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Wander, Seth A. "p27 and Metastatic Progression: Molecular Mechanisms Underlying Bone Metastasis". Scholarly Repository, 2011. http://scholarlyrepository.miami.edu/oa_dissertations/690.
Pełny tekst źródłaNordman, Ina IC Clinical School St Vincent's Hospital Faculty of Medicine UNSW. "Surrogate endpoints of survival in metastatic carcinoma". Publisher:University of New South Wales. Clinical School - St Vincent's Hospital, 2008. http://handle.unsw.edu.au/1959.4/42791.
Pełny tekst źródłaSolberg, Arne. "Outcome Assessments in Non- Metastatic Prostate Cancer". Doctoral thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for kreftforskning og molekylær medisin, 2011. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-13881.
Pełny tekst źródłaPaon, Lenaic Marie Pierre. "Gene expression profiling of metastatic gastric cancer". Thesis, University of Liverpool, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.490659.
Pełny tekst źródłaPelon, Floriane. "Fibroblastic heterogeneity and metastatic spread in breast cancers Fibroblast heterogeneity drives metastatic spread in breast cancer through distinct mechanisms". Thesis, Sorbonne Paris Cité, 2018. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2392&f=17330.
Pełny tekst źródłaBreast cancers are the most common cancers in women and despite great improvements in treatments, they are still responsible for many deaths worldwide. They are classified into 3 main molecular subtypes: Luminal cancers are the most frequent ones, while HER2 and TN are the most aggressive. At diagnostic, lymph node involvement is also assessed as it constitutes, in addition to molecular classification, a strong prognostic marker. Indeed, it informs on the risk to develop further distant metastases, which is the main cause of death by cancer. Solid tumors, including breast cancers, are complex ecologies comprising numerous different cell types that interact with cancer cells. Among them, cancer-associated-fibroblasts (CAF) are the most abundant and actively participate in many tumor hallmarks such as tumor growth, invasion, immunosuppression and angiogenesis. However, they do not constitute a homogeneous population but so far, only few studies have characterized this heterogeneity and linked it to CAF previously described functions. In this project, we focused on the potential involvement of CAF heterogeneity in breast cancer metastatic spread. Combining the analysis of several CAF markers, we showed that invaded LN comprise 4 CAF subsets (CAF-S1, S2, S3 and S4), similar to those found in primary tumors. Interestingly, the two myofibroblastic subsets (αSMA+) CAF-S1 and especially CAF-S4 preferentially accumulate in metastatic LN and present the same transcriptomic profiles in both tumors and LN. Importantly, both CAF-S1 and CAF-S4 display pro-invasive properties, by acting at different levels on tumor cells. On the one hand, highly motile CAF-S1 stimulate breast cancer cell proliferation, migration and EMT initiation. On the other hand, CAF-S4 exhibit an important contractility and by remodeling the matrix they are able to promote tumor cell invasion in 3D. Functional studies highlight a CXCL12/TGFβ involvement in CAF-S1 functions while CAF-S4 pro-invasive phenotype appears to be Notch-dependent. In agreement with these data, we found that CAF accumulation and subset enrichment in involved LN were two new prognostic factors, independent of breast cancer molecular subtypes and LN status at diagnosis. Indeed, stromal rich LN with a predominance of CAF-S4 are associated with long distance metastases development and poor overall survival. Thus, we propose that analyzing LN fibroblastic content at diagnosis could constitute new and useful information to breast cancer patients’ care
Chiang, Yan Ting. "Identification of metastasis-driving genes as potential therapeutic targets/ biomarkers for metastatic prostate cancer". Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/52901.
Pełny tekst źródłaMedicine, Faculty of
Graduate
Nielsen, S. R. "Metastasis-associated macrophages orchestrate the formation of a hospitable metastatic niche in pancreatic cancer". Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3007527/.
Pełny tekst źródłaReed, Elizabeth. "The experience of living with metastatic breast cancer". Thesis, University of Southampton, 2012. https://eprints.soton.ac.uk/344746/.
