Journal articles on the topic 'Metastatic cancer'
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Yuk, Hyeong-Dong, Kyoung-Hwa Lee, Hye-Sun Lee, Seung-Hwan Jeong, Yongseok Kho, Chang-Wook Jeong, Hyeon-Hoe Kim, Ja-Hyeon Ku, and Cheol Kwak. "PDLIM2 Suppression Inhibit Proliferation and Metastasis in Kidney Cancer." Cancers 13, no. 12 (June 15, 2021): 2991. http://dx.doi.org/10.3390/cancers13122991.
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We evaluated the expression of PDLIM2 in human kidney cancer cell lines from primary or metastatic origins and found that PDLIM2 expression was highly elevated in metastatic kidney cancers. We evaluated the effect of PDLIM2 inhibition by RNA interference method. PDLIM2 knockdown showed the decreased proliferation and metastatic character in human metastatic kidney cancer cells. By repeated round of orthotopic injection of RenCa mouse kidney cancer cell line, we obtained metastatic prone mouse kidney cancer cell lines. PDLIM2 expression was highly expressed in these metastatic prone cells comparing parental cells. In addition, we evaluated the in vivo efficacy of PDLIM2 knockout on the tumor formation and metastasis of kidney cancer cells using a PDLIM2 knockout mice. The experimental metastasis model with tail vein injection and orthotopic metastasis model injected into kidney all showed reduced lung metastasis cancer formation in PDLIM2 knockout mice comparing control Balb/c mice. Overall, our findings indicate that PDLIM2 is required for cancer formation and metastasis in metastatic kidney cancer, indicating that PDLIM2 may be a new therapeutic target for metastatic kidney cancer.
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Singh Randhawa, Amritjot. "Metastatic Breast Cancer to the Uterine Cervix Mimicking Cervical Cancer." Indian Journal of Cancer Education and Research 8, no. 1 (June 1, 2020): 49–52. http://dx.doi.org/10.21088/ijcer.2321.9815.8120.8.
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Chen, Chao, Haozhen Liu, Qumiao Xu, Xiuqing Zhang, Feng Mu, and Jixian Liu. "Association of PTPRT Mutations with Cancer Metastasis in Multiple Cancer Types." BioMed Research International 2022 (June 25, 2022): 1–9. http://dx.doi.org/10.1155/2022/9386477.
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Metastasis is one of the characteristics of advanced cancer and the primary cause of cancer-related deaths from cancer, but the mechanism underlying metastasis is unclear, and there is a lack of metastasis markers. PTPRT is a protein-coding gene involved in both signal transduction and cellular adhesion. It is also known as a tumor suppressor gene that inhibits cell malignant proliferation by inhibiting the STAT3 pathway. Recent studies have reported that PTPRT is involved in the early metastatic seeding of colorectal cancer; however, the correlation between PTPRT and metastasis in other types of cancer has not been revealed. A combined analysis using a dataset from the genomics evidence neoplasia information exchange (GENIE) and cBioPortal revealed that PTPRT mutation is associated with poor prognosis in pan-cancer and non-small-cell lung cancer. The mutations of PTPRT or “gene modules” containing PTPRT are significantly enriched in patients with metastatic cancer in multiple cancers, suggesting that the PTPRT mutations serve as potential biomarkers of cancer metastasis.
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Ganguly, Debolina, Marcel Schmidt, Morgan Coleman, Tuong-Vi Ngo, Noah Sorrelle, Adrian Dominguez, Jason Toombs, et al. "Abstract B016: Pleiotrophin drives a pro-metastatic immune niche within the breast tumor microenvironment." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): B016. http://dx.doi.org/10.1158/1538-7445.metastasis22-b016.
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Abstract Metastatic cancer cells adapt to thrive in secondary organs. To investigate metastatic adaptation, we performed transcriptomic analysis of metastatic and non-metastatic murine breast cancer cells. We found that pleiotrophin (PTN), a neurotrophic cytokine, is a metastasis-associated factor that is expressed highly by aggressive breast cancers. Moreover, elevated PTN in plasma correlated significantly with metastasis and reduced survival of breast cancer patients. Mechanistically, we find that PTN activates NF-kB in cancer cells leading to altered cytokine production, subsequent neutrophil recruitment and an immune suppressive microenvironment. Consequently, inhibition of PTN, pharmacologically or genetically, reduces the accumulation of tumor associated neutrophils and reverts local immune suppression resulting in increased T cell activation and attenuated metastasis. Furthermore, inhibition of PTN significantly enhanced the efficacy of immune checkpoint blockade + chemotherapy in reducing metastatic burden in mice. These findings establish PTN as a previously unrecognized driver of a pro-metastatic immune niche and thus represents a promising therapeutic target for the treatment of metastatic breast cancer. Citation Format: Debolina Ganguly, Marcel Schmidt, Morgan Coleman, Tuong-Vi Ngo, Noah Sorrelle, Adrian Dominguez, Jason Toombs, Cheryl Lewis, Yisheng Fang, Fatima Mora, David Ortega, Anton Wellstein, Rolf Brekken. Pleiotrophin drives a pro-metastatic immune niche within the breast tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B016.
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Park, Jinkyung, Dahee Jeong, Meeryoung Song, and Bonglee Kim. "Recent Advances in Anti-Metastatic Approaches of Herbal Medicines in 5 Major Cancers: From Traditional Medicine to Modern Drug Discovery." Antioxidants 10, no. 4 (March 27, 2021): 527. http://dx.doi.org/10.3390/antiox10040527.
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Metastasis is the main cause of cancer-related death. Despite its high fatality, a comprehensive study that covers anti-metastasis of herbal medicines has not yet been conducted. The aim of this study is to investigate and assess the anti-metastatic efficacies of herbal medicines in the five major cancers, including lung, colorectal, gastric, liver, and breast cancers. We collected articles published within five years using PubMed, Google Scholar, and Web of Science with “cancer metastasis” and “herbal medicine” as keywords. Correspondingly, 16 lung cancer, 23 colorectal cancer, 10 gastric cancer, 10 liver cancer, and 18 breast cancer studies were systematically reviewed. The herbal medicines attenuated metastatic potential targeting various mechanisms such as epithelial mesenchymal transition (EMT), reactive oxygen species (ROS), and angiogenesis. Specifically, the drugs regulated metastasis related factors such as matrix metalloproteinase (MMP), serine-threonine protein kinase/extracellular regulated protein kinase (AKT/ERK), angiogenic factors, and chemokines. Overall, the present study is the first review, comprehensively investigating the anti-metastasis effect of herbal medicines on five major cancers, providing the experimental models, doses and durations, and mechanisms. Herbal medicines could be a potent candidate for anti-metastatic drugs.
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Cheng, Liang, David G. Bostwick, Guang Li, Shaobo Zhang, Alexander O. Vortmeyer, and Zhengping Zhuang. "Conserved Genetic Findings in Metastatic Bladder Cancer." Archives of Pathology & Laboratory Medicine 125, no. 9 (September 1, 2001): 1197–99. http://dx.doi.org/10.5858/2001-125-1197-cgfimb.
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Abstract Context.—Molecular analysis of microsatellite alterations of biologically distinct tumor cell subpopulations from the same patient may aid in the determination of tumor origin and further our understanding of the genetic basis of cancer progression. Design.—The authors examined the pattern of allelic loss with polymorphic microsatellite markers on chromosome 9p21 (D9S161, D9S171, IFNA), regions of putative tumor suppressor gene p16, and on chromosome 17p13 (TP53), the p53 locus, in matched primary and metastatic bladder cancers from 9 patients. All patients underwent cystectomy for bladder cancer and had regional lymph node metastases at the time of surgery. Genomic DNA was prepared from primary cancers and matched synchronous lymph node metastases using a microdissection method. Results.—The overall frequency of allelic loss was 78% in primary cancer and 89% in paired metastatic cancer. The frequency of allelic loss in the primary cancer was 86% with D9S161, 67% with D9S171, 71% with IFNA, and 80% with TP53. The frequency of allelic loss in matched metastatic cancer was 100% with D9S161, 62% with D9S171, 71% with IFNA, and 80% with TP53. An identical pattern of allelic imbalance (allelic loss or retention) at multiple DNA loci was observed in matched primary and metastatic carcinoma in 8 (88%) cases. One case showed allelic loss in the metastasis, but not in the primary cancer. Conclusions.—The pattern of allelic loss at chromosome 9p21 (p16) and 17p13 (p53) was generally maintained during cancer progression to metastasis, and identical allelic loss in primary cancer was conserved in paired metastatic carcinoma. These data suggest that these genetic changes may be useful in establishing a diagnosis and determining tumor origins in difficult cases.
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Wan, Xiaochun, and Junxin Li. "DcR3 acts as a tumor marker of metastatic cancers." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 178.45. http://dx.doi.org/10.4049/jimmunol.200.supp.178.45.
