influences; and it is the most common malignancy in women worldwide, often fatal because of metastasis dissemination. Aberrant miRNA expression can influence several gene networks and pathways implicated in tumorigenesis and metastasis formation.
To unravel the role of miRNAs during breast cancer progression we investigated miRNA expression in 77 ductal breast carcinoma biopsies and 17 mammoplasties by microarray analysis. Sixteen differentially expressed miRNAs were identified comparing patients with or without disease relapse, within 72 months from surgery. This signature correlates with survival and/or distinguishes tumor subtypes in different datasets.
Among them, miR-148b, down-regulated in aggressive breast tumors, was found to be a major coordinator of malignancy. In fact, it is able to oppose various steps of tumor progression when overexpressed in cell lines by influencing invasion, survival to anoikis, extravasation, lung metastasis formation, and chemotherapy response. miR-148b controls malignancy by coordinating a novel pathway involving over 130 genes and, in particular, it directly targets players of the integrin signaling, such as ITGA5, ROCK1, PIK3CA/p110α, and NRAS, as well as CSF1, a growth factor for stroma cells.
Our findings reveal the importance of the identified 16 miRNAs for disease outcome predictions and suggest a critical role for miR-148b in the control of breast cancer progressionIl tumore al seno è una malattia multifattoriale controllata sia da un ampio spettro di variazioni genetiche ed epigenetiche che si verificano all'interno di una cellula, sia da fattori ambientali. E’ sicuramente la neoplasia più diffusa tra le donne di tutto il mondo ed è spesso fatale a causa della diffusione metastatica. Recentemente è emerso che l’espressione aberrante dei miRNA può influenzare il comportamento di diverse reti genetiche e pathway biologici implicati nel processo tumorigenico e nella formazione di metastasi. Per meglio comprendere il ruolo dei miRNA, durante la progressione tumorale, abbiamo definito il loro profilo trascrizionale, utilizzando una piattaforma microarray, in settantasette pazienti affetti da carcinoma mammario duttale e diciassette mammoplastie (controlli sani). Abbiamo identificato sedici miRNA differenzialmente espressi in grado di discriminare i pazienti che presentano, o meno, recidiva dopo 72 mesi dall’intervento chirurgico. E’ interessante notare come l’espressione di questo gruppo di miRNA correla con la sopravvivenza dei pazienti e sia in grado di distinguere sottotipi tumorali in altri dataset di espressione. All’interno di questo gruppo è stato identificato il miR-148b, sottoespresso nei pazienti con prognosi più infausta, che si è dimostrato essere uno dei principali coordinatori del processo metastatico. In particolare questo miRNA, una volta sovraespresso nelle linee cellulari, è in grado di bloccare la formazione di metastasi influenzando l’invasività, la sopravvivenza delle cellule tumorali nel torrente circolatorio (anoikis), la fuoriuscita dai vasi sanguigni, la formazione di metastasi polmonari e la risposta alla chemioterapia. Abbiamo dimostrato che il miR-148b coordina l’azione di 130 geni e, in particolare, regola direttamente l’espressione di vari membri della via di segnalazione mediata dalle integrine tra cui ITGA5, ROCK1, PIK3CA/p110α e NRAS, così come CSF1, che è un fattore di crescita delle cellule stromali. I nostri dati dimostrano il valore prognostico dei 16 miRNA identificati e suggeriscono un ruolo critico del miR-148b nel controllo del processo metastatico in pazienti affetti da carcinoma mammario
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Messenger, J. R. "Characterisation of interlenkin-8 signalling in prostate cancer : Implications for the progression to castrate resistant metastatic disease." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517064.
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Bhim, Nazreen. "Dysphagia progression-free survival in patients with locally advanced and metastatic oesophageal cancer receiving palliative radiation therapy." Master's thesis, Faculty of Health Sciences, 2021. http://hdl.handle.net/11427/32591.
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Purpose: In patients with advanced oesophageal carcinoma palliation of dysphagia is important to maintaining a reasonable quality of life. The primary aim of this study was to determine the dysphagia progression-free survival (DPFS) in patients with advanced oesophageal carcinoma treated with palliative radiotherapy (RT). Methods: The medical records of all patients with oesophageal carcinoma presenting to Groote Schuur Hospital, Cape Town between January 2015-December 2016 were reviewed and patients who were not candidates for curative treatment and received palliative RT were selected. For these patients, the dysphagia score (DS) was recorded prior to RT, 6 weeks after RT and at each follow-up visit. The DPFS was calculated as the time from completion of RT to worsening in DS by ≥1 point or until death. Other outcomes measured were objective change in DS and survival post RT. Results: The study population comprised 84 patients. Squamous cell cancer was the primary histological subtype (93%). The median duration of DPFS after RT was 73 days, with approximately two-thirds of patients remaining able to swallow at least liquids and soft diet until death. The difference in median duration of DPFS was not statistically significant in stented versus non-stented patients (54 days vs 83 days; p =0.224). The mean change in DS was 0.45 ± 0.89 points following RT and the post RT survival was significantly shorter in patients with stent insertion (81 days vs 123 days; p=0.042). Conclusion: Palliative RT can be used successfully to prolong DPFS in patients with locally advanced and metastatic squamous cell cancer of the oesophagus.
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Sharma, Purva, James Kim, Devapiran Jaishankar, and Sakshi Singal. "EXTENDED PROGRESSION-FREE SURVIVAL ON FIRST LINE TREATMENT WITH DOCETAXEL IN PATIENT WITH METASTATIC TRIPLE NEGATIVE BREAST CARCINOMA." Digital Commons @ East Tennessee State University, 2021. https://dc.etsu.edu/asrf/2021/presentations/43.
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Docetaxel is a chemotherapeutic agent in the taxane group of drugs which is commonly used in the first line setting for metastatic hormone receptor negative breast cancer. We present a case of a 46 year old female who was diagnosed with de novo triple negative metastatic breast carcinoma, and has had an extended progression free survival (PFS) of almost 5 years on first line single agent treatment with Docetaxel.
46 year old female presented with a large left breast mass as well as axillary mass which revealed grade 3 invasive ductal carcinoma of breast on biopsy of both sites. Tumor was estrogen and progesterone receptor negative. Pathology showed discordance in HER2 testing between FISH and IHC, however on repeat testing, HER2 was confirmed to be negative. PET/CT scan for staging revealed large left sided pleural effusion and abnormal soft tissue in the lower anterior and posterior chest on the left concerning for pleural metastases. Patient underwent CT guided biopsy of left lower pleural space which was consistent with metastatic adenocarcinoma with breast primary.
She was started on first line single agent chemotherapy with Docetaxel 100mg/m2 every 3 weeks. Tumor markers were non-contributory to assess disease response. Repeat systemic imaging in 3 months showed excellent partial response with decrease in size of breast mass, conglomerate axillary lymph nodes as well as pleural based metastatic foci. Patient had grade 1 neuropathy secondary to Docetaxel which was tolerable. Patient also had significant fatigue with warranted dose reduction by 20% after 6 months. She also demonstrated other adverse effects of Docetaxel such as nail dystrophy and mild blepharitis which were also tolerable.
Patient showed good tolerance to chemotherapy, with intermittent treatment holidays. CT scans continued to demonstrate good response with stable size of breast and lung masses. After two years of stable disease and fair tolerance (after completing 34 cycles), chemo regimen was changed to every 4 weeks per patient’s wish. She was also started on Gabapentin for chemotherapy related neuropathy.
At the end of 4 years, patient had completed 55 cycles of agent Docetaxel, maintaining ECOG of 1, with grade 2 neuropathy controlled with gabapentin.
Patient is currently 56 months out from her initial diagnosis of metastatic triple negative breast cancer and follow-up scans continue to show stable disease. She has developed profound fatigue after several months of treatment. Patient has also faced challenges with fluid retention secondary to Docetaxel. Although her performance status remains fair, patient is contemplating changing frequency of chemotherapy to every 5 or every 6 weeks.
Triple negative breast cancer is an aggressive disease with limited options of treatment with chemotherapy agents and no role for endocrine therapy or HER2 targeted treatment options. Docetaxel has shown to have median survival ranging between 10.1 to 14.7 months depending on the dose. Our patient has so far shown extended PFS of 56 months, with single agent Docetaxel in first line setting which surpasses current national averages.
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RODA, NICOLO'. "SINGLE-CELL TRANSCRIPTIONAL LINEAGE TRACING REVEALS COMPLEXITY AND PLASTICITY OF BREAST CANCER PRO-METASTATIC PHENOTYPES." Doctoral thesis, Università degli Studi di Milano, 2022. http://hdl.handle.net/2434/906906.
