Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression.

Biswas S, Guix M, Rinehart C, Dugger TC, Chytil A, Moses HL, Freeman ML, Arteaga CL
J Clin Invest. 2007 117 (5): 1305-13

PMID: 17415413 · PMCID: PMC1838926 · DOI:10.1172/JCI30740

We investigated whether TGF-beta induced by anticancer therapies accelerates tumor progression. Using the MMTV/PyVmT transgenic model of metastatic breast cancer, we show that administration of ionizing radiation or doxorubicin caused increased circulating levels of TGF-beta1 as well as increased circulating tumor cells and lung metastases. These effects were abrogated by administration of a neutralizing pan-TGF-beta antibody. Circulating polyomavirus middle T antigen-expressing tumor cells did not grow ex vivo in the presence of the TGF-beta antibody, suggesting autocrine TGF-beta is a survival signal in these cells. Radiation failed to enhance lung metastases in mice bearing tumors that lack the type II TGF-beta receptor, suggesting that the increase in metastases was due, at least in part, to a direct effect of TGF-beta on the cancer cells. These data implicate TGF-beta induced by anticancer therapy as a pro-metastatic signal in tumor cells and provide a rationale for the simultaneous use of these therapies in combination with TGF-beta inhibitors.

MeSH Terms (17)

Animals Antibodies, Blocking Antigens, Polyomavirus Transforming Cell Line, Tumor Female Humans Lung Neoplasms Mammary Neoplasms, Experimental Mammary Tumor Virus, Mouse Mice Mice, Transgenic Neoplasms, Radiation-Induced Neoplastic Cells, Circulating Retroviridae Infections Signal Transduction Transforming Growth Factor beta Tumor Virus Infections

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