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Abstract Decoy receptor 3 (DcR3) is a soluble protein that competitively binds Fas ligand and has an anti-apoptotic role. Abnormally elevated DcR3 in malignant tumors may help cancer cells metastasize by suppressing immune responses and establishing metastatic lesions. However, whether DcR3 is valuable in differentiating cancer metastasis from non-metastasis remains largely unclear. In this study, we produced anti-DcR3 monoclonal antibodies and established a sensitive ELISA (11–12000 pg/ml, R2= 0.9941) to measure serum levels of DcR3 in cancer patients. DcR3 was significantly elevated in gastric cancer (2.04 ± 1.01, P = 0.0061), lymphoma (1.62 ± 0.75, P = 0.041) and breast cancer (1.53 ± 0.51, P = 0.023). ROC (Receiver Operating Characteristic) analysis suggested DcR3 was a suitable biomarker for the diagnosis of gastric cancer (Sensitivity = 85.7%, Specificity = 90.0%, AUC = 82.3%). Importantly, serum DcR3 was positively correlated with platelet distribution width (PDW) (P = 2.45×10−6, R = 0.63) in metastatic cancers while negatively correlated with hemoglobin (HGB) (P = 0.002, R = −0.59) and hematocrit (HCT) (P = 0.001, R = −0.62) in non-metastatic cancers. DcR3×PDW÷(HGB×HCT), the novel indicator could be used to differentiate cancer metastasis from non-metastasis (Sensitivity = 75.0%, Specificity = 80.9%, AUC = 79.0%). These results reveal that DcR3 has a predictive value for cancer metastasis in combination with hematological traits.
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Tarragó-Celada, Josep, and Marta Cascante. "Targeting the Metabolic Adaptation of Metastatic Cancer." Cancers 13, no. 7 (April 1, 2021): 1641. http://dx.doi.org/10.3390/cancers13071641.
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Metabolic adaptation is emerging as an important hallmark of cancer and metastasis. In the last decade, increasing evidence has shown the importance of metabolic alterations underlying the metastatic process, especially in breast cancer metastasis but also in colorectal cancer metastasis. Being the main cause of cancer-related deaths, it is of great importance to developing new therapeutic strategies that specifically target metastatic cells. In this regard, targeting metabolic pathways of metastatic cells is one of the more promising windows for new therapies of metastatic colorectal cancer, where still there are no approved inhibitors against metabolic targets. In this study, we review the recent advances in the field of metabolic adaptation of cancer metastasis, focusing our attention on colorectal cancer. In addition, we also review the current status of metabolic inhibitors for cancer treatment.
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Park, Misung, Dohee Kim, Sunghyub Ko, Ayoung Kim, Kyumin Mo, and Hyunho Yoon. "Breast Cancer Metastasis: Mechanisms and Therapeutic Implications." International Journal of Molecular Sciences 23, no. 12 (June 18, 2022): 6806. http://dx.doi.org/10.3390/ijms23126806.
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Breast cancer is the most common malignancy in women worldwide. Metastasis is the leading cause of high mortality in most cancers. Although predicting the early stage of breast cancer before metastasis can increase the survival rate, breast cancer is often discovered or diagnosed after metastasis has occurred. In general, breast cancer has a poor prognosis because it starts as a local disease and can spread to lymph nodes or distant organs, contributing to a significant impediment in breast cancer treatment. Metastatic breast cancer cells acquire aggressive characteristics from the tumor microenvironment (TME) through several mechanisms including epithelial–mesenchymal transition (EMT) and epigenetic regulation. Therefore, understanding the nature and mechanism of breast cancer metastasis can facilitate the development of targeted therapeutics focused on metastasis. This review discusses the mechanisms leading to metastasis and the current therapies to improve the early diagnosis and prognosis in patients with metastatic breast cancer.
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Pein, Maren, and Thordur Oskarsson. "Microenvironment in metastasis: roadblocks and supportive niches." American Journal of Physiology-Cell Physiology 309, no. 10 (November 15, 2015): C627—C638. http://dx.doi.org/10.1152/ajpcell.00145.2015.
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In many cancers, malignant cells can spread from the primary tumor through blood circulation and initiate metastasis in secondary organs. Metastatic colonization may depend not only on inherent properties of cancer cells, but also on suitable microenvironments in distant sites. Increasing evidence suggests that the nature of the microenvironment may determine the fate of disseminated cancer cells, providing either hindrance or support for cancer cell propagation. This can result in strong selective pressure where the vast majority of cancer cells, invading a secondary organ, are either eliminated or maintained in a dormant state. The ability of cancer cells to fend off or circumvent anti-metastatic signals from the stroma and the capacity to manipulate the local microenvironment towards a supporting environment, a metastatic niche, may be essential for metastatic growth. The molecular interactions between cancer cells and the stroma are still enigmatic, but recent studies are beginning to reveal their nature. Here, we discuss the interactive relationship between metastatic cancer cells and host stroma, involving selection and adaptation of metastasis-initiating cells and host tissue remodeling. Understanding the dynamic and continuously evolving cross talk between metastatic cancer cells and the stroma may be crucial when developing cancer treatments.
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Horiuchi, Atsushi, Keijiro Nozawa, Takuya Akahane, Ryu Shimada, Hajime Shibuya, Yoshiko Aoyagi, Keisuke Nakamura, et al. "Skin Metastasis From Sigmoid Colon Cancer." International Surgery 96, no. 2 (April 1, 2011): 135–38. http://dx.doi.org/10.9738/1391.1.
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Abstract Skin metastases from visceral cancers are rare and the reported incidence from all visceral cancers is 1.4% to 10%. Skin metastases from colorectal cancers account for only 5% of metastatic skin cancers, among which scalp metastases are very rare. We describe a 53-year-old man with scalp metastasis derived from sigmoid colon cancer that was diagnosed and surgically resected in 2005. Metastatic lung tumors that developed thereafter were surgically resected and then chemotherapy was administered. However, metastatic brain tumors occurred in 2008, and these were treated by γ-knife radiosurgery. Around the same time, a raised lesion that appeared on the scalp was diagnosed as skin metastasis and treated with best supportive care. Thereafter, the brain metastases continued to spread, and the patient died in October 2008.
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Liu, Heshu, Tao Wen, Ying Zhou, Xiaona Fan, Tan Du, Tianbo Gao, Lina Li, et al. "DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells." BioMed Research International 2019 (May 15, 2019): 1–8. http://dx.doi.org/10.1155/2019/1061979.
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Background. Doublecortin-like kinase 1 (DCLK1) has been universally identified as a cancer stem cell (CSC) marker and is found to be overexpressed in many types of cancers including breast cancer. However, there is little data regarding the functional role of DCLK1 in breast cancer metastasis. In the present study, we sought to investigate whether and how DCLK1 plays a metastatic-promoting role in human breast cancer cells.Methods. We used Crispr/Cas9 technology to knock out DCLK1 in breast cancer cell line BT474, which basically possesses DCLK1 at a higher level, and stably overexpressed DCLK1 in another breast cancer cell line, T47D, that basically expresses DCLK1 at a lower level. We further analyzed the alterations of metastatic characteristics and the underlying mechanisms in these cells.Results. It was shown that, compared with the corresponding control cells, DCLK1 overexpression led to an increase in metastatic behaviors including enhanced migration and invasion of T47D cells. By contrast, forced depletion of DCLK1 drastically inhibited these metastatic characteristics in BT474 cells. Mechanistically, the epithelial-mesenchymal transition (EMT) program, which is critical for cancer metastasis, was prominently activated in DCLK1-overexpressing cancer cells, evidenced by a decrease in an epithelial marker ZO-1 and an enhancement in several mesenchymal markers including ZEB1 and Vimentin. In addition, DCLK1 overexpression induced the ERK MAPK pathway, which resultantly enhanced the expression of MT1-MMP that is also involved in cancer metastasis. Knockout of DCLK1 could reverse these events, further supporting a metastatic-promoting role for DCLK1.Conclusions. Collectively, our data suggested that DCLK1 overexpression may be responsible for the increased metastatic features in breast cancer cells. Targeting DCLK1 may become a therapeutic option for breast cancer metastasis.
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Sharma, Rajesh, Zinal Chheda, Venkatakrishna Jala, and Bodduluri Haribabu. "Interactions within the tumor microenvironment imprint metastatic traits in cancer cells (TUM6P.1001)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 141.25. http://dx.doi.org/10.4049/jimmunol.194.supp.141.25.
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Abstract Metastasis accounts for majority of deaths across cancer types. Tumor microenvironment plays an impotant role in enhancing metastatic propensity of cancer cells. To explore the mechanisms, we herein established a model by in vivo passaging the Lewis lung carcinoma (3LL) cells with 1-2 week of culture in between passages. When injected subcutaneously, 3LL cells have minimal metastasis, while in vivo passaged (p-)3LL cells showed robust metastasis. Sorted p-3LL cells from tumors of the whole body RFP transgenic mice were equally metastatic suggesting that cancer cell intrinsic changes are responsible for the metastatic imprinting. To identify the stromal cell population/s that crosstalk and imprint the metastatic traits in cancer cells, in vivo passages were performed in Rag2-/- mice and WT mice depleted of NK cells that resulted in similar metastatic imprinting excluding the role of adaptive immune and NK cells in this process. Depletion studies in WT mice and/or co-culture of 3LL cells with sorted myeloid cells indicated a critical role for CD11b+Gr1dim myeloid cells in metastatic imprinting. Comparison of gene expression profiles between 3LL and p-3LL cells by microarray showed enhanced expression of claudin-9 in p-3LL cells which was validated at protein levels in mouse and human lung cancers. These results indicate that interaction of CD11b+Gr1dim myeloid cells with cancer cell within tumor microenvironment imprints claudin-9 dependent metastatic traits in cancer cells.