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Breast cancer (BC) represents a major clinical hurdle, with metastatic outcome accounting for poor patient prognosis. Phenotypic intra-tumor heterogeneity inversely correlates with prognosis in BC and is considered at the basis of metastatization. Traditionally, BC poly-clonal structure was investigated through the genetic barcoding of cells followed by the tracing of the offspring. However, this analysis did not allow a solid investigation of the transcriptional profile associated to clones throughout tumor progression.
In this work, we exploited a recently published library of expressed barcodes to perform concomitant clonal and transcriptional tracing in breast cancer by single-cell RNA sequencing. We applied this technology to the triple-negative BC cell line MDA-MB-231 and the luminal B patient-derived xenograft MBC26 to study the transcriptional profile of clones during BC metastatization.
We found that clonal populations in vivo display proliferative heterogeneity, with some clones expanding more than others. Furthermore, we showed that single clones mainly activate one of two distinct transcriptional programs, either highly-proliferative or migratory/stressed/stem-like. Remarkably, we found that most times the same clones in distinct tumors display a high similarity in terms of transcriptional profile. In this scenario, however, we found that the metastatic progression of a clone is not determined by the clonal lineage, as a given clone can spread metastases in one tumor without being metastatic in another one. We found that the metastases to lungs and liver are composed of an overlapping setting of clones, with the vast majority of metastatic cells deriving from a single pro-metastatic clone. Notably, we showed that the pro-metastatic clones upregulate a set of genes that significantly distinguish them from the non-metastatic ones. These genes display a strong and significant clinical value, as they can be condensed in gene signatures predicting worse BC patient prognosis. Mechanistically, the pro-metastatic clones were shown to hyper-activate pathways involved in extracellular matrix (ECM) deposition, hypoxia response, unfolded protein response (UPR), type-I interferon (IFN) response, and migration, thereby reinforcing the role of these pathways in metastasis spreading. In line with this, we demonstrated that the knock-down of five that were upregulated by the pro-metastatic clones and involved in the above-mentioned processes (i.e., ANGPTL4, KCNQ1OT1, ITGB4, LY6E, and IFI6) significantly reduced the metastatic burden in vivo. Therefore, our work provided an unprecedented insight in the clonal phenotype that fosters metastatic progression in BC.
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Xu, Wei. "Cytogenetic analysis of a murine mammary carcinoma in vitro and during progression from primary to metastatic growth in vivo." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq20717.pdf.
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Johnson, Jacqueline Lea. "Matrix Metalloproteinase genes are transcriptionally regulated by E2F transcription factors: a link between cell cycle control and metastatic progression." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4092.
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The RbµE2F transcriptional regulatory pathway plays a critical role in the cell cycle. Rb is inactivated through multiple waves of phosphorylation, mediated mainly by cyclin D and cyclin E associated kinases. Once Rb is inactivated, cells can enter Sµphase. Collectively, three Rb family members and ten E2F proteins coordinate every additional stage of the cell cycle, from quiescence to mitosis. However the RbµE2F pathway is frequently altered in cancer. Aside from cell proliferation, the RbµE2F pathway regulates other essential cellular processes including apoptosis, cell differentiation, angiogenesis and DNA damage repair pathways, but its role in invasion and cancer progression is less clear. We demonstrate here that matrix metalloproteinases genes (MMPs), which regulate the invasion, migration and collagen degradation activities of cancer cells during metastasis are transcriptionally regulated by the RbµE2F pathway. Unlike E2F target genes involved in cell proliferation, which are solely regulated by the E2F activators (E2F1µ3), additional E2F family members can regulate MMP9, MMP14, and MMP15. While we had previously shown that Rafµ1 kinase physically interacts with Rb, and that disruption of this interaction with a small molecule inhibitor of the RbµRafµ1 interaction (RRDµ251) can inhibit cell proliferation, angiogenesis, and growth of tumors in mouse models, we now show RRDµ251 inhibits the expression of MMPs and the biological functions mediated by MMPs as well—including invasion, migration, and collagen degradation. RRDµ251 also inhibits metastatic foci development in a tail vein lung colonization model in mice. These results suggest that E2F transcription factors may play a role in promoting metastasis through regulation of MMP genes. Conversely, another MMP gene connected to metastasis, MMP2, is transcriptionally repressed by E2F1 in lung cancer cells through a p53µKAP1µHDAC1µmediated mechanism. However, E2F1 cannot repress the MMP2 promoter in cells that are lacking any component of this complex, such as p53 mutant breast cancer cells. Therefore the role of the RbµE2F pathway in MMP transcription and metastasis is cell type dependent. In addition to growth factors, nicotine can also induce cell proliferation, angiogenesis, EMT, and progression of lung cancer. In our studies, nicotine induced invasion, collagen degradation, and transcription of MMP2, MMP9, MMP14, and MMP15 required nAChRs, and multiple E2F family members. Our studies also show that nicotine not only promotes tumor growth in vivo through the nAChRµE2F pathway—it also results in metastasis to the liver and brain. Taken together, these studies link the RbµE2F pathway to the regulation of many facets of cancer.
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Alkhatib, Suehyb. "Characterizing the role of Nucleosome Remodeling Factor (NURF) in tumorigenesis and metastatic progression using mouse models of breast cancer." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/376.
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Increasingly the role of epigenetic machinery as a bridge between underlying DNA sequence and cellular phenotype is being discovered. The establishment of a myriad of unique cellular types sharing identical gene sequences in a multicellular organism gives a broad sense for the inherent role of epigenetic influence on cell differentiation. Importantly, the epigenetic mechanisms involved in establishing cell identity unsurprisingly contribute to diseased states, including cancer. Recent research continues to elucidate contributory roles of epigenetic mechanisms, such as DNA methylation, histone modification, and microRNA regulation, in human cancers. Additionally, chromatin remodelers, such as the Nucleosome Remodeling Factor (NURF), have been identified as important regulators for normal cell biology. While much has been done to identify and characterize the role of NURF chromatin remodeling complex as a key regulator of development in a number of model organisms, little has been published on the implications of NURF in diseases such as cancer. Our preliminary data shows dysregulation of E-cadherins, N-cadherins, and MHC-I genes in Bptf (an essential subunit of NURF) knocked down murine breast cancer cell lines. These proteins have well documented roles in the development and metastatic progression of cancers. To study the effect of Bptf knockdown on the development and progression of cancer we injected Bptf knocked down mouse breast cancer cell lines, 4T1, 66cl4, and 67NR, into syngenic BALB/c mice. Our findings reveal decreased tumor growth in 66cl4 and 67NR as measured by tumor weight at 3-4 weeks post injection. Tumor growth did not appear to be significantly affected in 4T1 challenged mice. However, mice inoculated with Bptf knockdown 4T1 cell lines have decreased metastasis to lungs as compared to control while metastasis of 66cl4 tumors to the lungs appear unaffected. To assess the role of the immune system in decreasing tumor growth in BALB/c mice, we injected 66cl4 tumors into NOD-SCID-Gamma (NSG) immune deficient mice. The tumors from these mice show no difference in tumor growth between Bptf knockdown and control tumors, implicating a role for the immune system regulating the decreased tumor weight in BALB/c mice. To delineate which immune cell effector may impede breast cancer carcinogenesis, we performed an in vitro natural killer (NK) cell cytotoxicity assay against 66cl4 tumors and found greater susceptibility to NK killing in Bptf knockdown tumors.
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REGGIANI, FRANCESCA. "GM-CSF AND MMP9 ARE KEY REGULATORS OF THE EFFECT OF ADIPOSE PROGENITORS OVER BREAST CANCER ONSET AND METASTATIC PROGRESSION." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/468900.
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Recent epidemiological and clinical data underlined the critical role of obesity in breast cancer (BC) progression. Among several white adipose tissue (WAT) cells, which may promote a permissive tumor microenvironment, a population with progenitor-like phenotype (CD45-CD34+) was reported to support local and metastatic BC. This population is composed by distinct WAT progenitors: adipose-derived stem cells (ASCs) and endothelial progenitor cells (EPCs), displaying complementary role in BC progression in preclinical models. However, molecular mechanisms involved in this interaction have been so far elusive and need to be clarified.
An extensive screening of candidate molecules revealed two proteins being significantly up-regulated in WAT-derived progenitors after being co-cultured with several BC cells: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and Matrix metallopeptidase 9 (MMP9). Both factors were detected over-expressed in orthotopic xenograft models, when co-injected with BC and human WAT progenitors. ASC and EPCs displayed similar ability to induce GM-CSF/MMP9, suggesting a complementary role in their release. GM-CSF neutralization in WAT progenitors inhibited MMP9 secretion, which was also reduced by IL-1β neutralization. GM-CSF displayed an additional positive feedback regulation on its own release.