Pełny tekst źródłaHe, Felicia Jane. "Targeting Metastatic Breast Cancer Using Dual-Ligand Nanoparticles". Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1499699087340348.
Pełny tekst źródłaDonald, 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.
Pełny tekst źródłaLoughlin, Paula Mary. "Immune responses in primary and metastatic breast cancer". Connect to e-thesis, 2009. http://theses.gla.ac.uk/877/.
Pełny tekst źródłaMenssouri, Naoual. "Genomic Profiling Of Metastatic Castration-Resistant Prostate Cancer". Thesis, université Paris-Saclay, 2022. http://www.theses.fr/2022UPASL099.
Pełny tekst źródłaProstate cancer is the most common cancer in men worldwide and the third most common cause of cancer deaths in industrialized countries. First line systemic therapy for metastatic prostate cancer usually includes androgen-deprivation therapy using surgical or pharmacological castration. Metastatic castration-resistant prostate cancer (mCRPC) is considered incurable. Its treatment is usually based on the chemotherapy or androgen receptor pathway inhibitors (ARPIs) such as enzalutamide or abiraterone. Although ARPIs are initially effective in the majority of patients, up to 20% of patients do not benefit from them (primary resistance) and those in whom the treatment is effective eventually develop ARPI-resistant disease (secondary or acquired resistance). The mechanisms of resistance are multiple and extremely complex. Several studies have focused on primary resistance mechanisms, but there are very few studies focused on mechanisms of secondary resistance. Previous studies, a majority of which used preclinical models, suggested that alterations in the androgen receptor itself such as splice variants (particularly AR-V7) are associated with primary and secondary resistance. However, this biomarker is not used in routine practice. Activation of alternative signaling pathways may also be responsible for resistance. Additional mechanisms of resistance, although still poorly known and studied, include epigenetic modifications and activation of other transcription factors.The aim of this thesis was to study the mechanisms of resistance to the new ARPIs in patients with mCRPC. To do so, we developed a prospective study (MATCH-R) to collect tumor biopsies from patients treated with ARPIs. Exome and transcriptome sequencing were performed. The relationships between genomic alterations and the occurrence of resistance to ARPIs were analyzed. The results suggest that primary resistance to ARPIs results from the activation of several biological pathways including those related to (1) a reduction in AR pathway activity (2) activation of the epithelial-mesenchymal transition and stem cell program, and (3) activation of the Hedgehog (Hh) signaling pathway protein, suggesting a potential benefit of Hh pathway inhibition among patients with Hh activation. DNA abnormalities that may cause primary resistance have not yet been identified. Collection of multiple samples at the time of secondary resistance allowed characterization of the clonal evolution of these tumors, which essentially follows a "branching" evolutionary pattern with sequential acquisition of important new gene alterations (AR, PTEN, RB1). Transcriptome analysis shows the activation of signaling pathways involved in cell proliferation and pathways leading to neuroendocrine differentiation. Further research is needed to validate these results in independent studies at the mCRPC stage or at earlier stages given the earlier use of ARPIs, particularly in the situation of hormone-sensitive prostate cancer.Ongoing work is underway in the laboratory with preclinical experimental models to functionally validate the potential value of Hh inhibitors that are already used in the treatment of other cancer in order to develop targeted therapeutic options
Charnley, Richard Michael. "The early detection of recurrent and metastatic colorectal cancer". Thesis, University of Nottingham, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.277384.
Pełny tekst źródłaIamshanova, Oksana. "Role of NALCN channel in prostate cancer metastatic behaviours". Thesis, Lille 1, 2017. http://www.theses.fr/2017LIL10205.
