Inhibition of TGF-β with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression
Swati Biswas, Marta Guix, Cammie Rinehart, Teresa C. Dugger, Anna Chytil, Harold L. Moses, Michael L. Freeman, Carlos L. Arteaga
Swati Biswas, Marta Guix, Cammie Rinehart, Teresa C. Dugger, Anna Chytil, Harold L. Moses, Michael L. Freeman, Carlos L. Arteaga
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Research Article

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

Abstract

We investigated whether TGF-β 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-β1 as well as increased circulating tumor cells and lung metastases. These effects were abrogated by administration of a neutralizing pan–TGF-β antibody. Circulating polyomavirus middle T antigen–expressing tumor cells did not grow ex vivo in the presence of the TGF-β antibody, suggesting autocrine TGF-β is a survival signal in these cells. Radiation failed to enhance lung metastases in mice bearing tumors that lack the type II TGF-β receptor, suggesting that the increase in metastases was due, at least in part, to a direct effect of TGF-β on the cancer cells. These data implicate TGF-β induced by anticancer therapy as a prometastatic signal in tumor cells and provide a rationale for the simultaneous use of these therapies in combination with TGF-β inhibitors.

Authors

Swati Biswas, Marta Guix, Cammie Rinehart, Teresa C. Dugger, Anna Chytil, Harold L. Moses, Michael L. Freeman, Carlos L. Arteaga

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Figure 6

Absence of TGFβRII in tumor cells abrogates radiation-induced increase in lung metastases.

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Absence of TGFβRII in tumor cells abrogates radiation-induced increase i...
(A–C) PyVmT/TGFBR2flox/flox and PyVmT/TGFBR2KO cells stably expressing luciferase were injected via the tail vein in virgin 8-week-old female FVB mice that had received or not 10 Gy to the thorax 1 hour prior to tumor cell injection. Two weeks later, surface lung metastases were evaluated by bioluminescence (A), by histology (B), and by manually counting surface lung metastases (C) as described in Methods. Data are mean ± SD of 4 mice per group. (D) PCR from genomic DNA extracted from both cell lines, showing the presence of a recombined band only in PyVmT/TGFBR2KO cells. **P < 0.01 versus control.