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Nakayama, Jun, Yuxuan Han, Yuka Kuroiwa, Kazushi Azuma, Yusuke Yamamoto, and Kentaro Semba. "The In Vivo Selection Method in Breast Cancer Metastasis." International Journal of Molecular Sciences 22, no. 4 (February 14, 2021): 1886. http://dx.doi.org/10.3390/ijms22041886.
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Metastasis is a complex event in cancer progression and causes most deaths from cancer. Repeated transplantation of metastatic cancer cells derived from transplanted murine organs can be used to select the population of highly metastatic cancer cells; this method is called as in vivo selection. The in vivo selection method and highly metastatic cancer cell lines have contributed to reveal the molecular mechanisms of cancer metastasis. Here, we present an overview of the methodology for the in vivo selection method. Recent comparative analysis of the transplantation methods for metastasis have revealed the divergence of metastasis gene signatures. Even cancer cells that metastasize to the same organ show various metastatic cascades and gene expression patterns by changing the transplantation method for the in vivo selection. These findings suggest that the selection of metastasis models for the study of metastasis gene signatures has the potential to influence research results. The study of novel gene signatures that are identified from novel highly metastatic cell lines and patient-derived xenografts (PDXs) will be helpful for understanding the novel mechanisms of metastasis.
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Yachida, Shinichi, and Christine A. Iacobuzio-Donahue. "The Pathology and Genetics of Metastatic Pancreatic Cancer." Archives of Pathology & Laboratory Medicine 133, no. 3 (March 1, 2009): 413–22. http://dx.doi.org/10.5858/133.3.413.
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Abstract Context.—Metastatic disease is the most critical determinant of resectability of pancreatic cancer and accounts for the poor outcome of patients with this disease. Thus, a better understanding of metastatic pancreatic cancer will afford new opportunities for therapeutic intervention. Objective.—To summarize and discuss the current understanding of the clinical and molecular features of metastatic pancreatic cancer. Data Sources.—Published literature on advanced stage pancreatic cancer, pancreatic cancer metastasis, and autopsy findings in patients with pancreatic cancer. Conclusions.—In the clinical setting, it can be difficult to distinguish a metastatic pancreatic carcinoma from primary neoplasms in the liver, lung, or ovary. However, immunolabeling for DPC4 protein as part of a diagnostic panel is useful for making this distinction. Emerging data from a variety of investigators now indicate that overexpression of EphA2, loss of DPC4 and MKK4, and aberrant activation of the Hedgehog signaling pathway are associated with metastatic propensity of pancreatic cancers, providing novel therapeutic targets for the most lethal stage of this disease.
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Faltermeier, Claire M., Justin M. Drake, Peter M. Clark, Bryan A. Smith, Yang Zong, Carmen Volpe, Colleen Mathis, et al. "Functional screen identifies kinases driving prostate cancer visceral and bone metastasis." Proceedings of the National Academy of Sciences 113, no. 2 (November 30, 2015): E172—E181. http://dx.doi.org/10.1073/pnas.1521674112.
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Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention.
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Zarin, Bahare, Laleh Rafiee, Parnaz Daneshpajouhnejad, and Shaghayegh Haghjooy Javanmard. "A review on the role of CAFs and CAF-derived exosomes in progression and metastasis of digestive system cancers." Tumor Biology 43, no. 1 (August 18, 2021): 141–57. http://dx.doi.org/10.3233/tub-200075.
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Cancers evolve as a result of the accelerated proliferation of cancer cells in a complicated, enriched, and active microenvironment. Tumor microenvironment (TME) components are the master regulators of any step of cancer development. The tumor microenvironment is composed of many cellular and noncellular components that contribute to the evolution of cancer cells. Cancer-associated fibroblasts (CAFs) are activated fibroblasts in the TME that implicate in tumor progression and metastasis dissemination through secretion of oncogenic factors which are carried to the secondary metastatic sites through exosomes. In this review, we aimed to assess the role of CAF-derived exosomes in TME construction and pre-metastatic niche formation in different cancers of the digestive system in order to better understand some important mechanisms of metastasis and provide possible targets for clinical intervention. This review article is divided into two thematic parts explaining the general mechanisms of pre-metastatic niche formation and metastasis and the role of CAF-derived exosomes in different digestive system cancers including colorectal, gastric, esophageal, pancreatic, and liver cancers.
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Adachi, Y., H. Yamamoto, F. Itoh, Y. Hinoda, Y. Okada, and K. Imai. "Contribution of matrilysin (MMP-7) to the metastatic pathway of human colorectal cancers." Gut 45, no. 2 (August 1, 1999): 252–58. http://dx.doi.org/10.1136/gut.45.2.252.
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BACKGROUND/AIMMatrilysin is one of the matrix metalloproteinases that has a critical role in tumour invasion, and is often expressed in gastrointestinal cancers. The aim of this study was to examine the role of matrilysin in metastasis of human colorectal cancers.PATIENTS (SUBJECTS)/METHODSThe relation between matrilysin expression and Dukes’s type was investigated immunohistochemically in 83 surgically resected colorectal cancers, including five with liver metastasis. Moreover, the effects of matrilysin on the in vivo invasive and metastatic potential of colon cancer cells transfected with matrilysin cDNA were examined after subcutaneous injection into SCID mice.RESULTSIn 46% of primary and all of metastatic liver tumours, over 10% of cancer cells were stained positively for matrilysin. The expression of matrilysin correlated significantly with the presence of nodal or distant metastases (p<0.05). In addition, matrilysin transfectants formed invasive tumours and multiple liver metastases in SCID mice, without producing any significant difference in the subcutaneous tumour growth from mock transfectants. Casein zymography showed that the invading and metastasised tumours showed conspicuous matrilysin activity, which correlated with the number of metastatic lesions (p<0.001).CONCLUSIONSMatrilysin showed a correlation with metastasis in a cohort of 83 colorectal cancer patients and marked metastatic potentiation in human colorectal cancer xenografts, indicating that it may play a critical role in the metastatic pathway of colorectal cancers.
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Werner-Klein, Melanie. "Abstract IA024: Cellular plasticity during metastatic colony formation in patients." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): IA024. http://dx.doi.org/10.1158/1538-7445.metastasis22-ia024.
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Abstract Systemic cancer spread is a process whose complexity is only poorly understood. We have learned over the past years that metastatic dissemination starts very early in the evolution of a malignant clone of most cancers and that disseminated cancer cells (DCC) continue to acquire genomic alterations at the distant site. Consequently, it seems plausible that cellular phenotypes change during metastatic colony formation as well, although the impact of genotype changes on the cellular phenotypes is not clear at all. We studied this process in malignant melanoma, exploiting the unique chance that routine sentinel lymph node (SLN) biopsies provide for a cancer that is diagnosed much earlier and at smaller size than most other cancers. Moreover, mouse models suggest that lymph nodes serve as exit routes for systemic dissemination of cancer cells and that their colonization indues tumor-immune tolerance promoting distal metastasis. Melanoma DCC enter SLNs and may or may not give rise to a metastatic colony. We therefore first assessed in a large patient cohort comprising more than 500 early-stage melanoma patients, which melanoma marker is best suited to identify candidate metastasis founder cells and then progressed to provide their detailed molecular characterization. We found that melanoma cellular phenotypes indeed change over metastatic colony formation, indicating that differential molecular stage-specific targeting may be required to prevent metastasis formation. Of note, we observed mechanisms of very early immune suppression via DCC-derived EVs suggesting early DCC must find immune-escape strategies at the metastatic site. Citation Format: Melanie Werner-Klein. Cellular plasticity during metastatic colony formation in patients [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA024.
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Meiliana, Anna, Nurrani Mustika Dewi, and Andi Wijaya. "Targeting Metastatic Cancer: Disseminated Tumor Cells and Premetastatic Niches." Indonesian Biomedical Journal 14, no. 4 (December 1, 2022): 329–48. http://dx.doi.org/10.18585/inabj.v14i4.2035.
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BACKGROUND: Metastases are simply known as cancers spread to another part of the body, and often be responsible for the severity of cancer prognosis. Somehow, the complex mechanisms of metastases are not fully understood yet.CONTENT: The characteristic of cancer is akin to a never-healing wound. Cancer cells are plastic and dynamic as they build their niches and developed into metastases, even when they seem dormant. Therefore, cancer cells can survive the immune system. Recent research has shown the distinct biology of metastasis-initiating cell, which leads to tumor development in distant organs, immune surveillance evasion, and co-option of metastatic micro-environments. Effective cancer therapies must consider the regenerative states of metastatic malignancies and have careful observation of patient phenotypes.SUMMARY: This review aimed to provide an insight on genesis and characteristics of metastases, starting from its seeding and dormancy, until the advance phase. Thus, developing therapy for cancer metastases should not start as it grows, but even as earlier strategies since the primary tumor was detected.KEYWORDS: cancer metastasis, DTC, CTC, CSC, dormancy, pre-metastatic niche, plasticity
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Achariyapota, Vuthinun, Tuenjai Chuangsuwanich, and Mongkol Benjapibal. "Inflammatory Breast Cancer from Metastatic Ovarian Cancer." Case Reports in Obstetrics and Gynecology 2016 (2016): 1–3. http://dx.doi.org/10.1155/2016/3476143.
