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 4

Prior radiation is permissive for metastatic lung colonization in tumor-free mice.

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Prior radiation is permissive for metastatic lung colonization in tumor-...
(A) MMTV/PyVmT cells in 100-mm dishes in serum-free medium were treated with 1.25–7.5 Gy. Cell-conditioned medium was collected 72 hours later, and TGF-β1 levels were determined by ELISA as described in Methods. (B) MMTV/PyVmT cells stably expressing luciferase were injected via tail vein in virgin female FVB mice. Where indicated, mice received 10 Gy to the thorax 1 hour prior to injection of cells. Cancer cells in lungs were visualized by mouse bioluminescence 2 weeks after inoculation (top). In some cases, lungs were surgically removed after administration of d-luciferin and imaged ex vivo (bottom). Controls are shown on the left and irradiated mice are shown on the right. (C) Representative lung whole mounts (top) and H&E sections of lungs (bottom; original magnification, ×100) from control and irradiated mice. (D) Quantification of surface lung metastasis (left) and lung weight (right) in control and irradiated mice. Data are mean ± SD of 5 mice per group in 2 independent experiments. **P < 0.01, ***P < 0.001 versus control.