The inhibition of GM-CSF in diet-induced obese (DIO) syngeneic mice led to reduced intratumor vascularization and strong impairment of immunosuppressive microenvironment, targeting mainly tumor-associated macrophages (TAMs), myeloid derived suppressor cells (MDSCs) and T-regulatory (T-regs) cells. This resulted in a significant impairment of local BC growth and a slower metastatic progression.
Conversely, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth. The combined GM-CSF/MMP9 inhibition synergically impaired tumor angiogenesis, local and metastatic BC growth.
Metformin was reported to significantly affect tumor progression and neoplastic angiogenesis, targeting both BC and WAT cells. In the present study, Metformin inhibited GM-CSF and MMP9 release from WAT progenitors in vitro and in xenograft models. Metformin had similar effects of GM-CSF/MMP9 specific inhibitions in DIO syngeneic mice, but was more effective in reducing tumor angiogenesis and targeted different immune cells.
Collectively, these results indicate GM-CSF and MMP9 as new potential targets to prevent the pro-tumorigenic effect of WAT progenitors on BC.
Furthermore, Metformin ability to reduce GM-CSF and MMP9 supports Metformin administration in clinical studies on BC, especially in a setting of obesity and/or insulin resistance.
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BERNARDELLI, CLARA. "DIFFERENT EXTRACELLULAR VESICLES SUBPOPULATIONS CHARACTERIZE METASTATIC PROGRESSION: QUALITATIVE AND QUANTITATIVE ANALYSIS OF ISOGENIC MELANOMA CELL LINES AND THEIR SECRETED FACTORS." Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/559532.
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The survival and proliferation of metastases is a consequence of the pre-metastatic niche (PMN) evolution, an abnormal, tumor growth-favoring microenvironment devoid of cancer cells. Among tumor derived secreted factors, extracellular vesicles (EVs) are key players in PMN establishment and facilitate organotropic metastasis. Compared to normal melanocytes, melanoma cells produce a large quantity of EVs, that can be detected in the plasma of melanoma patients. For this reason, a full characterization of secreted vesicles subpopulations and of their cargo is necessary to understand how EVs affect PMN formation.
In this study, we demonstrated for the first time that EVs secreted by isogenic primary tumor and metastatic melanoma cell lines are quantitatively and qualitatively different, suggesting that diverse EVs subpopulations characterize metastatic progression. We also set a deep quantitative proteomics protocol to analyze the proteome of these cells and of their EVs and soluble secreted factors. WNT5A was found as an important component of primary tumor secreted EVs; on the contrary, we observed a specific APOE and Fibronectin sorting to EVs in in metastasis versus primary tumor cell. Finally, we observed that increased levels of RAB27A protein in metastatic cells do not correlate with an increased EVs secretion. Our preliminary results demonstrate that EVs secreted by RAB27A-KD cells maintain cancer cells clonogenic ability and that low levels of RAB27A expression correlate with higher cells motility. These findings suggest a paracrine activity of a RAB27A -independent EVs subpopulation in tumor-PMN communication to promote cancer progression.
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Efstathiou, Antonia [Verfasser], and Klaus [Akademischer Betreuer] Pantel. "Potential involvement of Jagged1, integrin alpha5 beta1 and VCAM1 proteins in metastatic progression of human breast carcinomas / Antonia Efstathiou ; Betreuer: Klaus Pantel." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2018. http://d-nb.info/1153124173/34.
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Olivera-Salguero, Rubén 1991. "New roles for Snail1 -expressing CAF during primary tumor progression and secondary niche colonization." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/667308.
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Snail1 is the master regulator of the Epithelial-to-Mesenchymal Transition (EMT) and is also crucial for fibroblast activation upon TGFβ signaling. In cancer, Snail1 expression in primary tumors correlates with the appearance of metastasis. We have previously shown that Snail1-expressing cancer-associated fibroblasts (CAF) enhance metastasis. Here we demonstrate that Snail1-expressing CAF attenuate the anti-tumor effector immune response. We observed that Snail1-expressing CAF determine macrophages to present a pro-tumor phenotype in vitro and in the in vivo model of breast cancer MMTV-PyMT what enhanced tumor progression. Moreover, in the context of metastasis, we show that Snail1-dependent TGFβ-induced activation of liver fibroblasts is determinant for colorectal cancer colonization of the organ. Snail1-expressing CAF determine cancer cell evasion of the adaptive anti-tumor effector immunity. In consequence, the absence of Snail1 prevents CAF activation in newly formed metastases and allows immune rejection. These new roles for Snail1-expressing CAF during primary tumor progression and secondary niche colonization increase the relevance of Snail1 protein in oncology.Snail1 és el principal regulador de la Transició Epiteli-Mesènquima (EMT, per les sigles en anglès) i també resulta crucial per a l’activació dels fibroblasts en presència de TGFβ. En càncer, l’expressió de Snail1 en tumors primerencs correlaciona amb l’aparició de metàstasis. Prèviament, el nostre grup va demostrar que els fibroblasts actius associats a tumors (CAF) que expressen Snail1 desencadenen metàstasis. Aquí demostrem que els CAF que expressen Snail1 atenuen la resposta immunitària efectora anti-tumoral. Hem observant que els CAF que expressen Snail1 determinen un fenotip pro-tumoral en macròfags in vitro i també in vivo fent servir el model de càncer de mama MMTV-PyMT on la progressió tumoral es veia accentuada. En el context metastàtic, mostrem que l’activació dels fibroblasts del fetge induïda per TGFβ és determinant per a la colonització d’aquest òrgan per part del càncer colorectal. Els CAF que expressen Snail1 determinen que les cèl·lules del càncer evadeixin la resposta immunitària anti-tumoral. En conseqüència i malgrat la senyalització per TGFβ, l’absència de Snail1 anul·là la presència de CAF actius en les noves metàstasis i foren rebutjades. Aquestes noves funcions dels CAF que expressen Snail1 durant la progressió del tumor primari i la colonització d’un nínxol secundari incrementen la rellevància de la proteïna Snail1 en oncologia.
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Bista, Bigyan R. (Bigyan Raj). "Adhesion-GPCRs in cancer progression and metastasis." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/104169.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2016.Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references.
Adhesion-GPCRs, a novel family of G protein-coupled receptors (GPCRs), are characterized by an extended extracellular region linked to a seven-pass transmembrane moiety via GPCR proteolytic site (GPS)-containing stalk region known as GAIN domain. The name adhesion refers to the presence of functional domains in the extracellular region that commonly mediate cell-cell and cell-matrix interactions in various contexts. Recently, many genome-scale analyses of genetic alterations across diverse cancer types have revealed significant alterations (copy number and mutational) in adhesion-GPCRs, yet no comprehensive examination of their roles in cancer biology exists. Through a systematic screening for all adhesion-GPCRs by RT-qPCR in murine mammary carcinoma cell lines with varying metastatic abilities as well as tumor samples of different grades, I have identified several candidate genes with possible roles in breast cancer progression and metastasis. Based on these analyses and cross-referencing with the published gene expression data on human breast cancer cell lines and patient samples, I chose two candidate genes, CELSR2 and GPR126, for more detailed investigation. To elucidate their functions in cancer biology, I investigated the effects of their perturbations using RNAi (loss-of-function) methods both in vitro and in vivo. The results from my work reveal that loss of CELSR2 affects neither tumor growth nor lung metastasis in a xenograft mouse model of breast cancer, despite enhancing invadopodial activity in vitro. I also show that highly metastatic breast cancer and melanoma cells have elevated levels of GPR126, and confirm the significance of this result by revealing (a) reduction in pulmonary metastasis without affecting primary tumor growth in a spontaneous metastasis model of breast cancer, and (b) reduction in lung metastasis in three different experimental metastasis models of breast cancer and melanoma, upon shRNA-mediated knockdown of GPR126. After probing the different steps in the metastatic cascade to investigate how GPR126 promotes metastasis, I demonstrate that GPR126 specifically affects extravasation, most likely through its engagement with type IV collagen in the sub-endothelial basement membrane. Thus, the work described in this thesis contributes to our overall understanding of the perplexing problem of cancer metastasis via identification of novel regulators of distinct steps along the ominous path of malignant cells from primary sites to distant organs.
by Bigyan R. Bista.
Ph. D.
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Lopez, Jose Ignacio. "CD44 Attenuates Metastasis During Breast Cancer Progression." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/193882.