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Metastases to the breast from tumors other than breast carcinomas are extremely rare and represent only 0.2–1.3% of all diagnosed malignant breast tumors. Furthermore, while the most common sites for advanced ovarian cancer metastases are the liver, lung, and pleura, metastasis to the breast from a primary ovarian cancer is uncommon and has only been reported in 0.03–0.6% of all breast cancers. Here we describe a case report of a 50-year-old female patient with a rare case of breast metastases from an advanced ovarian cancer, presenting as inflammatory breast cancer. Our observations emphasize the clinical importance of distinguishing between primary and metastatic breast cancer during diagnosis for the purpose of appropriate prognosis and treatment.
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Ali, Sheikh Muhammad Ebad, Badaruddin Sahito, Muhammad Amin Chinoy, Ahmed Nadeem Abbasi, and Adil Khatri. "Cord Compression from Bony Metastasis: An Important Quality of Life Issue which can be Resolved by a Spinal MDT Tumor Board." National Journal of Health Sciences 5, no. 3 (March 30, 2021): 92–93. http://dx.doi.org/10.21089/njhs.53.0092.
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Cancer prevalence is increasing over the past few decades. Spinal osseous metastasis is one of the most common sites of secondary neoplastic disease among cancer patients [1]. Spinal malignancies can broadly be classified into primary spinal cancers and secondary spinal metastasis. Metastatic spinal cancers are more common than primary malignancy of the spine. Metastatic spinal cancers are further subdivided into two parts based on the involvement of the dura mater; metastasis external to dura mater can be termed as metastatic epidural spinal cancers (MESC); metastasis inside the dura mater is called metastatic intradural spinal cancers (MISC) [2]. Bony involvements of vertebrae are common at the presentation of MESC while the involvement of the spinal cord and meninges is a prominent feature of MISC. However, the clinical presentation is quite overlapping and timely-decision making is quite challenging in several cases. Several grading systems have been developed to assess the severity of spinal cancers [3-6]. Such ambiguities require a need for teamwork between different specialties to decide the management plan for better patient care. Multidisciplinary Tumor Boards (MDT) are the practical venue where different specialists are present for the discussion [7].
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Warren, Janine, Yuxuan Xiao, and John Lamar. "YAP/TAZ Activation as a Target for Treating Metastatic Cancer." Cancers 10, no. 4 (April 10, 2018): 115. http://dx.doi.org/10.3390/cancers10040115.
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Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses.
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Calvo-Alcañiz, Camilo, Padma S. Rajagopal, Sanju Sinha, Fiorella Schischlik, Antonios Papanicolau-Sengos, Nishanth Ulhas Nair, and Eytan Ruppin. "Abstract 985: Is the transcriptome of primary and metastatic cancers closer to their origin or target tissues." Cancer Research 82, no. 12_Supplement (June 15, 2022): 985. http://dx.doi.org/10.1158/1538-7445.am2022-985.
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Abstract Introduction: Most cancer deaths are caused by metastasis, yet understanding how metastatic cancers adapt from their origin tissues to their target tissues remains a fundamental scientific and clinical challenge. To date, no studies have systematically analyzed the transcriptomic similarity of metastatic cancers to their target tissues in a genome wide manner. Here, we ask if the overall gene expression of primary and metastatic tumors is closer to their tissue of origin or closer to their target tissue? Next, we aim to identify the key pathways in metastatic tumors whose gene expression becomes markedly closer to their target than primary tissue of origin. Methods: We analyzed the expression profiles of: (a) primary tumors of 9 cancer types, which have metastasized to the liver, lung, or brain (TCGA data, n = 306), (b) metastatic tumors of 12 cancer types (MET500 collection, n = 194) and (c) their origin and target normal tissue samples (GTEx, n = 5,663). We computed the similarity (Euclidean distance) between the expression profiles of the tumors (either primary or metastasis) to the mean expression of their corresponding normal tissue of origin and target tissues, termed their transcriptomic distance (TD). For each tumor sample’s expression profile (either primary tumor or metastasis), we compute the ratio of its TD to the tissue of origin over its TD to the target tissue to get its TD ratio. Results: 1) We find that while most primary tumors are more similar to the tissue of origin than to the target tissues, there is a shift in expression patterns in metastatic tumors towards their target. 2) Across cancer types that metastasize to the liver, cell cycle and growth pathways are significantly transcriptomically closer to the tissue of origin; while the expression of pathways related to more specialized liver cellular functions, such as coagulation and bile acid metabolism are becoming significantly closer to the liver. 3) We tested our key findings by analyzing a matched cohort of primary breast cancers and metastasis samples, reassuringly finding that they overall recapitulate the key results emerging from the non-matched analysis. The key pathways altered when metastasizing to four target tissues (liver, lung, ovary, skin) are adipogenesis, fatty acid metabolism, coagulation, xenobiotic metabolism, and bile acid metabolism. Conclusions: Quite surprisingly, this the first systematic analysis comparing the landscape of primary and metastatic transcriptional alterations of the same cancer type, providing a genome wide view of how cancers adapt to new environments during metastasis. The systematic identification of the specific pathways whose expression shifts towards the target tissues in metastatic tumors provides important leads to their potential targeting. Citation Format: Camilo Calvo-Alcañiz, Padma S. Rajagopal, Sanju Sinha, Fiorella Schischlik, Antonios Papanicolau-Sengos, Nishanth Ulhas Nair, Eytan Ruppin. Is the transcriptome of primary and metastatic cancers closer to their origin or target tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 985.
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Nizam, Amanda, Donald L. Trump, and Jeanny B. Aragon-Ching. "Molecular characterization of brain metastases in patients with metastatic urothelial cancer." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 509. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.509.
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509 Background: Urothelial cancers are the 6th most common cause of all new cancer cases in 2017. Metastatic disease to the brain is rare but has a poor prognosis. There is little information regarding the phenotypic and molecular characteristics of urothelial cancers involving the brain. We sought to evaluate the clinical and tumor molecular characteristics in patients with metastatic urothelial cancer to the brain. Methods: In a single institution retrospective chart review, 48 patients were found to have metastatic bladder cancer from 2006 to 2015, 4 had brain metastases. The demographics, stage, phenotypic characteristics and molecular characteristics using Oncomine, a cancer microarray platform targeting 143 cancer genes, was determined. Results: Of the 4 patients identified with metastatic brain urothelial cancer, 3 were men. 2 had both upper tract and bladder urothelial cancers and 2 had bladder cancer alone. 3 had prior nephroureterectomy and/or radical cystectomy initially and had subsequent development of initial distant metastases at a median of 7.9 months, and time between the first to brain metastases at a median onset of 11.8 months. Median overall survival (OS) was short upon diagnosis of brain metastasis with a median OS of 119 days (range: 96 – 391 days) from the time of brain metastasis diagnosis. All received surgical resection followed by radiation for brain metastases. Three patients had brain tumor examined for comprehensive somatic tumor profiling using the Oncomine panel. Results showed APC mutation in patient 1, loss of TP53, BRCA-2 loss of function mutation with MSH2 deletion in patient 2, as well as FGFR3 gene mutation and TP53 mutation in patient 3. All patients received prior platinum-based systemic therapy with additional FGFR3-therapy for patient 3 and atezolizumab for patient 4. Conclusions: Metastatic brain urothelial cancers are rare events with a uniformly poor prognosis. The role for targeted therapy and immunotherapy is still evolving.
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Khan, Shaheena, Jennifer L. Taylor, and Carrie W. Rinker-Schaeffer. "Disrupting Ovarian Cancer Metastatic Colonization: Insights from Metastasis Suppressor Studies." Journal of Oncology 2010 (2010): 1–7. http://dx.doi.org/10.1155/2010/286925.
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Ovarian cancer affects approximately 25,000 women in the United States each year and remains one of the most lethal female malignancies. A standard approach to therapy is surgical cytoreduction, after which the remaining microscopic residual disease is treated with chemotherapy. The vast majority of patients have disease recurrence, underscoring the crucial need for approaches to control the regrowth, or colonization, of tissues after local treatment. Improved therapies require mechanistic information about the process of metastatic colonization, the final step in metastasis, in which cancer cells undergo progressive growth at secondary sites. Studies of metastasis suppressors are providing insights into events controlling metastatic colonization. This paper reviews our laboratory's approach to the identification, characterization, and functional testing of the JNKK1/MKK4 metastasis suppressor in ovarian cancer metastatic colonization. Specifically, we demonstrate that interaction of ovarian caner cells with the omental microenvironment activates JNKK1/MKK4 resulting in decreased proliferation without affecting apoptosis. The potential role of the omental microenvironment, specifically milky spot structures, is also described. It is our goal to provide this work as a usable paradigm that will enable others to study metastasis suppressors in clinical and experimental ovarian cancer metastases.
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Park, Eun Jung, and Seung Hyuk Baik. "Surgical treatment for metastatic colorectal cancer." Journal of the Korean Medical Association 65, no. 9 (September 10, 2022): 568–76. http://dx.doi.org/10.5124/jkma.2022.65.9.568.