Pełny tekst źródłaImportantly, altered Na+ homeostasis was implemented in prostate carcinogenesis. However, until now nothing was known about a newly discovered Na+ leak channel, NALCN, and its role in prostate malignancy. Therefore, the main objective of this study was to investigate the involvement of NALCN as a potential candidate of the deregulated Na+-dependent signalling mechanisms in prostate cancer. Interestingly, NALCN represented distinctly different localization patterns and levels of expression between human healthy and cancer prostate tissues. Indeed, NALCN was expressed preferentially in highly aggressive prostate cancer cell lines. Na+ imaging results verified on functionality of NALCN channelosome in these cells. Our study also revealed that NALCN was not involved in cell cycle, viability, apoptosis and proliferation, but significantly affected motility, migration and invasiveness of the prostate cancer cells. Interestingly, it was already reported that protooncogene Src family kinase is recruited to the NALCN complex. In this study, we confirmed that NALCN and Src kinase are co-localized in human prostate cancer cells, particularly in the structures that represent invadopodia formation sites. Furthermore, in vivo studies confirmed that NALCN downregulation inhibits tumour growth and metastasis formation. Overall, these data provide evidence on NALCN contribution to the increased metastatic potential of human prostate cancer cells in vitro and in vivo. Therefore, NALCN could provide new perspective molecular target for the disease suppression, in particular at its advanced stages
James, Mark Ian. "Treatment of metastatic colorectal cancer : a role for curcumin?" Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/32351.
Pełny tekst źródłaFulton, Colette Louise. "The rehabilitation needs of women with metastatic breast cancer". Thesis, University of Edinburgh, 1993. http://hdl.handle.net/1842/19769.
Pełny tekst źródłaGross, Brett Patrick. "Therapeutic vaccination for the treatment of metastatic breast cancer". Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6119.
Pełny tekst źródłaGooding, 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.
Pełny tekst źródłaKwok, Mon-sze, i 郭夢思. "Study of metastatic suppressing genes on ovarian carcinomas". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B45010729.
Pełny tekst źródłaLee, Yee-ki Carol, i 李綺琪. "Effect of dietary fatty acids on metastatic hepatocellularcarcinoma". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39707349.
Pełny tekst źródłaPéladeau, Christine. "Isoform Specific Function of the Metastatic Formin FMNL2". Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/24396.
Pełny tekst źródłaMalek, Joël. "Genetic alterations of the metastatic lesions in ovarian carcinoma". Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T109.
Pełny tekst źródłaOvarian cancer is the most deadly gynecological cancer. The high rate of mortality is due to the large tumor burden with extensive metastatic lesion of the abdominal cavity. There are few studies on genetic alterations and their consequences in peritoneal metastatic tumors when compared to their matched ovarian primary tumors. Our hypothesis is that differences between the metastatic and primary lesions might be the cause of residual disease and, most importantly may have a role in post-chemotherapeutic recurrences. Methods: We conducted integrated genomics analysis on matched primary and metastatic tumors from 9 patients. In the papers presented here we analyze genome-wide Copy Number Variations (CNVs) using SNP Arrays targeting peritoneal metastasis differences, Gene expression differences using Microarrays also targeting peritoneal metastasis differences, and for some patients, Single Nucleotide Polymorphisms (SNPs) in genes through Exome sequencing.Results: Here we show that CNVs vary significantly between primary and metastatic tumors and include genes that have been considered potential chemotherapeutic targets based on primary tumor only data. Gene expression differences, while minor, showed highly statistically significant enrichment of genes in ovarian cancer critical pathways. In agreement with findings in other cancers, exome sequencing data revealed very few SNP differences of which most metastasis enriched SNPs were present at very low levels in the primary tumor. The results presented here should allow better design of therapies to target residual ovarian cancer disease
Frieling, Jeremy S. "Functional Roles of Matrix Metalloproteinases in Bone Metastatic Prostate Cancer". Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6841.
Pełny tekst źródłaConway, Brianna. "Searching for Synergy: FAK Inhibition in Metastatic Breast Cancer Treatment". Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37304.
Pełny tekst źródłaAlsulaiman, Abdullah. "Investigation of the role of CD24 in metastatic colorectal cancer". Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/55401/.
Pełny tekst źródłaVang, Yeeleng Scott. "An Ensemble Prognostic Model for Metastatic, Castrate-Resistant Prostate Cancer". Thesis, University of California, Irvine, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10162542.
