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Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma.

ABSTRACT: Although metastasis is the leading cause of cancer-related death, it is not clear why some patients with localized cancer develop metastatic disease after complete resection of their primary tumor. Such relapses have been attributed to tumor cells that disseminate early and remain dormant for prolonged periods of time; however, little is known about the control of these disseminated tumor cells. Here, we have used a spontaneous mouse model of melanoma to investigate tumor cell dissemination and immune control of metastatic outgrowth. Tumor cells were found to disseminate throughout the body early in development of the primary tumor, even before it became clinically detectable. The disseminated tumor cells remained dormant for varying periods of time depending on the tissue, resulting in staggered metastatic outgrowth. Dormancy in the lung was associated with reduced proliferation of the disseminated tumor cells relative to the primary tumor. This was mediated, at least in part, by cytostatic CD8+ T cells, since depletion of these cells resulted in faster outgrowth of visceral metastases. Our findings predict that immune responses favoring dormancy of disseminated tumor cells, which we propose to be the seed of subsequent macroscopic metastases, are essential for prolonging the survival of early stage cancer patients and suggest that therapeutic strategies designed to reinforce such immune responses may produce marked benefits in these patients.

SUBMITTER: Eyles J

PROVIDER: S-EPMC2877955 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma.

Eyles Jo J Puaux Anne-Laure AL Wang Xiaojie X Toh Benjamin B Prakash Celine C Hong Michelle M Tan Tze Guan TG Zheng Lin L Ong Lai Chun LC Jin Yi Y Kato Masashi M Prévost-Blondel Armelle A Chow Pierce P Yang Henry H Abastado Jean-Pierre JP

The Journal of clinical investigation 20100524 6

Although metastasis is the leading cause of cancer-related death, it is not clear why some patients with localized cancer develop metastatic disease after complete resection of their primary tumor. Such relapses have been attributed to tumor cells that disseminate early and remain dormant for prolonged periods of time; however, little is known about the control of these disseminated tumor cells. Here, we have used a spontaneous mouse model of melanoma to investigate tumor cell dissemination and ...[more]

PMID: 20501944

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Project description:Despite advances in treatment for metastatic melanoma patients, patients with liver metastasis have an unfavorable prognosis. A better understanding of the development of liver metastasis is needed. The multifunctional cytokine Transforming Growth Factor β (TGF-β) plays various roles in melanoma tumors and metastasis, affecting both tumor cells and cells from the surrounding tumor microenvironment. To study the role of TGF-β in melanoma liver metastasis, we created a model to activate or repress the TGF-β receptor pathway in vitro and in vivo in an inducible manner. For this, we engineered B16F10 melanoma cells to have inducible ectopic expression of a constitutively active (ca) or kinase-inactive (ki) TGF-β receptor I, also termed activin receptor-like kinase (ALK5). In vitro, stimulation with TGF-β signaling and ectopic caALK5 expression reduced B16F10 cell proliferation and migration. Contrasting results were found in vivo; sustained caALK5 expression in B16F10 cells in vivo increased the metastatic outgrowth in liver. Blocking microenvironmental TGF-β did not affect metastatic liver outgrowth of both control and caALK5 expressing B16F10 cells. Upon characterizing the tumor microenvironment of control and caALk5 expressing B16F10 tumors, we observed reduced (cytotoxic) T cell presence and infiltration, as well as an increase in bone marrow-derived macrophages in caALK5 expressing B16F10 tumors. This suggests that caALK5 expression in B16F10 cells induces changes in the tumor microenvironment. A comparison of newly synthesized secreted proteins upon caALK5 expression by B16F10 cells revealed increased secretion of matrix remodeling proteins. Our results show that TGF-β receptor activation in B16F10 melanoma cells can increase metastatic outgrowth in liver in vivo, possibly through remodeling of the tumor microenvironment leading to altered infiltration of immune cells. These results provide insights in the role of TGF-β signaling in B16F10 liver metastasis and could have implications regarding the use of TGF-β inhibitors for the treatment of melanoma patients with liver metastasis.

Dataset Information

Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma.

Publications

Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma.

Similar Datasets

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