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Background: Stage IV colorectal cancer (CRC) exhibits heterogeneous characteristics in tumor extent and biology. The overall survival of patients with metastatic CRC has improved with the development of multimodal treatments and new chemotherapeutic drugs.Current Concepts: Resection of metastatic CRC is performed for liver, lung, or peritoneal metastases. Conversion surgeries to resect oligometastatic lesions have been developed with tumor regression using chemotherapeutic agents. Two-stage hepatectomy has extended the surgical indications for patients with metastatic CRC. Synchronous liver and primary tumor resection can be considered in patients with adequate conditions. Local ablation with radiotherapy can be used to treat lung metastasis. Meanwhile, for treating patients with CRC with peritoneal metastasis, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy can be considered. Surgical treatments should be performed in patients with symptomatic primary tumors with unresectable metastasis. However, in recent studies, primary tumor resection in patients with asymptomatic CRC with synchronous, unresectable metastases did not show overall survival benefits.Discussion and Conclusion: The treatment of metastatic CRC is challenging because of the variable tumor extent and heterogenous characteristics. Tailored surgical treatments and multidisciplinary approaches may improve the survival and quality of life of patients with metastatic CRC.
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Ebert, Matthias P. A., Jun Yu, Juliane Hoffmann, Alba Rocco, Christoph Röcken, Sabine Kahmann, Oliver Müller, Murray Korc, Joseph J. Sung, and Peter Malfertheiner. "Loss of Beta-Catenin Expression in Metastatic Gastric Cancer." Journal of Clinical Oncology 21, no. 9 (May 1, 2003): 1708–14. http://dx.doi.org/10.1200/jco.2003.10.017.
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Purpose: Beta-catenin (β-catenin) participates in intercellular adhesion and is an integral part of the Wnt signaling pathway. The role of β-catenin in the pathogenesis of gastric cancer and its metastasis is largely unknown. Patients and Methods: Immunohistochemistry and Western blot analysis were used to analyze the expression of β-catenin in 87 human gastric cancers, in metastasis and cancer cell lines. The β-catenin and the adenomatous polyposis coli (APC) genes were analyzed for gene mutations. Furthermore, methylation of the β-catenin promoter in cell lines was assessed by treatment with 5′-azadeoxycytidine and sodium bisulfite genomic sequencing. Results: β-Catenin expression was present at either the cell membrane or the cytoplasm in 34 of 75 primary gastric cancers. Expression of β-catenin was significantly more frequent in intestinal-type (P = .0049) and well-differentiated gastric cancers (P < .001). There were no quantitative differences between gastric cancers and the nonmalignant gastric tissues, as determined by Western blot analysis. One of 18 metastatic cancer lesions and four of five gastric cancer cell lines expressed β-catenin protein. N87 cells, derived from the liver metastasis of a gastric cancer, did not express β-catenin. Treatment with 5′-azadeoxycytidine restored β-catenin protein levels in this cell line, which exhibited significantly more 5-methylcytosines in the β-catenin promoter compared with the other cell lines. Conclusion: β-Catenin expression is lost in a subgroup of primary gastric cancers, is frequently absent in metastases, and exhibits nuclear localization in cancers with either β-catenin or APC gene mutations. Interestingly, the loss of β-catenin expression in metastatic gastric cancers may result from hypermethylation of the β-catenin promoter.
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Winkler, Juliane, Weilun Tan, Angela O. Pisco, Andrei Goga, Spyros Darmanis, and Zena Werb. "Abstract 964: Tumor cell plasticity promotes metastasis across heterogeneous tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 964. http://dx.doi.org/10.1158/1538-7445.am2022-964.
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Abstract Metastasis, the growth of secondary tumors in distant organs, is the major cause of cancer-related deaths due to insufficient therapeutic effects of conventional treatment. Individual tumor cells exhibit heterogeneous features and growth potentials within the same tumor that may influence metastasis formation. During the metastatic cascade, tumor cells adapt their phenotype to various microenvironments that are distinct from their original site resulting in heterogeneous metastatic cells that often are resistant to conventional treatment. The underlying mechanisms of why some tumor cells can give rise to metastases, whereas others cannot are remarkably poorly understood. We established patient-derived xenograft (PDX) models of breast cancer with different metastatic potential and preserved tumor heterogeneity. We analyzed the intrinsic cellular programs of individual tumor cells that influence the metastatic potential of breast cancers using different single-cell RNA-sequencing protocols (MULTI-Seq and Smart-Seq2). Using gene expression profiling of matched primary tumor and metastatic cells of 13 human breast cancers, we demonstrated that while human tumors showed profound inter-patient heterogeneity, they also shared signatures of differentially expressed genes between primary tumor and metastatic cells. Tumors with similar metastatic capabilities shared similar signatures, suggesting potential targets to directly treat metastasis. Additionally, we found that the plasticity of tumor cells is a common feature across tumors that is beneficial for the formation of metastasis. Tumors with higher levels of plastic tumor cells have a greater ability to form metastases. Moreover, we identified a subset of tumor cells expressing both markers of epithelial and mesenchymal characteristics, demonstrating in-vivo evidence for tumor epithelial-mesenchymal plasticity (EMP) in the metastatic cascade. The EMP is a continuum of states with epithelial and mesenchymal cell states as the two extremes of this continuum. The identified transition cells express distinct markers suggesting that these cells may represent a novel and overlooked cell type within the EMP continuum. Given the importance of tumor plasticity in the metastatic cascade, inhibiting the subset of tumor cells that are currently undergoing EMP may represent a novel treatment strategy for metastasis. Citation Format: Juliane Winkler, Weilun Tan, Angela O. Pisco, Andrei Goga, Spyros Darmanis, Zena Werb. Tumor cell plasticity promotes metastasis across heterogeneous tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 964.
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Danolić, Damir, Luka Marcelić, Ilija Alvir, Ivica Mamić, Lucija Šušnjar, Zrinka Rendić-Miočević, and Mario Puljiz. "Rare case of invasive lobular breast cancer metastasis to the endometrium." Libri Oncologici Croatian Journal of Oncology 48, no. 2-3 (December 21, 2020): 116–18. http://dx.doi.org/10.20471/lo.2020.48.02-03.19.
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Metastases to the female genital tract from extra-genital primary cancers are uncommon and usually occur during widespread metastatic disease. Breast cancers are the most frequent primaries, predominantly the lobular type. Here, we report a case of a 55-year-old woman with breast cancer endometrial metastasis who presented with postmenopausal vaginal bleeding. We highlight the importance of endometrial sampling to confirm the diagnosis and distinguish primary from metastatic cancer of the endometrium since the treatment and prognosis of these conditions are entirely different.
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Gerbec, Zachary J., Antonio Serapio-Palacios, Sarah E. Woodword, Jorge Pena Diaz, Brett Finlay, and Shoukat Dedhar. "Abstract A047: Tumor-derived bacteria drive breast cancer metastasis." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): A047. http://dx.doi.org/10.1158/1538-7445.metastasis22-a047.
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Abstract Metastasis is a major barrier to long-term survival and therapeutic options for aggressive, metastatic forms of breast cancer remain limited. Studies using patient samples have identified tumor-resident bacteria that preferentially associate with specific breast cancer types including highly aggressive TNBC. However, it is not yet understood how intratumoral bacteria directly contributes to disease progression and metastatic propensity independent of other prognostic factors. It is therefore the goal of the Dedhar and Finlay labs to identify how specific bacteria within metastatic breast cancer control immune and tumor cell functions to regulate metastatic potential and determine the outcome of disease progression. Using the syngenic, immunocompetent 4T1 and 67NR breast cancer models of metastatic and non-metastatic disease, we found microbiome depletion significantly reduces primary tumor growth highly metastatic 4T1 tumors specifically. We also found bacterial depletion reduces metastatic burden and extends survival time compared to microbiome-replete controls. Along with alterations in disease progression, microbiome depletion induces changes in immune cell function that occur specifically in the metastatic 4T1 tumors, revealing differential microbial-based regulation of metastatic versus non-metastatic disease. To identify bacteria that control metastasis in microbiome-replete controls, we plated surgically resected tumor suspensions on bacterial growth media and compared bacteria from the 4T1 and 67NR primary tumors. We identified several species of the Bacillus genus that were unique to 4T1 tumors and were present both within the primary tumor as well as metastatic nodules. To determine how these bacteria effect disease progression, we designed several in vivo model systems to directly test the ability of the isolated bacteria to promote metastasis. Using an orthotopic inoculation model with 4T1 or EMT6 cells, we found that following intratumoral injection, the 4T1- derived Bacillus species was actually able to augment metastasis when introduced directly back into primary tumors. To determine the specificity of this phenomenon, we then compared the effects of the 4T1 and 67NR-isolated bacteria on metastasis by injecting 4T1 cells that had been co-cultured with either bacteria prior to injection. Interestingly, we found that while the 67NR-derived bacteria had little effect on metastasis, the 4T1-derived Bacillus species significantly enhanced metastatic tumor burden compared to all other groups including those cultured with the 67NR-derived bacteria. These data demonstrate the ability of certain bacteria to promote metastatic disease. Based on these findings, we hypothesize specific bacteria play a causative role in augmenting metastatic propensity, and seek to determine functional differences between intratumoral bacteria to identify mechanistic targets for prevention of metastasis. We also seek to expand this work into clinical models to identify potential prognostic factors as well as mechanistic targets for disease treatment. Citation Format: Zachary J. Gerbec, Antonio Serapio-Palacios, Sarah E. Woodword, Jorge Pena Diaz, Brett Finlay, Shoukat Dedhar. Tumor-derived bacteria drive breast cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A047.