Pełny tekst źródłaMetastatic, castrate-resistant prostate cancer (mCRPC) is one of the most prevalent cancers and is the third leading cause of cancer death among men. Several treatment options have been developed to combat mCRPC, however none have produced any tangible benefits to patients' overall survivability. As part of a crowd-sourced algorithm development competition, participants were asked to develop new prognostic models for mCRPC patients treated with docetaxel. Such results could potentially assist in clinical decision making for future mCRPC patients.
In this thesis, we present a new ensemble prognostic model to perform risk prediction for mCRPC patients treated with docetaxel. We rely on traditional survival analysis model like the Cox Proportional Hazard model, as well as more recently developed boosting model that incorporates smooth approximation of the concordance index for direct optimization. Our model performs better than the the current state-of-the-art mCRPC prognostic models for the concordance index performance measure and is competitive with these models on the integrated time-dependent area under the receiver operating characteristic curve.
Roda, Ana Sofia Martins. "Nanoparticles for recognition and delivery in metastatic colorectal cancer cells". Master's thesis, Universidade Nova de Lisboa. Instituto de Tecnologia Química e Biológica António Xavier, 2016. http://hdl.handle.net/10362/63808.
Pełny tekst źródłaN/A
Garg, Ayush A. "Electromagnetic Fields Alter the Motility of Metastatic Breast Cancer Cells". The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1563816767104018.
Pełny tekst źródłaMitchell, Jill Laurin. "Construction of meaning in women's experiences with metastatic breast cancer". Diss., Restricted to subscribing institutions, 2006. http://proquest.umi.com/pqdweb?did=1251832051&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
Pełny tekst źródłaTomlinson, James S. "Molecular basis of the metastatic phenotype of inflammatory breast cancer". Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=1872078261&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
Pełny tekst źródłaCasey, Susan Marie. "Metastatic recurrent breast cancer : the couples' experience with role changes /". Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/7253.
Pełny tekst źródłaNordstrand, Annika. "Prostate cancer and bone cell interactions : implications for metastatic growth and therapy". Doctoral thesis, Umeå universitet, Onkologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-131809.
Pełny tekst źródłaReedy, Jessica Leigh. "Pyridinium derivatives for metastatic melanoma therapy". Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/6628.
Pełny tekst źródłaWen, Wucheng. "Development and Evaluation of Nano-herbal Therapy for Metastatic Breast Cancer Treatment". Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/534260.
Pełny tekst źródłaPh.D.
Triptolide (TPL), a diterpenoid triepoxide that is extracted from a traditional Chinese herb called Tripterygium Wilfordii (also known as ‘Thunder God Vine’) has recently drawn increasing interests from pharmaceutical and biomedical researchers, especially in the aspect of its potential efficacy on multiple cancer treatment. TPL has shown significant growth and proliferation inhibition activities in a broad range of cancer cell types. Moreover, it has shown the inhibition of osteoclastogenesis by breast cancer bone metastasis. However, due to its limitation in toxicity, solubility and non-specific biodistribution, it is challenging for the application of TPL in clinical study. Besides, TPL can rapidly distribute in most vital organs and no evidences shown tissue accumulation of drug. It is indispensable to overcome those barriers and optimize the properties and performance of the promising drug molecule. Lipid-based nanocarriers such as nanostructured lipid carriers (NLC) have been extensively studied for delivery of poorly-water soluble drug compounds. They also have the potential to optimize the physicochemical properties of the drug and may enhance a targeted delivery of the drug to specific therapeutic site. Alendronate (Fosamax®), an FDA approved bisphosphonate drug for osteoporosis, osteogenesis imperfecta and several other bone diseases, has been used as a bone targeting decoration agent. Breast cancer cell line MDA-MB-231 and other type of cancer cell lines have been used to study the in vitro cytotoxicity of TPL and the carriers while MC3T3-E1 cell line was used for toxicity assessment. Rats have also been used to study the in vivo performance of the drug. After modifying and optimizing the formulation of the particle, the formulation had the ability to remain structurally and functionally stable when being in the bio-simulated media at 37 °C and in water at room temperature with high encapsulation efficiency. In vitro study illustrated that both TPL free drug (stock solution 10mg/mL dissolved in DMSO) and TPL nanoparticle without alendronate (TPL-NP) had similar cytotoxicity on MDA-MB-231 and some other type of cancer cell lines. The ALE decoration on the particle (ALE-NP-TPL) has enhanced the anti-cancer effect especially with breast cancer cell line. The in vivo study shows that after 24 hours of the dose injection at local bone site, the formulation and TPL can remained at the location without random distribution to other organs. TPL-NP has not only successfully optimized the physicochemical properties of the drug, but also shows great enhancement of therapeutic effect both in vitro and in vivo study.