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Progression to metastatic disease is the leading cause of deaths resulting from breast cancer. Understanding the mechanisms underlying a cell's ability to move away from its site of origin and populate a distant site is important for the future development of therapies. The interactions between a tumor cell and the microenvironment can modulate a cell's ability to invade through tissues and access distant organs. In this study we present evidence indicating the differential modulation of invasive and proliferative phenotypes by hyaluronan present in the cellular microenvironment.We establish the role of CD44, the primary receptor for hyaluronan, in breast cancer progression and metastasis through the use of transgenic mouse models of breast cancer. While no differences were seen in the onset of primary breast tumors, mice expressing CD44 had a reduced rate of pulmonary metastasis compared to mice that lacked CD44. This establishes an anti-invasive role for CD44 in breast tumor progression. We also identify a decreased population of alveolar macrophages in CD44 negative mice that could affect metastatic breast cancer cell colonization of the lungs.We then focused our study in vitro, where we assessed the invasive properties of breast cancer cells as they move through three dimensional (3D) matrices containing or lacking hyaluronan. We show that in 3D type I collagen gels, breast cancer cells invade more readily in the absence of hyaluronan compared to when hyaluronan (HA) is embedded within the gel. HA mediated inhibition of invasion is dependent on CD44 binding as demonstrated through the use of a CD44 functional blocking antibody.We also show that HA promotes differential phenotypes of breast cancer cell. HA promotes filopodia formation and invasion when soluble in the cell microenvironment. Alternatively, matrix-embedded HA inhibits invasion and promotes migration through the formation of lamellipodia. The differential HA invasive and proliferative phenotypes are mediated by differential activation of ERK or γPAK. Activation of γPAK is mediated by CD44 while ERK activation by HA occurs by CD44 independent mechanisms.We also demonstrate an inhibition of MMP9 mediated invasion by HA when embedded within a type IV collagen matrix, but not a type I collagen matrix. This differential activity indicates that it is not only the immobilization of HA in a matrix that determines its activity, but also the context in which it is present within the matrix.These data underscore the importance of studying matrix components in an environment that closely resembles in vivo conditions. HA is a prime example as it has the capability of both promoting and inhibiting invasion depending on how it is presented to a cell. Differential HA activity also underlies the importance of understanding extracelluar matrix degradation and the release of matrix components as these can adversely affect disease progression.
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Marshall, John Francis. "The role of integrins in melanoma progression and metastasis." Thesis, Open University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295235.
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Zaimenko, Inna. "Molecular and metabolic determinants of metastasis development and progression." Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19078.
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MACC1, ein Hauptregulator von Metastasen, ist an zahlreichen Kennzeichen von Krebs beteiligt, einschließlich dereguliertem Metabolismus. Dennoch ist seine Rolle im Krebsstoffwechsel unklar. In der vorliegenden Arbeit wurde eine systematische Analyse von MACC1-getriebenen metabolischen Netzwerken durchgeführt. MACC1 erhöhte die GLUT1 auf Zellmembrane, was zu einer erhöhten Glukoseanreicherung, einem erhöhten Glukosefluss und somit zu einer erhöhten Zellproliferation führte. Außerdem, reduzierte MACC1 den Glutaminfluss unabhängig von der Nährstoffverfügbarkeit. Bei Glucoseentzug erhöhte MACC1 die Pyruvataufnahme und zeigte aber die geringe Auswirkungen auf den Pyruvatfluss. In vivo, MACC1 zeigte erhöhte Aufnahme von 18F-FDG und 18F-Glutamat in Lebermetastasen. Zusammengefasst zeigen diese Ergebnisse, dass MACC1 mehrere Wirkungen auf den Krebs-Metabolismus zeigt, was es attraktiv macht, seine Wirkungen in Krebsmodellen weiter zu untersuchen.
Metastasierung ist die Haupttodesursache bei Darmkrebs. Fünfzehn bis zwanzig Prozent der Darmkrebs Patienten im Stadium II entwickeln im Verlauf der Erkrankung Metastasen, jedoch bleiben die Kriterien der Wahrscheinlichkeit mit welcher Patienten von Chemotherapie profitieren werden ungenau. Hier wurde das Potenzial der Plasma-Metabolomik zur Vorhersage von Metachronmetastasen untersucht. Plasma metabolische Profile wurden wesentlich unterschiedlich zwischen nicht-metastasierten und metachron metastasierten Patienten gefunden. Wie Klassifikationsmodelle aus Entscheidungsbäumen und Support-Vektor-Maschinen gezeigt haben die Plasmametaboliten haben die Fähigkeit nicht-metastasierte von metachron metastasierten Darmkrebs Patienten zu unterscheiden, mit einer durschnittlichen Vorhersagegenauigkeit von 0,75 bzw. 0,82 für jede der Methoden, angemessen. Zusammen, zeigen diese Ergebnisse, dass Plasmametaboliten das Potenzial haben, Darmkrebs Patienten gemäß ihrem Metastasierungsrisiko nichtinvasiv zu stratifizieren.MACC1, a master regulator of metastasis, is involved in most hallmarks of cancer, including deregulated metabolism. Yet, fragmentary data on its role in cancer metabolism exist. Here, a systematic analysis of MACC1-driven metabolic networks by elucidation of cell nutrient preferences, environment dependent alterations of nutrient utilization, metabolic pathway functionality and metabolic tracing using 13C-labeled metabolic substrates had been performed. MACC1 was found to enhance surface GLUT1 thus leading to increased glucose depletion, glucose flux and hence increased cell proliferation. Besides, MACC1 was found to reduce glutamine flux independent of nutrient availability. Upon glucose deprivation MACC1 was found to enhance pyruvate uptake exhibiting minor effects on pyruvate flux. In vivo, MACC1 increased uptakes of 18F-FDG and 18F-glutamate in liver metastatic lesions. Together, these findings demonstrate that MACC1 exhibits multiple effects on cancer metabolism, thus making it attractive to further study its effects in cancer models. Metastasis is the main cause of death from colorectal cancer (CRC). Fifteen to twenty percent of stage II CRC patients develop metastasis during the course of disease, however the criteria of likely benefitting patients from chemotherapy remain imprecise. Here, the potential of plasma metabolomics to predict metachronous metastasis was assessed. Plasma metabolic profiles were shown to be significantly different between non-metastasized and metachronously metastasized CRC patients. As demonstrated by supervised classifications using decision trees and support vector machines plasma metabolites have the power to distinguish non-metastasized from metachronously metastasized CRC patients giving average prediction accuracy of 0.75 and 0.82 for each of the methods, respectively. Together, these results demonstrate that plasma metabolites have the potential to non-invasively stratify CRC patients according to their metastasis risk.
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Minutentag, Iael Weissberg. "Identificação de alterações no transcritoma associadas à progressão metastática em adenocarcinoma de reto." Botucatu, 2019. http://hdl.handle.net/11449/180847.
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Orientador: Sandra Aparecida Drigo LindeResumo: Introdução: Apesar dos avanços no tratamento, cerca da metade dos pacientes com câncer de reto (CR) desenvolverá metástase à distância. No entanto, as vias biológicas envolvidas na progressão do câncer não são totalmente conhecidas. Neste estudo, investigamos os perfis moleculares e imunológicos em adenocarcinomas de reto relacionados à progressão metastática visando identificar biomarcadores moleculares e/ou alvos terapêuticos. Pacientes e Métodos: O transcritoma de 15 tecidos de CR metastático (M) e não-metastático (NM) pré-tratamento e de duas amostras de tecido de reto normais foi avaliado utilizando a plataforma Clariom D. Os genes foram considerados diferencialmente expressos quando a alteração de expressão era maior que 2 vezes e o valor de p <0,05 e detectados com o pacote limma. As funções moleculares e vias biológicas foram determinadas com a ferramenta Enricher. Os achados foram validados utilizando dados do TCGA e o perfil imunológico determinado com o algorótimo xCell. Resultados: A comparação entre os grupos M e NM revelou 52 genes diferencialmente expressos, sendo 27 regulados positivamente e 25 regulados negativamente. O gene ANLN foi detectado com o maior valor de fold change nos tumores metastáticos. Além disso, expressão aumentada de ANLN foi associada com menor sobrevida em pacientes com CR. A via do fator de crescimento endotelial vascular (VEGF) foi detectada como alterada nos tumores M. Validação dos resultados com dados do TCGA confirmou o gene ANLN co... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Introduction: Despite advances in treatment, about half of patients with rectal cancer (RC) will develop distant metastasis. However, the biological pathways underpinning the cancer progression are not fully understood. In this study, we sought to identify molecular and immunological profiles in rectal adenocarcinomas related to metastatic progression aiming to identify molecular biomarkers and/or therapeutic targets. Patients and Methods: Transcriptome analysis of 15 pre-treatment metastatic (M) and non-metastatic (NM) rectal cancer tissues and two normal rectal tissue samples was evaluated using Clariom D platform. Genes were considered differentially expressed when presenting 2-fold change and p<0.05 and were obtained with limma package . Molecular function and biological pathways with the Enricher package. Our findings were validated from the TCGA database and the immunological profile was determined using the xCell algorithm. Results: The comparison of M with NM groups revealed 52 differentially expressed genes, being 27 up-regulated and 25 down-regulated. ANLN gene was detected as the top gene upregulated in M tumours. Additionally, ANLN overexpression was associated with shorter survival in RC patients. Vascular endothelial growth factor (VEGF) pathway was detected as altered in M tumours. Cross-study validation with TCGA dataset confirmed ANLN gene as associated with M tumours. Furthermore, KIF14, XRCC2 and GPX3 genes, which have important carcinogenesis functions, we... (Complete abstract click electronic access below)
Mestre
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Chin, Nikeisha L. "The Role of Endothelin 3 in Melanoma Progression and Metastasis." FIU Digital Commons, 2015. http://digitalcommons.fiu.edu/etd/2286.