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Park, Hyung Kyu, Joungho Han, Ghee Young Kwon, Min-Kyung Yeo, and Go Eun Bae. "Patterns of Extrathoracic Metastasis in Lung Cancer Patients." Current Oncology 29, no. 11 (November 16, 2022): 8794–801. http://dx.doi.org/10.3390/curroncol29110691.
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Metastasis is a major cause of death in lung cancer patients. Therefore, a deeper understanding of the metastatic mechanisms is important for developing better management strategies for lung cancer patients. This study evaluated the patterns of extrathoracic metastases in lung cancer. We retrieved data for 25,103 lung cancer patients from an institutional database and then evaluated the impacts of clinicopathologic factors on metastasis patterns. We found that 36.5% of patients had extrathoracic metastasis. Younger patients had a significantly higher extrathoracic metastasis rate in most histologic subtypes. Metastases to the bone (58.3%), central nervous system (CNS) (44.3%), liver (26.6%) and adrenal gland (18.3%) accounted for 85.5% of all extrathoracic metastases. Patients with nonmucinous adenocarcinoma had significantly higher bone metastasis rate. Patients with small cell carcinoma and large cell neuroendocrine carcinoma (LCNEC) had significantly higher liver metastasis rates. Further, patients with LCNEC also had a significantly lower bone metastasis rate, and patients with squamous cell carcinoma had a significantly lower CNS metastasis rate. Patients with multiple cancers had similar patterns of metastasis compared to patients with only lung cancer. In conclusion, different histologic subtypes of lung cancer have different metastatic patterns. Our study might help clinicians decide on follow-up strategies.
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Wai Wong, Chee, Danielle E. Dye, and Deirdre R. Coombe. "The Role of Immunoglobulin Superfamily Cell Adhesion Molecules in Cancer Metastasis." International Journal of Cell Biology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/340296.
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Metastasis is a major clinical problem and results in a poor prognosis for most cancers. The metastatic pathway describes the process by which cancer cells give rise to a metastatic lesion in a new tissue or organ. It consists of interconnecting steps all of which must be successfully completed to result in a metastasis. Cell-cell adhesion is a key aspect of many of these steps. Adhesion molecules belonging to the immunoglobulin superfamily (Ig-SF) commonly play a central role in cell-cell adhesion, and a number of these molecules have been associated with cancer progression and a metastatic phenotype. Surprisingly, the contribution of Ig-SF members to metastasis has not received the attention afforded other cell adhesion molecules (CAMs) such as the integrins. Here we examine the steps in the metastatic pathway focusing on how the Ig-SF members, melanoma cell adhesion molecule (MCAM), L1CAM, neural CAM (NCAM), leukocyte CAM (ALCAM), intercellular CAM-1 (ICAM-1) and platelet endothelial CAM-1 (PECAM-1) could play a role. Although much remains to be understood, this review aims to raise the profile of Ig-SF members in metastasis formation and prompt further research that could lead to useful clinical outcomes.
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Robinson, Nathaniel J., Chevaun D. Morrison-Smith, Alex J. Gooding, Barbara J. Schiemann, Mark W. Jackson, Derek J. Taylor, and William P. Schiemann. "SLX4IP and telomere dynamics dictate breast cancer metastasis and therapeutic responsiveness." Life Science Alliance 3, no. 4 (February 18, 2020): e201900427. http://dx.doi.org/10.26508/lsa.201900427.
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Metastasis is the leading cause of breast cancer-related death and poses a substantial clinical burden owing to a paucity of targeted treatment options. The clinical manifestations of metastasis occur years-to-decades after initial diagnosis and treatment because disseminated tumor cells readily evade detection and resist therapy, ultimately giving rise to recurrent disease. Using an unbiased genetic screen, we identified SLX4-interacting protein (SLX4IP) as a regulator of metastatic recurrence and established its relationship in governing telomere maintenance mechanisms (TMMs). Inactivation of SLX4IP suppressed alternative lengthening of telomeres (ALT), coinciding with activation of telomerase. Importantly, TMM selection dramatically influenced metastatic progression and survival of patients with genetically distinct breast cancer subtypes. Notably, pharmacologic and genetic modulation of TMMs elicited telomere-dependent cell death and prevented disease recurrence by disseminated tumor cells. This study illuminates SLX4IP as a potential predictive biomarker for breast cancer progression and metastatic relapse. SLX4IP expression correlates with TMM identity, which also carries prognostic value and informs treatment selection, thereby revealing new inroads into combating metastatic breast cancers.
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Ganesh, Karuna. "Abstract IA015: Combined single cell atlasing and organoid modeling reveal progressive plasticity during human colorectal cancer metastasis." Cancer Research 82, no. 23_Supplement_1 (December 1, 2022): IA015. http://dx.doi.org/10.1158/1538-7445.crc22-ia015.
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Abstract Metastatic cancers invariably relapse due to the emergence of therapy resistant subclones that are capable of self-renewal, slow cell-cycling, tumor re-initiation and therapy resistance. However, the molecular mechanisms that underpin the phenotypic plasticity of metastasis stem cells, their relationship to tumor initiating cancer stem cells and macrometastasis, and the co-evolution of the immune response to dynamically emerging tumor regenerative states are not understood. We are adopting a patient-derived functional biospecimen approach combining (1) hypothesis-generation using transcriptomics, epigenomics and spatial/histological analysis of patient samples of primary and metastatic gastrointestinal (GI) cancer with (2) mechanistic dissection in cutting-edge patient-derived organoid models, including co-cultures with immune/stromal cells, and (3) genetically engineered and orthotopic transplantation models of metastatic GI cancer. By profiling, lineage tracing and genetically interrogating the evolving transcriptomic and chromatin landscapes of regenerative metastatic states, we are defining the molecular mechanisms that underpin the phenotypic plasticity of metastatic cancer, and the co-evolution of the tumor microenvironmental response to dynamically emerging tumor regenerative states. Our approach is unveiling crucial signaling nodes required for metastatic plasticity that can be therapeutically targeted to improve outcomes for patients with advanced cancer. Citation Format: Karuna Ganesh. Combined single cell atlasing and organoid modeling reveal progressive plasticity during human colorectal cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA015.
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Polynovskiy, A., D. Kuz'michev, Z. Mamedli, Sergey Tkachev, M. Chernich, Yu Suraeva, J. Madyarov, A. Aniskin, and E. Kolobanova. "Successful Case of Treatment the Patient with Synchronous Rectal and Sigmoid Cancers and Synchronous Lung Metastasis." Medical Radiology and radiation safety 66, no. 3 (July 20, 2021): 76–81. http://dx.doi.org/10.12737/1024-6177-2021-66-3-76-81.
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Colorectal cancers (CRC) takes the leading position in the incidence of morbidity and mortality worldwide. Metastatic CRC in the primary diagnosis ranges from 15 to 35 %. Lung metastasis are the most frequent extraperitoneal manifestation of the metastatic process. Such patients are relatively rare and there are no clear recommendations for their treatment tactics to date. This clinical case describes a successful strategy of using preoperative prolonged chemoradiotherapy on a primary tumor and stereotactic irradiation of lung metastasis, with courses of chemotherapy, with further radical laparoscopic operation, in a patient with disseminated primary multiple rectal cancer, synchronous sigmoid colon cancer and 2 metastatic focuses in both lungs.
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Qian, Bin-Zhi, Hui Zhang, Jiufeng Li, Tianfang He, Eun-Jin Yeo, Daniel Y. H. Soong, Neil O. Carragher, et al. "FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis." Journal of Experimental Medicine 212, no. 9 (August 10, 2015): 1433–48. http://dx.doi.org/10.1084/jem.20141555.
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Although the link between inflammation and cancer initiation is well established, its role in metastatic diseases, the primary cause of cancer deaths, has been poorly explored. Our previous studies identified a population of metastasis-associated macrophages (MAMs) recruited to the lung that promote tumor cell seeding and growth. Here we show that FMS-like tyrosine kinase 1 (Flt1, also known as VEGFR1) labels a subset of macrophages in human breast cancers that are significantly enriched in metastatic sites. In mouse models of breast cancer pulmonary metastasis, MAMs uniquely express FLT1. Using several genetic models, we show that macrophage FLT1 signaling is critical for metastasis. FLT1 inhibition does not affect MAM recruitment to metastatic lesions but regulates a set of inflammatory response genes, including colony-stimulating factor 1 (CSF1), a central regulator of macrophage biology. Using a gain-of-function approach, we show that CSF1-mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity of FLT1-inhibited MAMs. Thus, CSF1 is epistatic to FLT1, establishing a link between FLT1 and inflammatory responses within breast tumor metastases. Importantly, FLT1 inhibition reduces tumor metastatic efficiency even after initial seeding, suggesting that these pathways represent therapeutic targets in metastatic disease.
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Sepúlveda, Luis, Tiago Gorgal, Vanessa Pires, and Filipe Rodrigues. "Prostate Cancer Metastatic to the Cervical Lymph Nodes." Case Reports in Urology 2015 (2015): 1–4. http://dx.doi.org/10.1155/2015/263978.