Temple University--Theses
Del, Pozo Martin Y. "The mesenchymal status of metastatic cancer cells promotes a stromal crosstalk leading to epithelial re-acquisition and metastatic colonisation". Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1473399/.
Pełny tekst źródłaCrnalic, Sead. "Metastatic spinal cord compression in prostate cancer : clinical and morphological studies". Doctoral thesis, Umeå universitet, Ortopedi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-54461.
Pełny tekst źródłaKeskin, Doruk. "Functional Contribution of PDGFRbeta+ Cells in Angiogenesis and Metastatic Breast Cancer". Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11085.
Pełny tekst źródłaMcBride, John William. "A bio-inspired gene therapy approach to treat metastatic prostate cancer". Thesis, Queen's University Belfast, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.678937.
Pełny tekst źródłaPinto, Pedro Miguel Teixeira. ""Comparison of Methodologies for Kras Mutation Detection in Metastatic Colorectal Cancer"". Master's thesis, Instituto de Ciências Biomédicas Abel Salazar, 2008. http://hdl.handle.net/10216/20041.
Pełny tekst źródłaBradbury, Robyn. "The interplay between MDM2 and PSMA in metastatic breast cancer cells". Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/100068/.
Pełny tekst źródłaWeber, Zachary Thomas. "Applications of ctDNA Genomic Profiling to Metastatic Triple Negative Breast Cancer". The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1586787923790178.
Pełny tekst źródłaGagliardo, Camille, Megan Lybeck i Harmony Bowles. "A Retrospective Evaluation of Eribulin Dosing Schedules in Metastatic Breast Cancer". The University of Arizona, 2016. http://hdl.handle.net/10150/613986.
Pełny tekst źródłaObjectives: To determine the number of patients treated with eribulin who required an alternate dosing schedule other than “day 1/day 8” due to side effects. Methods: Chart reviews were conducted on all patients who met inclusion criteria. Data collected included patient demographics, history of surgery/radiation, number of past chemotherapy treatments, and lab values prior to each eribulin cycle. Results: A total of 37 patients met inclusion criteria for this study. Ten patients were initially started on the “day 1/day 8” schedule and 3 of those patients required a change to the extended “day 1/day 15” schedule. The remaining 27 patients were started on the extended schedule. Conclusions: The number of patients requiring a dosing schedule change due to side effects was not statistically significant. This finding was due to the fact that the majority of patients were started on an alternate dosing schedule in the beginning of treatment. More extensive studies would be required to determine if a majority of patients would require this alternate dosing schedule, and if this should be initiated in all patients starting on eribulin.
Pinto, Pedro Miguel Teixeira. ""Comparison of Methodologies for Kras Mutation Detection in Metastatic Colorectal Cancer"". Dissertação, Instituto de Ciências Biomédicas Abel Salazar, 2008. http://hdl.handle.net/10216/20041.
Pełny tekst źródłaSchroeder, Krista Marie. "Disparities in Monoclonal Antibody Treatment of Elderly Metastatic Colorectal Cancer Patients". ScholarWorks, 2015. https://scholarworks.waldenu.edu/dissertations/1421.
Pełny tekst źródłaPritchard, Rhys. "The Function of NSAIDs including Celecoxib as Therapies for Metastatic Cancer". Thesis, Griffith University, 2019. http://hdl.handle.net/10072/389567.