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Endothelin receptor b (Ednrb) and its ligand Endothelin 3 (Edn3) have been implicated in melanoma. Several studies have shown an upregulation of EDNRB and EDN3 at both the protein and mRNA levels, as melanoma becomes more aggressive. This study investigated the putative role played by Edn3 over-expression in melanoma progression and angiogenesis in vivo. We crossed Tg(Grm1)Epv transgenic mice that aberrantly express metabotropic glutamate receptor1 under the Dopachrome tautomerase promoter, leading to spontaneous melanocytic lesions in the ears and tails that do not metastasize, with transgenics that overexpress Edn3 under the Keratin 5 promoter (K5-Edn3) or overexpress Ednrb in melanocytes (Tg(Ednrb)1Lk). In both the Tg(Grm1)Epv/K5-Edn3 and Tg(Grm1)Epv/Tg(Ednrb)1Lk mice, tumors appeared earlier and grew significantly larger and faster when compared to Tg(Grm1)Epv mice. Approximately eighty-one percent of Tg(Grm1)Epv/ K5-Edn3 mice and 76% of Tg(Grm1)Epv/Tg(Ednrb)1Lk mice had pigmented lesions in distant organs such as the lung and brain. Real-Time PCR analysis showed higher expression levels of genes involved in cell-cell and cell-matrix interactions and angiogenesis in lesions of Tg(Grm1)Epv/K5-Edn3 when compared to controls. Considering the rapid tumor growth rate of in the Tg(Grm1)Epv/K5-Edn3 mice, differences in the angiogenic response compared to control mice were investigated. Immunofluorescence analysis with the endothelial cell marker CD31 showed that there were more endothelial cells per tumor area in the Tg(Grm1)Epv/K5-Edn3 mice than the controls. Proteome analysis showed that the Dct-Grm1/K5-Edn3 mice had significant increases in other angiogenic related genes such as Angiogenin, CXCL 16 and Endoglin, when compared to controls, while real time PCR analysis of tail tumors also showed higher expression levels of angiogenic related genes such as Hif-1α. The results of this study showed that the EDNRB/EDN3 axis is sufficient to alter the kinetics of melanocytic tumors’ progression, lead them to a fully malignant state, and increase the tumor angiogenic response.
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Dombrovsky, Alexander. "The effect of vascular aging on cancer progression and metastasis." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96853.
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As one ages, the risk of developing cancer increases. However, the severity and course of the disease can vary greatly at different stages of life. This thesis explores the effects that host age has on blood vessel dependent aspects of the cancer process, such as growth, organ specific metastasis, and tumour responsiveness to antiangiogenic treatments. In the mouse model, older age had a negative impact on tumour growth and lung metastasis; while seemingly the opposite effect is seen with liver metastasis. Also, a targeted, antiangiogenic treatment with Sutent resulted in a greater anti‐tumour efficacy in aged animal hosts. When taken together, and by extension, these results suggest the importance of patient age as a factor that should be considered when developing targeted anti‐tumour agents, especially in the context of organ‐specific metastasis in order to maximize therapeutic responses. As targeted agents enter pediatric oncology, age considerations deserve special attention.En tant qu'un vieillit, le risque de développer le cancer augment considérablement. Cependant, la sévérité et le cours de la maladie peuvent changer considérablement à différentes étapes de la vie. Cette thèse explore les effets que l'âge d'hôte a sur des aspects dépendants de vaisseau sanguin du processus de cancer tels que la croissance, la métastase spécifique d'organe, et la réponse de tumeur aux traitements antiangiogénique. Dans le modèle de souris, un âge plus vieux a semblé avoir un impact négatif sur la croissance de tumeur et la métastase des poumons; tandis qu'apparemment l'effet opposé est vu avec la métastase du foie. En outre, un traitement visé et antiangiogénique avec Sutent a eu comme conséquence une plus grande efficacité antitumorale dans des animaux âgés. Une fois pris ensemble, tous ces résultats suggéreraient l'âge des patients avec cancer comme facteur important qui devrait être considéré en développant des agents antitumoraux visés, particulièrement dans le contexte de la métastase organe‐spécifique afin de maximiser des réponses thérapeutiques. Car les agents visés vont se présenter dans l'oncologie pédiatrique, ces considérations méritent d'attention spéciale.
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Snyder, Kimberly Ashley. "The role of podocalyxin in breast cancer progression and metastasis." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/46014.
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Wong, Sunny Y. "Genetic and mechanistic determinants of prostate cancer progression and metastasis." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/38626.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2007.Includes bibliographical references.
In order to study a complex biological phenomenon such as tumor cell metastasis, one must focus on examining discrete aspects of the process which are amenable to experimentation. In this thesis, I made use of xenograft and spontaneous in vivo mouse models of prostate cancer to approach this problem from two perspectives. First, I sought to identify genes which were involved with metastasis. Second, I focused on the mechanistic elements involved with tumor cell intravasation into lymphatics. The results from this work have shown that loss of Protein 4.1B, a 4.1/ezrin/radixin/moesin (FERM) domain-containing cytoskeletal protein, is a frequent event in prostate cancer. The significance of this finding was confirmed by experimental ablation of 4.1B, which enhanced tumor progression and metastasis, at least in part, by protecting cells against apoptosis. This thesis has also shown that metastatic dissemination to lymph nodes is mediated primarily by peritumoral lymphatic vessels, which surround the tumor at the invasive margins. In contrast, inhibition of intratumoral lymphatics did not affect metastatic spread, indicating that these vessels were unnecessary for tumor cell dissemination.
(cont.) The genetic and mechanistic findings from this thesis were consistent across both model systems examined, and are also in concordance with observations made in human clinical prostate cancer. Thus, the results of this work have contributed small pieces of knowledge to our overall understanding of how tumors initiate, and frequently complete, the elaborate and often lethal process of spreading throughout the body.
by Sunny Y. Wong.
Ph.D.
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MARTINO, VALENTINA. "THE ROLE OF MIR199A IN BREAST CANCER PROGRESSION AND METASTASIS." Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/217467.
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Metastasis remains one of the leading causes of death in cancer patients. The epithelial to mesenchymal transition (EMT) is proposed as a preliminary event underlying the metastatic process, allowing tumor cells to migrate and colonize new tissues and organs. EMT is a trans-differentiation program active during embryonic development that produces mesechymal-like cells from epithelial sheets by loss of cell adhesion and leading to increased cell motility. Dissecting molecular pathways associated to EMT and to its metastasis-promoting potential is essential to develop therapeutic strategies against cancer metastasis.
Our group developed a model of mammary carcinogenesis based on the rat cancer stem cell line LA7, that when engrafted at the single cell level in immuno-compromised mice, recapitulates the entire process of tumor development including the EMT process that lead to metastasis formation, through the generation of fibroblast-like cells (LA7-Elongated cells). Using the LA7 system we found miR-199a up regulated during in vivo EMT transition. Ectopic expression of the miR-199a in LA7 induced cell shape modification and changes in marker expression coherent with an epithelial to mesenchymal trans-differentiation, recapitulating the fibroblast-like LA7 counterpart phenotype (LA7-Elongated). These results suggest that miR-199a is an effective inducer of EMT. We demonstrate that the action of miR-199a is directed on adherens junction proteins such as E-Cadherin and β-Catenin, gatekeepers of EMT, through leukocyte antigen-related tyrosine phosphatase (LAR or PTPRF) protein down-regulation. Furthermore, the induction of EMT in LA7 by TGF-β treatment resulted in miR-199a up-regulation through TWIST1 induction, while the down-regulation of miR-199a abrogated the invasion capacity of the LA7-Elongated fibroblast-like cells in 3D cell culture assays.