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Prostate cancer is the most common cancer in men, often presenting with regional lymph node or bone metastasis and rarely with supradiaphragmatic lymph node involvement. Most metastatic cancers involving the cervical lymph nodes are from cancers of the upper aerodigestive tract. In this report, we describe two cases with cervical lymph node enlargement due to metastatic prostate cancer as the initial clinical presentation: a 43-year-old male, initially misdiagnosed with a tumor of the upper aerodigestive tract and an 87-year-old male with right lobe pneumonia and cervical lymph node enlargement, initially attributed to be an acute inflammatory lymph node reaction. To the best of our knowledge, there are less than 50 cases reported in the literature of adenocarcinoma of prostate metastatic to the cervical lymph nodes and only one case presenting in men younger than 45 years. The authors intend to highlight the importance of digital rectal exam and PSA test in case of persistent left cervical lymph node enlargement, including men younger than 45 years of age.
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Bodogai, Monica, Purevdorj Olkhanud, Yrina Rochman, Enkhzol Malchinkhuu, Katarzyna Wejksza, Ronald Gress, Charles Hesdorffer, Warren Leonard, and Arya Biragyn. "Thymic stromal lymphopoietin mediates breast cancer progression and metastasis (48.9)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 48.9. http://dx.doi.org/10.4049/jimmunol.186.supp.48.9.
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Abstract Breast cancer escape and metastasis is an active process that requires inflammation and participation of immune cells. We have previously reported that this is a primary tumor-controlled process which activates lungs to produce CCL17 and CCL22 to facilitate lung metastasis together with the recruitment of CCR4+ regulatory T cells (Tregs). To understand the mechanism of this process, we performed expression array analysis in both metastatic and non-metastatic cancer cells and found that metastatic cells produced thymic stromal lymphopoietin (TSLP), an IL-7-like type 1 inflammatory cytokine that is often associated with the induction of Th2-type allergic responses in the lungs. Moreover, TSLP was also abundantly expressed in variety of human solid tumors, including breast, lung, colon and ovarian cancers. To gain further insights into the role of TSLP in cancer progression, we have blocked TSLP expression in cancer cells and found that TSLP is required for efficient breast cancer escape and metastasis. Moreover, utilizing adoptive transfer studies in TSLPR deficient mice, we demonstrated that by targeting CD4+ T cells to induce Th2-type inflammatory responses, cancer-produced TSLP promoted cancer escape. Taken together, our data indicate that TSLP is an important factor that needs to be controlled to effectively combat with cancer escape.
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Sasaki, Ryo, Mitsuhiko Osaki, and Futoshi Okada. "MicroRNA-Based Diagnosis and Treatment of Metastatic Human Osteosarcoma." Cancers 11, no. 4 (April 18, 2019): 553. http://dx.doi.org/10.3390/cancers11040553.
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Osteosarcoma is a malignant tumor of the bones that commonly occurs in young individuals. The 5-year survival rate of osteosarcoma patients is 60–70%. Metastasis to the lungs leads to death in 30–40% of osteosarcoma patients. Therefore, the development of effective strategies for early detection and treatment of this disease are important to improve the survival of osteosarcoma patients. However, metastatic markers for osteosarcoma and molecules that might be targeted for the treatment of metastatic osteosarcoma have not been identified yet. Therefore, the mechanism of metastasis to the lungs needs to be explored from a novel viewpoint. Recently, the aberrant expression of microRNAs (miRNAs) has been reported to be involved in the carcinogenesis and cancer progression of many cancers. Furthermore, miRNAs in the blood have been reported to show an aberrant expression unique to several cancers. Therefore, miRNAs are gaining attention as potential diagnostic markers for cancers. On the other hand, normalizing the dysregulated expression of miRNAs in cancer cells has been shown to alter the phenotype of cancer cells, and thus treatment strategies targeting miRNAs are also being considered. This review summarizes the abnormality of miRNA expression associated with the metastasis of osteosarcoma and describes the present situation and issues regarding the early diagnosis and development of treatment strategies for metastatic osteosarcoma based on the current understanding of this disease.
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Williams, Carly B., Kendall Phelps-Polirer, Ivan P. Dingle, Christina J. Williams, Matthew J. Rhett, Scott T. Eblen, Kent Armeson, Elizabeth G. Hill, and Elizabeth S. Yeh. "HUNK phosphorylates EGFR to regulate breast cancer metastasis." Oncogene 39, no. 5 (October 9, 2019): 1112–24. http://dx.doi.org/10.1038/s41388-019-1046-5.
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Abstract Epidermal growth factor receptor (EGFR) is commonly over-expressed in metastatic breast cancer yet metastatic breast cancer is generally resistant to anti-EGFR therapies, and the mechanism for resistance to EGFR inhibitors in this setting is not fully understood. Hormonally up-regulated neu-associated kinase (HUNK) kinase is up-regulated in aggressive breast cancers and is thought to play a role in breast cancer metastasis. However, no studies have been conducted to examine a relationship between EGFR and HUNK in breast cancer metastasis. We performed a kinase substrate screen and identified that EGFR is phosphorylated by HUNK. Our studies show that HUNK phosphorylates EGFR at T654, enhancing receptor stability and downstream signaling. We found that increased phosphorylation of T654 EGFR correlates with increased epithelial to mesenchymal, migration and invasion, and metastasis. In addition, we found that HUNK expression correlates with overall survival and distant metastasis free survival. This study shows that HUNK directly phosphorylates EGFR at T654 to promote metastasis and is the first study to show that the phosphorylation of this site in EGFR regulates metastasis.
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Chernosky, Noah M., and Ilaria Tamagno. "The Role of the Innate Immune System in Cancer Dormancy and Relapse." Cancers 13, no. 22 (November 10, 2021): 5621. http://dx.doi.org/10.3390/cancers13225621.
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Metastatic spread and recurrence are intimately linked to therapy failure, which remains an overarching clinical challenge for patients with cancer. Cancer cells often disseminate early in the disease process and can remain dormant for years or decades before re-emerging as metastatic disease, often after successful treatment. The interactions of dormant cancer cells and their metastatic niche, comprised of various stromal and immune cells, can determine the length of time that cancer cells remain dormant, as well as when they reactivate. New studies are defining how innate immune cells in the primary tumor may be corrupted to help facilitate many aspects of dissemination and re-emergence from a dormant state. Although the scientific literature has partially shed light on the drivers of immune escape in cancer, the specific mechanisms regulating metastasis and dormancy in the context of anti-tumor immunity are still mostly unknown. This review follows the journey of metastatic cells from dissemination to dormancy and the onset of metastatic outgrowth and recurrent tumor development, with emphasis on the role of the innate immune system. To this end, further research identifying how immune cells interact with cancer cells at each step of cancer progression will pave the way for new therapies that target the reactivation of dormant cancer cells into recurrent, metastatic cancers.
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Ahrenfeldt, Johanne, Ditte S. Christensen, Mateo Sokač, Judit Kisistók, Nicholas McGranahan, and Nicolai J. Birkbak. "Computational Analysis Reveals the Temporal Acquisition of Pathway Alterations during the Evolution of Cancer." Cancers 14, no. 23 (November 25, 2022): 5817. http://dx.doi.org/10.3390/cancers14235817.
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Cancer metastasis is the lethal developmental step in cancer, responsible for the majority of cancer deaths. To metastasise, cancer cells must acquire the ability to disseminate systemically and to escape an activated immune response. Here, we endeavoured to investigate if metastatic dissemination reflects acquisition of genomic traits that are selected for. We acquired mutation and copy number data from 8332 tumours representing 19 cancer types acquired from The Cancer Genome Atlas and the Hartwig Medical Foundation. A total of 827,344 non-synonymous mutations across 8332 tumour samples representing 19 cancer types were timed as early or late relative to copy number alterations, and potential driver events were annotated. We found that metastatic cancers had a significantly higher proportion of clonal mutations and a general enrichment of early mutations in p53 and RTK/KRAS pathways. However, while individual pathways demonstrated a clear time-separated preference for specific events, the relative timing did not vary between primary and metastatic cancers. These results indicate that the selective pressure that drives cancer development does not change dramatically between primary and metastatic cancer on a genomic level, and is mainly focused on alterations that increase proliferation.
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Karlow, Jennifer A., Siddhartha Devarakonda, Xiaoyun Xing, Hyo Sik Jang, Ramaswamy Govindan, Mark Watson, and Ting Wang. "Developmental Pathways Are Epigenetically Reprogrammed during Lung Cancer Brain Metastasis." Cancer Research 82, no. 15 (June 15, 2022): 2692–703. http://dx.doi.org/10.1158/0008-5472.can-21-4160.
