Inhibition of TGF-β with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression
Swati Biswas, … , Michael L. Freeman, Carlos L. Arteaga
Swati Biswas, … , Michael L. Freeman, Carlos L. Arteaga
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1305-1313. https://doi.org/10.1172/JCI30740.
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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.