Moreover when injected in NOD/SCID mice, LA7 cells in which we induced modulation of miR-199a were unable to form metastasis, even if their tumor seeding ability was not affected.
Taken together our results support that miR-199a is a component of the pathway that commits epithelial cells to the EMT program and an important factor in the metastatic cascade engagement. Research concerning miRs identified using the LA7 model system and their possible use as therapeutic agents is ongoing in our lab and will provide new useful tools for cancer therapy.
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Cameron, M. Dianne. "Temporal progression of lung metastasis, cell survival, dormancy and location dependence." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0017/NQ58117.pdf.
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Chu, Chia-Yi. "The Role of Rankl in Prostate Cancer Progression and Bone Metastasis." Digital Archive @ GSU, 2011. http://digitalarchive.gsu.edu/biology_diss/118.
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This study focused on the role of RANKL in prostate cancer EMT progression and metastasis. Activation of RANK, a receptor activator of NF-kB, by its ligand RANKL, in a paracrine manner is responsible for osteoclast differentiation and bone remodeling. RANK activation in cancer cells, however, is thought to be promoted by both autocrine and paracrine mechanisms because RANKL has been shown to be derived from either tumor or its microenvironment, such as osteoblasts, infiltrating inflammatory cells and stromal fibroblasts. In the present study, we demonstrated that autocrine and paracrine RANKL-RANK signaling could be responsible for driving prostate cancer bone metastasis by promoting epithelial to mesenchymal transition (EMT). We further characterized a novel converging RANKL-c-Met signaling network in which the activation of RANKL was found to promote the expression of both RANKL and c-Met in an autocrine manner in prostate cancer cells. The induced RANKL and c-Met in prostate cancer cells is biologically functional and contributes to increased osteoclastogenesis, epithelial to mesenchymal transition (EMT), cell motility, migration and invasion and conferred bone and soft tissue metastases. Remarkably, RANKL expression by 1,000 prostate cancer cells can provoke bone and soft tissue metastases of a “dormant” population of prostate cancer cells which by themselves failed to form tumors and colonize mouse skeleton, suggesting RANKL can serve as a factor in “reawakening” cancer dormancy to initiate the re-growth and metastasis of cancer cells. We also showed that RANKL-induced RANKL feed-forward autocrine regulation is mediated through cMyc transactivation, allowing the establishment of a “vicious cycle” further promoting prostate cancer growth and metastasis. The converging RANKL-c-Met signaling network is therefore a novel target that could be further manipulated for delaying the lethal progression of castration-resistant human prostate cancer bone metastasis.
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Jenkinson, Sarah Rhiannon. "In vitro models to study the role of S100A4 in mammary epithelial cell metastasis." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367678.
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Ramchandani, Divya. "A Study of Genetic Alterations in Cancer Progression." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439295281.
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BRIVIO, SIMONE. "Molecular mechanisms of cholangiocarcinoma progression: emphasizing the role of tumor-stroma interactions." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2018. http://hdl.handle.net/10281/199031.
Full textAbstract:
Il colangiocarcinoma (CCA) è una neoplasia epiteliale che origina dai dotti biliari, ed è caratterizzata da una prognosi infausta, imputabile alla spiccata invasività e alla resistenza alla chemioterapia. L’aggressività delle cellule di CCA è esacerbata dallo stroma desmoplastico che si sviluppa contestualmente alla crescita tumorale, contenente fibroblasti cancro-associati (CAF), macrofagi tumore-associati e cellule endoteliali linfatiche (LEC). Durante il mio dottorato, ho analizzato la natura e la rilevanza biologica dei segnali paracrini intercorrenti tra cellule stromali e tumorali nel CCA, nel tentativo di chiarire i meccanismi molecolari che guidano la progressione tumorale. In un primo studio, abbiamo esaminato la citochina pleiotropica Leukemia Inhibitory Factor (LIF), che abbiamo scoperto essere secreta non solo dalle cellule di CCA, ma anche dalle cellule infiammatorie e dai CAF all’interno del microambiente tumorale. Abbiamo dimostrato che il LIF ostacolava l’induzione di apoptosi in cellule di CCA trattate con gemcitabina e cisplatino, tramite attivazione del pathway PI3K/Akt, e conseguente up-regolazione della proteina anti-apoptotica Myeloid Cell Leukemia (Mcl)-1. In un secondo studio, abbiamo considerato un tipico readout delle interazioni stroma-tumore, ovvero la transizione epitelio-mesenchimale (EMT) delle cellule carcinomatose, un fenomeno alla base dell’invasione tumorale. In precedenza, avevamo dimostrato che S100A4, un biomarcatore della EMT, promuove attivamente l’invasività del CCA quando espresso nel nucleo delle cellule tumorali. Abbiamo quindi osservato che la nuclearizzazione di S100A4 era dipendente dalla sua SUMOilazione, che poteva essere inibita trattando le cellule di CCA con dosi nanomolari di paclitaxel. La riduzione dei livelli nucleari di S100A4 si associava ad una diminuzione dell’attività di RhoA e Cdc42, della secrezione della metalloproteinasi della matrice (MMP)-9, e dell’espressione della MMP di membrana di tipo 1. Inoltre, il paclitaxel a basse dosi attenuava l’invasività delle cellule di CCA, sia in vitro sia in un modello xenograft. In un terzo studio, abbiamo ipotizzato che la comunicazione tra cellule di CCA e CAF potesse promuovere la linfoangiogenesi tumorale, un processo di fondamentale importanza per la metastatizzazione del CCA. Abbiamo dimostrato che, dopo stimolazione con il Platelet-Derived Growth Factor (PDGF)-D, un mediatore cruciale del reclutamento dei CAF da parte delle cellule di CCA, i fibroblasti incrementavano la secrezione del Vascular Endothelial Growth Factor (VEGF)-A e del VEGF-C, in virtù dell’attivazione delle chinasi ERK1/2 e JNK. Coerentemente, il medium condizionato derivato da fibroblasti trattati con il PDGF-D promuoveva la migrazione delle LEC e il loro assemblaggio in strutture vascolari 3D, ed entrambi gli effetti erano prevenuti bloccando il recettore β del PDGF a livello dei fibroblasti, o i recettori 2 e 3 dei VEGF a livello delle LEC. Anche la permeabilità di LEC in monostrato era aumentata dai fibroblasti stimolati con il PDGF-D, così da favorire la migrazione trans-endoteliale delle cellule di CCA. In conclusione, i nostri risultati confermano che lo stroma tumorale è in grado di alimentare la progressione del CCA, sia modulando direttamente il comportamento delle cellule tumorali, sia allestendo un microambiente favorevole alla diffusione metastatica. Una piena comprensione delle interazioni tra cellule neoplastiche e stromali nel CCA potrebbe portare in futuro allo sviluppo di terapie innovative e “multi-target” in grado di eradicare più efficacemente il tumore.Cholangiocarcinoma (CCA) is an epithelial cancer arising from the biliary tree. CCA carries a poor prognosis, owing to early and pronounced invasiveness, and resistance to chemotherapy. The aggressiveness of CCA cells is exacerbated by the desmoplastic stroma developing in conjunction with tumor outgrowth, which mainly consists of cancer-associated fibroblasts (CAFs), tumor-associated macrophages, and lymphatic endothelial cells (LECs). During my PhD studies, I sought to dissect the nature and the biological relevance of the dense paracrine communications between stromal and cancer cells in CCA, in an effort to unveil the molecular mechanisms driving tumor progression. In a first study, we focused on a pleiotropic cytokine named leukemia inhibitory factor (LIF), which we found to be released not only by CCA cells, but also by inflammatory cells and CAFs within the tumor microenvironment. We showed that LIF hindered the induction of apoptosis in CCA cells treated with gemcitabine plus cisplatin, an effect dependent on the up-regulation of the anti-apoptotic protein myeloid cell leukemia (Mcl)-1, occurring downstream of PI3K activation. Therefore, targeting the LIF/PI3K/Mcl-1 axis may represent a feasible strategy to increase CCA responsiveness to chemotherapy. In a second study, we considered a classic readout of tumor-stroma interactions, i.e., the epithelial-to-mesenchymal transition (EMT) of cancer cells, a process underlying carcinoma invasion and metastasis. Previously, we had shown that S100A4, an EMT biomarker, acts as a mechanistic determinant of CCA invasiveness when expressed in the nucleus of cancer cells. We then demonstrated that the nuclearization of S100A4 was dependent on its SUMOylation, which could be inhibited by treating CCA cells with paclitaxel at nanomolar doses. Down-modulation of nuclear S100A4 hampered the activity of RhoA and Cdc42, the secretion of matrix metalloproteinase (MMP)-9, and the expression of membrane-type (MT)1-MMP. Moreover, low-dose paclitaxel significantly impaired CCA cell invasiveness, both in vitro and in a SCID mouse xenograft model, implying that a selective reduction in S100A4 nuclear expression may prevent tumor dissemination in CCA patients. In a third study, we aimed at clarifying whether the interplay between CCA cells and CAFs could drive tumor lymphangiogenesis, a process of utmost importance for CCA metastatization. We showed that, upon stimulation with platelet-derived growth factor (PDGF)-D, a major mediator of CAF recruitment by CCA cells, fibroblasts increased the secretion of vascular endothelial growth factor (VEGF)-A and VEGF-C, due to the activation of ERK1/2 and JNK. Consistently, conditioned medium from PDGF-D-treated fibroblasts promoted the recruitment of LECs, along with their assembly in 3-D vascular structures, and both effects could be prevented by antagonizing either PDGF receptor β on fibroblasts, or VEGF receptors 2 and 3 on LECs. The permeability of LEC monolayers was also increased by PDGF-D-treated fibroblasts, supporting the trans-endothelial migration of CCA cells. Overall, we unveiled the presence of a sequential cross-talk among CCA cells, CAFs and LECs, whose disruption may interfere with CCA metastatic spread. In conclusion, our results validate the notion that the tumor stroma strongly promotes the progression of CCA, both by directly shaping the behavior of cancer cells, and by setting up a microenvironment conducive to metastasis. Hopefully, a comprehensive understanding of the mutual interactions between cancer and stromal cells will lead to the development of innovative, multitargeted therapies that may more effectively eradicate the tumor.