Pełny tekst źródłaThesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
Full Text
Beasley, Aaron. "Genetic markers in circulating tumour cells as a measure of the metastatic propensity of uveal melanoma". Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2017. https://ro.ecu.edu.au/theses/1968.
Pełny tekst źródłaUsmani, 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.
Pełny tekst źródłaHughes, Ellyn. "Treating metastatic disease through manipulation of regulatory T cells". Thesis, Cardiff University, 2017. http://orca.cf.ac.uk/103925/.
Pełny tekst źródłaPrice, John T. "The influence of cytokines/growth factors on the metastatic propensity of tumour cells". Thesis, University of Aberdeen, 1995. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU543602.
Pełny tekst źródłaSala, Faig Rita. "Targeted drug delivery for the selective elimination of CXCR4+ cancer cells in metastatic colorectal cancer models". Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/671312.
Pełny tekst źródłaEl cáncer colorrectal (CCR) representa la tercera causa de mortalidad por cáncer en países occidentales, siendo las metástasis la principal causa de muerte. Aunque el progreso en las estrategias de prevención ha reducido la incidencia y mortalidad del CCR, cerca de un cuarto de los pacientes aún son diagnosticados en estadios metastáticos avanzados, con una tasa de supervivencia a cinco años de solamente el 15%. Es por eso, que la inhibición del desarrollo de metástasis actuando sobre células madre cancerosas incrementará significativamente los beneficios de las terapias actuales. En colaboración con el grupo de investigación en Nanobiotecnología de la UAB, hemos desarrollado nanopartículas proteicas autoensamblables dirigidas al receptor CXCR4, la sobreexpresión del cual correlaciona con la diseminación tumoral, baja supervivencia, y recurrencia en pacientes de CCR. La evaluación preclínica de la eficacia y toxicidad del nanoportador T22-GFP-H6 y sus derivados terapéuticos, requiere el uso de modelos in vivo de CCR diseminados. Con este objetivo, hemos desarrollado modelos de CCR subcutáneos y altamente metastáticos que sobreexpresan CXCR4, derivados de la línea celular de CCR SW1417 o de la muestra de paciente SP5. Con el objetivo de incrementar la eficiencia metastática de los modelos CXCR4+ anteriores, implantamos ortotópicamente células SW1417 con expresión de luciferasa en el ciego de ratones con inmunodeficiencia severa. Los ratones NOD/SCID (deficientes en células T y B), presentaron tasas metastáticas bajas. Por contra, la microinyección ortotópica en ratones NSG (deficientes en células T, B y NK), replicó el patrón de diseminación observado en pacientes, provocando la muerte de los ratones y un mayor número y tamaño de metástasis hepáticas y pulmonares en comparación con los ratones NOD/SCID. En la evaluación de la biodistribución de las nanopartículas, tal y como indica la emisión de fluorescencia (alrededor del 70% del total), T22-GFP-H6 alcanzó una alta acumulación selectiva en tumores del modelo subcutáneo CXCR4+, mientras la acumulación en órganos no tumorales fue solamente transitoria. Demostramos que la acumulación en tumor del nanoportador es CXCR4-dependiente, porque el pretratamiento con AMD3100, un antagonista de CXCR4, redujo la acumulación tumoral. Además, la esta incrementó con la funcionalización del nanoportador con el péptido fusogénico HA2, que favorece el escapamiento endosomal. Por otra parte, observamos que el nanoconjugado terapéutico T22-GFP-H6-Aur mantuvo la biodistribución del nanoportador, pero su efecto antitumoral fue sorprendentemente bajo. T22-GFP-H6-Aur solamente inhibió metástasis transcelómicas en un modelo de CCR altamente metastático y además activó una respuesta inmunogénica letal en su administración repetida en ratones poco inmunodeprimidos. Como opción terapéutica alternativa, sustituimos la proteína GFP de la nanopartícula por la toxina PE24 desinmunizada, a fin de reducir su inmunogenicidad añadiendo al mismo tiempo una potent actividad citotóxica intrínseca. La administración de dosis bajas de la nanotoxina T22-PE24-H6, previno el desarrollo de metástasis linfáticas y hematógenas en el modelo de CCR altamente metastático sin toxicidad. Demostramos que la nanotoxina T22-PE24-H6 induce la muerte de las células tumorales por la vía no apoptótica de la piroptosis. En conclusión, el uso de la nanotoxina T22-PE24-H6 podría ser una estrategia prometedora para la eliminación selectiva de células madre de CCR CXCR4+ en ausencia de toxicidad sistémica, aplicable a CCR metastáticos y resistentes a la quimioterapia que se asocien a la sobreexpresión de CXCR4 y a mecanismos antiapoptóticos.
