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 5

TGF-β–neutralizing antibody 2G7 blocks radiation-induced increase in lung metastases.

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TGF-β–neutralizing antibody 2G7 blocks radiation-induced increase in lun...
(A and B) Eight-week-old tumor-bearing MMTV/PyVmT mice were administered 10 Gy to the thorax. Where indicated, mice were treated with 15 mg/kg of 2G7 twice a week until week 13, at which time surface lung metastases were counted (A). Data are mean ± SD of 5 mice per group. (B) Representative H&E stains of lung sections. The experiment was repeated once with similar results. (C) Blood was collected at the completion of the experiment via heart puncture and its cellular fraction evaluated for its ability to form colonies ex vivo as described in Methods. (D) At 13 weeks, blood was collected from tumor-bearing transgenic mice that were exposed to thorax irradiation. The cellular fraction was plated ex vivo as in C in the presence of 20 μg/ml 2G7 or PBS. Colonies measuring 50 μm or greater were counted manually 10–12 days later. Data are mean ± SD of 5 mice per group. *P < 0.05, **P < 0.01 versus control.