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 1

Radiation and chemotherapy increase circulating TGF-β1.

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Radiation and chemotherapy increase circulating TGF-β1. (A) FVB mice wer...
(A) FVB mice were subjected to 10 Gy delivered to the thorax (left) or pelvis (right). Blood was collected 24 hours later, and plasma TGF-β1 level was measured as described in Methods. (B) Eight-week-old tumor-bearing MMTV/PyVmT mice or nontransgenic FVB mice bearing PyVmT tumors of 200 mm3 or greater in mammary fat pad no. 4 were left untreated or administered 10 Gy to the thorax. Plasma TGF-β1 levels were measured 24 hours later. (C) Transgenic mice were treated 3 times with vehicle or doxorubicin (5 mg/kg i.p.) at 21-day intervals starting at week 8. TGF-β1 was measured in plasma collected at week 15. Data in A–C represent 3 independent experiments using 3 subjects per group. (D) FVB mice were administered 10 Gy to the thorax. Five weeks later, lungs from irradiated mice and controls were harvested and lysates (250 μg/ml) added in triplicate wells to mink lung epithelial cells that stably express a plasminogen activator inhibitor–1/luciferase reporter (PAI-1/luciferase reporter). After 24 hours, luciferase expression was measured as described in Methods. *P < 0.05, **P < 0.01, ***P < 0.001 versus control.