Colorectal cancer (CRC) remains the third cause of cancer-related mortality in Western countries, being metastases the main cause of death. Despite progress in prevention strategies that decreased CRC incidence and mortality, still nearly a quarter of patients are diagnosed at an advanced metastatic stage, with only a 15% five-year survival rate. Thus, inhibition of metastasis development by targeting cancer stem cells, which are associated with cancer dissemination, will significantly increase the benefits of current cancer therapies. In collaboration with the Nanobiotechnology group from de UAB, we developed self-assembling protein-based nanoparticles targeting the CXCR4 receptor whose overexpression correlates with tumor dissemination, poor survival, and recurrence in CRC patients. Preclinical evaluation of the efficacy and toxicity of the T22-GFP-H6 nanocarrier and its therapeutic derivatives required the use of adequate in vivo disseminated CRC models. For that purpose, we generated subcutaneous and highly metastatic models of CRC that overexpress CXCR4, derived from the SW1417 CRC cell line or the SP5 patient sample. In order to increase the metastatic efficiency of previous CXCR4+ CRC models, we orthotopically implanted luciferase expressing SW1417 cells in the cecum of severe immunodeficient mice. NOD/SCID mice (deficient in T and B cells) presented a low metastatic rate. In contrast, orthotopic microinjection in NSG mice (deficient in T, B and NK cells) replicated the dissemination pattern observed in patients, causing mice death and resulting in a higher number and size of hepatic and pulmonary metastases as compared to NOD/SCID mice. In the assessment of nanoparticles’ biodistribution, T22-GFP-H6 achieved a highly selective tumor uptake in a CXCR4+ CRC subcutaneous model, as detected by fluorescent emission (around 70% of the total), while displaying only transient accumulation in non-tumor organs. We demonstrated that the nanocarrier tumor accumulation was CXCR4-dependent because pre-treatment with AMD3100, a CXCR4 antagonist, reduced tumor uptake. Furthermore, tumor accumulation was increased by the functionalization of the nanocarrier with the fusogenic HA2 peptide, which promotes endosomal escape. On the one hand, we observed that the therapeutic nanoconjugate T22-GFP-H6-Aur maintained the nanocarrier’s biodistribution but its antitumoral effect was surprisingly poor. T22-GFP-H6-Aur inhibited only tanscelomic metastasis in a highly metastatic CRC model, while activating a lethal immunogenic response when repeatedly administered in low immunosuppressed mice. As an alternative therapeutic option, we replaced the GFP protein in the nanoparticle by the de-immunized PE24 toxin, to reduce its immunogenicity while promoting a potent and intrinsic cytotoxic activity. The administration of low doses of the T22-PE24-H6 nanotoxin prevented the development of lymphatic and hematogenous metastasis in the highly metastatic CRC model without toxicity. We demonstrated that the T22-PE24-H6 nanotoxin induced cancer cell death through the non-apoptotic pathway, pyroptosis. In conclusion, the use of the T22-PE24-H6 nanotoxin could be a promising strategy to selectively eliminate CXCR4+ CRC stem cells in the absence of systemic toxicity, applicable to chemotherapy-resistant and disseminated CRC associated with the upregulation of CXCR4 and antiapoptotic mechanisms.