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Lau, Sze-hang Billy. "Identification and characterization of key genes involved in the development and progression of hepatocellular carcinoma." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38589059.
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Liu, Chia Yi. "Tyrosine Phosphorylation of p68 RNA Helicase Promotes Metastasis in Colon Cancer Progression." Digital Archive @ GSU, 2012. http://digitalarchive.gsu.edu/biology_diss/117.
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The initiation of cancer metastasis usually requires Epithelial-Mesenchymal Transition (EMT), by which tumor cells lose cell-cell interactions and gain the ability of migration and invasion. Previous study demonstrated that p68 RNA helicase, a prototypical member of the DEAD-box RNA helicases, functions as a mediator to promote platelet-derived growth factor (PDGF)-induced EMT through facilitating nuclear translocation of β-catenin in colon cancer cells. In this context, p68 RNA helicase was found to be phosphorylated at the tyrosine 593 residue (referred as phosphor-p68) by c-Abl kinase, and this phosphorylation is required for the activation of β-catenin signaling and the consequent EMT. The phosphor-p68 RNA helicase-mediated EMT was characterized by the repression of an epithelial marker, E-cadherin, and the upregulation of a mesenchymal marker, Vimentin. E-cadherin, a major cell-cell adhesion molecule that is involved in the formation of adherens junctions, has been shown to sequester β-catenin at the cell membrane and thus inhibit its transcriptional activity. The functional loss of E-cadherin is the fundamental event of EMT. Despite the role of phosphor-p68 RNA helicase in regulating nuclear translocation of β-catenin, whether phosphor-p68 is involved in the regulation of E-cadherin remains unknown. Here, our data indicated that phosphor-p68 RNA helicase initiated EMT by transcriptional upregulation of Snail1, a master transcriptional repressor of E-cadherin. The data suggest that phosphor-p68 RNA helicase displaced HDAC1 from the chromatin remodeling MBD3:Mi-2/NuRD complex at the Snail1 promoter, thereby activating the transcription of Snail1. In the xenograft tumor model, abolishing the phosphorylation of p68 RNA helicase by the expression of Y593F mutant resulted in a significant reduction of metastatic potential in human colon cancer cells. Analyses in the colon cancer tissues also revealed that the tyrosine 593 phosphorylation level of p68 RNA helicase is substantially enhanced in the tumor tissues comparing to that in the corresponding normal counterparts, suggesting a correlation of phosphor-p68 and tumor progression. In conclusion, we showed that tyrosine phosphorylation of p68 RNA helicase positively correlated to the malignant status of colon cancer progression. The molecular basis behind this correlation could be partly through the transcriptional regulation of Snail1.
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SACHDEVA, MOHIT. "MiR-145 is a tumor suppressor in both tumor progression and metastasis." OpenSIUC, 2010. https://opensiuc.lib.siu.edu/dissertations/206.
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MicroRNAs (miRNAs) are non-coding small RNAs that regulate gene expression at the post-transcriptional level by interacting with the 3'-untranslated region (3'-UTR) of a target gene. Our previous studies indicate that miR-145 is downregulated in breast and colon cancer; moreover, it functions as a tumor suppressor capable of inhibiting tumor cell growth both in vitro and in vivo. In this study, we show that a putative tumor suppressor, miR-145, is regulated through the phosphoinositide-3 kinase (PI-3K)/Akt and p53 pathways. Importantly, p53 transcriptionally induces the expression of miR-145 by interacting with a potential p53 response element (p53RE) in the miR-145 promoter. We further show that c-Myc is a direct target for miR-145. Although miR-145 silences the expression of c-Myc, anti-miR-145 enhances its expression. This specific silencing of c-Myc by miR-145 accounts at least in part for the miR-145- mediated inhibition of tumor cell growth both in vitro and in vivo. Finally, the blockade of miR-145 by anti-miR-145 is able to reverse the p53-mediated c-Myc repression. Together, these results define the role of miR-145 in the posttranscriptional regulation of c-Myc by p53. in addition, we show that miR-145 exerts its growth inhibitory function in a cell-specific manner. Although miR-145 inhibits cell growth in MCF-7 and HCT-116 cells, it has no significant effect on cell growth in metastatic breast cancer cell lines. However, miR-145 significantly suppresses cell invasion in these cells; in contrast, the antisense oligo against miR-145 increases cell invasion. miR-145 is also able to suppress lung metastasis in an experimental metastasis animal model. This miR-145-mediated suppression of cell invasion is in part due to the silencing of the metastasis gene mucin 1 (MUC1). Using luciferase reporters carrying the 3′-untranslated region of MUC1 combined with Western blot and immunofluorescence staining, we identify MUC1 as a direct target of miR-145. Moreover, ectopic expression of MUC1 enhances cell invasion, which can be blocked by miR-145. Of interest, suppression of MUC1 by miR-145 causes a reduction of β catenin as well as the oncogenic cadherin 11. Finally, suppression of MUC1 by RNAi mimics the miR-145 action in suppression of invasion, which is associated with downregulation of β-catenin and cadherin 11. Taken together, these results suggest that as a tumor suppressor, miR-145 inhibits not only tumor growth but also cell invasion and metastasis.
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Piccolella, M. "Caratterizzazione del sistema attivatore del plasminogeno nella progressione metastatica del cancro prostatico umano." Doctoral thesis, Università degli Studi di Milano, 2007. http://hdl.handle.net/2434/166305.
Full textAbstract:
GnRH analogues are used for the treatment of prostate cancer (PCa) because their ability to suppress the activity of the pituitary-testicular axis, with consequent blockade of testosterone production. However, after an initial responsiveness to hormonal deprivation, PCa progresses and then metastatises. It is known that the system of the plasminogen activator (uPA, uPA inhibitors PAI-1/2 and uPA receptor, uPAR) has been involved in the local degradation of the extracellular matrix and PCa progression and metastases. Studies performed in our laboratory have demonstrated the presence of GnRH receptors, suggesting a direct effect of GnRH analogues in inhibiting the proliferation of human PCa cell lines. The aim of this study was to test the effect of an agonist (Leuprolide) and an antagonist (Cetrorelix) of GnRH on uPA/uPAR and PAI-1 expression and activity, on the migratory and invasion capabilities in the two androgen-independent cell lines, DU145 and PC3 cells. The results obtained in DU145 and PC3 cells show that both Leuprolide and Cetrorelix: 1) significantly decrease the enzymatic activity of uPA; 2) induce a marked decrease of uPA and a significant increase of PAI-1 protein levels; 3) increase the presence of soluble uPAR in the cell media; 4) decrease the migratory and invasion capabilities. In conclusions, GnRH analogues might interfere with the mechanisms of metastatic progression of human androgen-independent PCa by inhibiting the activity of the plasminogen activator system.
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Zhang, Yanyu. "Platelets – Multifaceted players in tumor progression and vascular function." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-306129.
