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 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.