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Abstract Non–small cell lung cancer (NSCLC) is one of the most commonly diagnosed and deadliest cancers worldwide, with roughly half of all patients initially presenting with both primary and metastatic disease. While the major events in the metastatic cascade have been identified, a mechanistic understanding of how NSCLC routinely and successfully colonizes the brain is largely unknown. Recent studies have begun demonstrating the role of epigenetic misregulation during tumorigenesis and metastasis, including widespread changes in DNA methylation and histone modifications. To better understand the role of altered DNA methylation in NSCLC metastasis to the brain, we measured DNA methylation during disease progression for 12 patients, globally profiling the methylation status of normal lung, primary lung tumor, and brain metastasis samples. The variation in methylation was similar during metastatic spread and primary tumorigenesis but less coordinated across genomic features during metastasis. The greatest recurrent changes during metastatic progression were methylation gains in DNA methylation valleys (DMV) harboring the constitutive heterochromatin mark H3K9me3 as well as bivalent marks H3K27me3 and H3K4me1. In a lymph node–derived cancer cell line, EZH2 binding within DMVs was lost, accompanied by an increase in DNA methylation, exemplifying epigenetic switching. The vast majority of the differentially methylated region–associated DMVs harbored developmental genes, suggesting that altered epigenetic regulation of developmentally important genes may confer a selective advantage during metastatic progression. The characterization of epigenetic changes during NSCLC brain metastasis identified recurrent methylation patterns that may be prognostic biomarkers and contributors to disease progression. Significance: Altered DNA methylation in lung cancer brain metastases corresponds with loss of EZH2 occupancy at developmental genes, which could promote stem-like phenotypes permissive of dissemination and survival in different microenvironments.
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Moore, Nicole M., and Larry A. Nagahara. "Physical Biology in Cancer. 1. Cellular physics of cancer metastasis." American Journal of Physiology-Cell Physiology 306, no. 2 (January 15, 2014): C78—C79. http://dx.doi.org/10.1152/ajpcell.00292.2013.
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One of the major challenges in cancer research today is developing new therapeutic strategies to control metastatic disease, the spread of cancer cells from a primary tumor to seed in a distant site. Advances in diagnosis and treatment options have increased the survival rate for most patients with local tumors; however, less progress has been made in treatment of disseminated disease. According to the SEER Cancer Statistics Review, 1975–2010, in the case of breast and prostate cancers, only one in four patients diagnosed with distant metastatic disease will survive more than five years. Current research efforts largely focus on identifying biological targets, such as specific genes and signaling pathways that drive two key steps of metastasis, invasion from the primary tumor and growth in the secondary site. On the other hand, there are phenotypic traits and dynamics in the metastatic process that are not encoded by single genes or signaling pathways but, rather, a larger system of events and biophysical characteristics. Connecting genomic and pathway investigations with quantitative physical phenotypic characteristics of cells, the physical microenvironment, and the physical spatiotemporal interactions of the metastatic process provides a stronger complementary understanding of the disease.
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Lin, Yu-Chun, and Dong-Qing Chin. "Suppressions of metastatic breast cancer invasion and metastasis to brain/cross talk HER2/ERK1/2/MMP-9 signaling pathway." American Journal of BioMedicine 4, no. 2 (June 29, 2016): 227–39. http://dx.doi.org/10.18081/2333-5106/016-227-239.
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Understanding the molecular pathways that contribute to the development of metastatic breast cancer invasion and metastasis to brain is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized therapy based on tumor-specific mutations. Little is known about the clinical significance of HER2/ERK1/2/MMP-9 signaling pathway in breast cancer. We performed Global exon array to study the expression of ERK1/2/MMP-9 signaling pathway in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of ERK1/2/MMP-9 proteins in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells.
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Lin, Yu-Chun, and Dong-Qing Chin. "Suppressions of metastatic breast cancer invasion and metastasis to brain/cross talk HER2/ERK1/2/MMP-9 signaling pathway." American Journal of BioMedicine 6, no. 4 (December 15, 2018): 349–61. http://dx.doi.org/10.18081/2333-5106/018-349-361.
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Understanding the molecular pathways that contribute to the development of metastatic breast cancer invasion and metastasis to brain is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized therapy based on tumor-specific mutations. Little is known about the clinical significance of HER2/ERK1/2/MMP-9 signaling pathway in breast cancer. We performed Global exon array to study the expression of ERK1/2/MMP-9 signaling pathway in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of ERK1/2/MMP-9 proteins in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells.
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Urooj, Tabinda, Bushra Wasim, Shamim Mushtaq, Syed Nudrat Nawaid Shah, and Muzna Shah. "Cancer Cell-derived Secretory Factors in Breast Cancer-associated Lung Metastasis: Their Mechanism and Future Prospects." Current Cancer Drug Targets 20, no. 3 (March 19, 2020): 168–86. http://dx.doi.org/10.2174/1568009620666191220151856.
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: In Breast cancer, Lung is the second most common site of metastasis after the bone. Various factors are responsible for Lung metastasis occurring secondary to Breast cancer. Cancer cellderived secretory factors are commonly known as ‘Cancer Secretomes’. They exhibit a prompt role in the mechanism of Breast cancer lung metastasis. They are also major constituents of hostassociated tumor microenvironment. Through cross-talk between cancer cells and the extracellular matrix components, cancer cell-derived extracellular matrix components (CCECs) such as hyaluronan, collagens, laminin and fibronectin cause ECM remodeling at the primary site (breast) of cancer. However, at the secondary site (lung), tenascin C, periostin and lysyl oxidase, along with pro-metastatic molecules Coco and GALNT14, contribute to the formation of pre-metastatic niche (PMN) by promoting ECM remodeling and lung metastatic cells colonization. Cancer cell-derived secretory factors by inducing cancer cell proliferation at the primary site, their invasion through the tissues and vessels and early colonization of metastatic cells in the PMN, potentiate the mechanism of Lung metastasis in Breast cancer. : On the basis of biochemical structure, these secretory factors are broadly classified into proteins and non-proteins. This is the first review that has highlighted the role of cancer cell-derived secretory factors in Breast cancer Lung metastasis (BCLM). It also enumerates various researches that have been conducted to date in breast cancer cell lines and animal models that depict the prompt role of various types of cancer cell-derived secretory factors involved in the process of Breast cancer lung metastasis. In the future, by therapeutically targeting these cancer driven molecules, this specific type of organ-tropic metastasis in breast cancer can be successfully treated.
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Ray, Upasana, Deok-Beom Jung, Ling Jin, Yinan Xiao, Subramanyam Dasari, Sayantani Sarkar Bhattacharya, Prabhu Thirusangu, et al. "Targeting LRRC15 Inhibits Metastatic Dissemination of Ovarian Cancer." Cancer Research 82, no. 6 (March 15, 2022): 1038–54. http://dx.doi.org/10.1158/0008-5472.can-21-0622.
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Abstract Dissemination of ovarian cancer cells can lead to inoperable metastatic lesions in the bowel and omentum that cause patient death. Here we show that LRRC15, a type-I 15-leucine–rich repeat-containing membrane protein, highly overexpressed in ovarian cancer bowel metastases compared with matched primary tumors and acts as a potent promoter of omental metastasis. Complementary models of ovarian cancer demonstrated that LRRC15 expression leads to inhibition of anoikis-induced cell death and promotes adhesion and invasion through matrices that mimic omentum. Mechanistically, LRRC15 interacted with β1-integrin to stimulate activation of focal adhesion kinase (FAK) signaling. As a therapeutic proof of concept, targeting LRRC15 with the specific antibody–drug conjugate ABBV-085 in both early and late metastatic ovarian cancer cell line xenograft models prevented metastatic dissemination, and these results were corroborated in metastatic patient-derived ovarian cancer xenograft models. Furthermore, treatment of 3D-spheroid cultures of LRRC15-positive patient-derived ascites with ABBV-085 reduced cell viability. Overall, these data uncover a role for LRRC15 in promoting ovarian cancer metastasis and suggest a novel and promising therapy to target ovarian cancer metastases. Significance: This study identifies that LRRC15 activates β1-integrin/FAK signaling to promote ovarian cancer metastasis and shows that the LRRC15-targeted antibody–drug conjugate ABBV-085 suppresses ovarian cancer metastasis in preclinical models.
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Ma, Chen-Sen, Yi-Xin Tong, and Jian-Ping Gong. "Distribution of Metastatic Cancer Cells in Colorectal Mesentery." World Journal of Surgery 44, no. 3 (December 9, 2019): 967–72. http://dx.doi.org/10.1007/s00268-019-05284-5.
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Abstract Background To investigate the distribution of metastatic cancer cells in the mesentery (referred to as metastasis V) and enrich the understanding of the metastasis of colorectal cancer. Methods A total of two hundred ninety-nine patients who received colorectal operations at the Department of Gastrointestinal Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology between April 2018 and December 2018 were included. Samples were acquired from the dissected mesentery after the operation, and hematoxylin–eosin staining or immunohistochemistry was used to detect metastatic cancer cells. Pathological factors, including tumor position, tumor size, invasion depth, tumor differentiation, lymph node involvement, local vessel invasion, and perineural invasion, were recorded. Results Metastatic cancer cells in the colorectal mesentery (metastasis V) were detected in 62 of 299 patients. Metastasis V was closely correlated with tumor invasion depth, lymph node metastasis, tumor differentiation, and perineural and vessel invasion by cancer cells. Metastasis V occurred more frequently in patients with T3 stage (26.27%) and T4 stage (40.00%) than in patients with T1 and T2 stages (0% and 2%, respectively). Metastasis V was frequently detected in patients with N2a and N2b stage tumors (51.72% and 61.54%, respectively). Metastasis V was more frequently detected in patients with perineural metastasis and local vessel invasion. In addition, metastasis V incidences in colon and rectal cancer were similar. Conclusion The incidence rate of metastasis V is correlated with tumor staging factors and occurs more frequently in advanced-stage patients.