Full textAbstract:
Platelets play a crucial role for blood hemostasis, the process that prevents bleeding. In addition, platelets have been demonstrated to promote cancer progression and cancer related complications like metastasis and thrombosis. Platelets can affect cancer related diseases either directly or by interacting with other blood cells or molecules in the circulation of individuals with cancer. The current thesis addresses the role of platelets in tumor progression and tumor-induced systemic effects of cancer, with a special focus on the effects on the vasculature. In the first paper, the role of platelets in tumor progression in histidine-rich glycoprotein (HRG)-deficient mice was addressed. We report that HRG-deficient mice show enhanced tumor growth, epithelial to mesenchymal transition (EMT) and metastasis. The enhanced platelet activity in the absence of HRG is responsible for the accelerated tumor progression. In the second paper, we demonstrate that platelet-derived PDGFB is a central player to keep the tumor vessels functional. Moreover, in a pancreatic neuroendocrine carcinoma model with PDGFB-deficient platelets, spontaneous liver metastasis was enhanced. With this finding we identify a previously unknown role of platelet derived PDGFB. In the third paper, we found that TBK1 mediates platelet-induced EMT by activation of NF-kB signaling, which suggest that TBK1 contributes to tumor invasiveness in mammary epithelial tumors. In the last paper, we report that the vascular function in organs that are neither affected by the primary tumor, nor represent metastatic sites, is impaired in mice with cancer. We show that tumor-induced formation of intravascular neutrophil extracellular traps (NETs), a fibril matrix consisting of neutrophils with externalized DNA and histones, granule proteases and platelets, are responsible for the impaired peripheral vessel function.
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Ahronian, Leanne G. "Identification and Characteristics of Factors Regulating Hepatocellular Carcinoma Progression and Metastasis: A Dissertation." eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/705.
Full textAbstract:
Hepatocellular carcinoma (HCC) is a common malignancy of the liver that is one of the most frequent causes of cancer-related death in the world. Surgical resection and liver transplantation are the only curative options for HCC, and tumor invasion and metastasis render many patients ineligible for these treatments. Identification of the mechanisms that contribute to invasive and metastatic disease may enlighten therapeutic strategies for those not eligible for surgical treatments. In this dissertation, I describe two sets of experiments to elucidate mechanisms underlying HCC dissemination, involving the activities of Krüppel-like factor 6 and a particular p53 point mutation, R172H.
Gene expression profiling of migratory HCC subpopulations demonstrated reduced expression of Krüppel-like factor 6 (KLF6) in invasive HCC cells. Knockdown of KLF6 in HCC cells increased cell transformation and migration. Single-copy deletion of Klf6 in a HCC mouse model results in increased tumor formation, increased metastasis to the lungs, and decreased survival, indicating that KLF6 suppresses both tumor formation and metastasis in HCC.
To elucidate the mechanism of KLF6-mediated tumor and metastasis suppression, we performed gene expression profiling and ChIP-sequencing to identify direct transcriptional targets of KLF6 in HCC cells. This analysis revealed novel transcriptional targets of KLF6 in HCC including CDC42EP3 and VAV3, both of which are positive regulators of Rho family GTPases. Concordantly, KLF6 knockdown cells demonstrate increased activity of the Rho family GTPases RAC1 and CDC42, and RAC1 is required for migration induced following KLF6 knockdown. Moreover, VAV3 and CDC42EP3 are also required for enhanced cell migration in HCC cells with KLF6 knockdown. Together, this work describes a novel signaling axis through which KLF6-mediated repression of VAV3 and CDC42EP3 inhibits RAC1Gmediated HCC cell migration in culture, and potentially HCC metastasis in vivo.
TP53 gene mutations are commonly found in HCC and are associated with poor prognosis. Prior studies have suggested that p53 mutants can display gain-of- function properties in other tumor types. Therefore, I sought to determine if a particular hotspot p53 mutation, p53R172H, provided enhanced, gain-of-function properties compared to p53 loss in HCC. In vitro, soft agar colony formation and cell migration is reduced upon knockdown of p53R172H, indicating that this mutation is required for transformation-associated phenotypes in these cells. However, p53R172H-expressing mice did not have enhanced tumor formation or metastasis compared to p53-null mice. These data suggest that p53R172H and p53 deletion are functionally equivalent in vivo, and that p53R172H is not a gain-of-function mutant in HCC. Inhibition of the related transcription factors p63 and p73 has been suggested as a potential mechanism by which mutant p53 exerts its gain-of-function effects. Analysis of p63 and p73 target genes demonstrated that they are similarly suppressed in p53-null and p53R172H-expressing HCC cell lines, suggesting a potential explanation for the phenotypes I observed in vivo and in vitro.
Together, the studies described in this dissertation increase our understanding of the mechanisms underlying HCC progression and metastasis. Specifically, we find and characterize KLF6 as a novel suppressor of HCC metastasis, and determine the contribution of a common p53 point mutation in HCC. This work contributes to ongoing efforts to improve treatment options for HCC patients.
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Morrison, Chevaun Danielle. "DYNAMIC INTERACTIONS OF P53 AND C-ABL IN REGULATING BREASTCANCER PROGRESSION AND METASTASIS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1481208229508494.
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Ahronian, Leanne G. "Identification and Characteristics of Factors Regulating Hepatocellular Carcinoma Progression and Metastasis: A Dissertation." eScholarship@UMMS, 2003. http://escholarship.umassmed.edu/gsbs_diss/705.
Full textAbstract:
Hepatocellular carcinoma (HCC) is a common malignancy of the liver that is one of the most frequent causes of cancer-related death in the world. Surgical resection and liver transplantation are the only curative options for HCC, and tumor invasion and metastasis render many patients ineligible for these treatments. Identification of the mechanisms that contribute to invasive and metastatic disease may enlighten therapeutic strategies for those not eligible for surgical treatments. In this dissertation, I describe two sets of experiments to elucidate mechanisms underlying HCC dissemination, involving the activities of Krüppel-like factor 6 and a particular p53 point mutation, R172H.
Gene expression profiling of migratory HCC subpopulations demonstrated reduced expression of Krüppel-like factor 6 (KLF6) in invasive HCC cells. Knockdown of KLF6 in HCC cells increased cell transformation and migration. Single-copy deletion of Klf6 in a HCC mouse model results in increased tumor formation, increased metastasis to the lungs, and decreased survival, indicating that KLF6 suppresses both tumor formation and metastasis in HCC.
To elucidate the mechanism of KLF6-mediated tumor and metastasis suppression, we performed gene expression profiling and ChIP-sequencing to identify direct transcriptional targets of KLF6 in HCC cells. This analysis revealed novel transcriptional targets of KLF6 in HCC including CDC42EP3 and VAV3, both of which are positive regulators of Rho family GTPases. Concordantly, KLF6 knockdown cells demonstrate increased activity of the Rho family GTPases RAC1 and CDC42, and RAC1 is required for migration induced following KLF6 knockdown. Moreover, VAV3 and CDC42EP3 are also required for enhanced cell migration in HCC cells with KLF6 knockdown. Together, this work describes a novel signaling axis through which KLF6-mediated repression of VAV3 and CDC42EP3 inhibits RAC1Gmediated HCC cell migration in culture, and potentially HCC metastasis in vivo.
TP53 gene mutations are commonly found in HCC and are associated with poor prognosis. Prior studies have suggested that p53 mutants can display gain-of- function properties in other tumor types. Therefore, I sought to determine if a particular hotspot p53 mutation, p53R172H, provided enhanced, gain-of-function properties compared to p53 loss in HCC. In vitro, soft agar colony formation and cell migration is reduced upon knockdown of p53R172H, indicating that this mutation is required for transformation-associated phenotypes in these cells. However, p53R172H-expressing mice did not have enhanced tumor formation or metastasis compared to p53-null mice. These data suggest that p53R172H and p53 deletion are functionally equivalent in vivo, and that p53R172H is not a gain-of-function mutant in HCC. Inhibition of the related transcription factors p63 and p73 has been suggested as a potential mechanism by which mutant p53 exerts its gain-of-function effects. Analysis of p63 and p73 target genes demonstrated that they are similarly suppressed in p53-null and p53R172H-expressing HCC cell lines, suggesting a potential explanation for the phenotypes I observed in vivo and in vitro.
Together, the studies described in this dissertation increase our understanding of the mechanisms underlying HCC progression and metastasis. Specifically, we find and characterize KLF6 as a novel suppressor of HCC metastasis, and determine the contribution of a common p53 point mutation in HCC. This work contributes to ongoing efforts to improve treatment options for HCC patients.