The evolution of tumor metastasis during clonal expansion with alterations in metastasis driver genes

Yamamoto, Kimiyo N.; Nakamura, Akira; Haeno, Hiroshi

doi:10.1038/srep15886

Cited by 15 publications

(14 citation statements)

References 33 publications

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“…Cancer relapse and metastasis represent major clinical challenges in the treatment of cancer [ 22 , 23 ]. Emerging evidence suggests that tumor cell EMT is an important prerequisite for the generation of CTCs and DTCs, which enables the dissemination of tumor cells into the circulation and surrounding tissues [ 16 , 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Tumor microenvironment promotes prostate cancer cell dissemination via the Akt/mTOR pathway

et al. 2018

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Metastasis causes high mortality in various malignancies, including prostate cancer (PCa). Accumulating data has suggested that cancer cells spread from the primary tumor to distant sites at early stage, which is characterized by disseminated tumor cells (DTCs). However, lack of direct evidence of partial localized PCa cells occurring epithelial-to-mesenchymal transition (EMT) and disseminating to distant sites (e.g bone marrow). In this study, we used luciferase labeled PCa cells to establish an EMT mouse model and to detect whether DTCs spread into the bone marrow. We observed tumor cells existing in mouse bone marrow when tumor grew subcutaneously at palpable stage. Studies also showed that ex vivo tumor cells exhibited increased proliferative, migratory, invasive and angiogenesis abilities. When compared ex vivo tumor cells with parental cells, hallmarks of EMT including E-cadherin, Vimentin, Snail, and ZO-1 were altered significantly. Specifically, the ex vivo tumor cells showed more mesenchymal properties. Angiogenesis markers, including VEGFR2, VEGFR3, MCP-3, I-TAC, I309, uPAR and GROα, were also increased in the ex vivo tumor cells. Intriguingly, MCP-1 expression was dramatically increased in those cells. Mechanistic analyses indicated that AP1 mediates PCa EMT and the appearance of DTCs via the Akt/mTOR pathway. This study may provide potential therapeutic targets and diagnostic biomarkers of PCa progression and metastasis.

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Section: Discussionmentioning

confidence: 99%

Tumor microenvironment promotes prostate cancer cell dissemination via the Akt/mTOR pathway

et al. 2018

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“…Tumor metastasis is still the main cause of cancer-related mortality, so it is important to identify the key molecules in each step of tumor metastasis and develop new strategies for prevention and control of tumor metastasis [ 1 – 3 ]. A key step in metastasis is that the extravasated carcinoma cells must survive in the foreign microenvironment and ultimately develop into macroscopic metastases.…”

Section: Introductionmentioning

confidence: 99%

Thrombospondin-1 promotes cell migration, invasion and lung metastasis of osteosarcoma through FAK dependent pathway

Wen

Gong

et al. 2017

Oncotarget

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Microenvironment at the metastatic locus usually differs greatly from that present in the site of primary tumor formation and it has a significant impact on the fate of the extravasated cancer cells. We compared gene expression signatures of primary tumors and lung metastatic tumors, and identified Thrombospondin-1 (TSP1) as highly up-regulated in the lung metastatic tumors. Immunohistochemical staining further indicated that TSP1 protein expression was higher in lung metastatic tumors compared to primary tumors in both osteosarcoma xenograft model and human clinical samples. TSP1 mRNA level is significantly associated with the Enneking stage of osteosarcoma and lung metastasis. TGF-β pathways could stimulate the TSP1 expression in osteosarcoma cells. Knockdown of TSP1 expression in osteosarcoma cells dramatically suppressed cell wound healing, migration and invasion. Treatment with recombinant TSP1 protein in osteosarcoma cells significantly promoted cell wound healing, migration and invasion. Meanwhile, suppression of TSP1 in osteosarcoma cells resulted in decreased pulmonary metastasis in vivo. Mechanistically, TSP1 increased expression of metastasis related genes, including MMP2, MMP9 and Fibronectin 1. TSP1 promoted osteosarcoma cell motility through the activation of FAK pathway. Taken together, our study provides evidence of the contributions of TSP1 to the lung metastasis of osteosarcoma and suggests that this protein may represent a potential therapeutic target for osteosarcoma lung metastasis.

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“…Many metastases might be established by a process which lies between these two extreme points, in which a tumor expands due to a balance of consecutive seeding events and subsequent cell divisions. However, previous mathematical models of metastasis have focused almost exclusively on extreme i , single-cell seeding (28–32). Although not yet studied in the context of cancer genetics, some mathematical models of consecutive immigration have been applied to other biological systems, in particular island populations (33–36).…”

mentioning

confidence: 99%

Consecutive seeding and transfer of genetic diversity in metastasis

Heyde

Reiter

Naxerova

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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During metastasis, only a fraction of genetic diversity in a primary tumor is passed on to metastases. We calculate this fraction of transferred diversity as a function of the seeding rate between tumors. At one extreme, if a metastasis is seeded by a single cell, then it inherits only the somatic mutations present in the founding cell, so that none of the diversity in the primary tumor is transmitted to the metastasis. In contrast, if a metastasis is seeded by multiple cells, then some genetic diversity in the primary tumor can be transmitted. We study a multitype branching process of metastasis growth that originates from a single cell but over time receives additional cells. We derive a surprisingly simple formula that relates the expected diversity of a metastasis to the diversity in the pool of seeding cells. We calculate the probability that a metastasis is polyclonal. We apply our framework to published datasets for which polyclonality has been previously reported, analyzing 68 ovarian cancer samples, 31 breast cancer samples, and 8 colorectal cancer samples from 15 patients. For these clonally diverse metastases, under typical metastasis growth conditions, we find that 10 to 150 cells seeded each metastasis and left surviving lineages between initial formation and clinical detection.

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The evolution of tumor metastasis during clonal expansion with alterations in metastasis driver genes

Cited by 15 publications

References 33 publications

Tumor microenvironment promotes prostate cancer cell dissemination via the Akt/mTOR pathway

Tumor microenvironment promotes prostate cancer cell dissemination via the Akt/mTOR pathway

Thrombospondin-1 promotes cell migration, invasion and lung metastasis of osteosarcoma through FAK dependent pathway

Consecutive seeding and transfer of genetic diversity in metastasis

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