Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression.
We investigated whether TGF-beta 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-beta1 as well as increased circulating tumor cells and lung metastases. These effects were abrogated by administration of a neutralizing pan-TGF-beta antibody. Circulating polyomavirus middle T antigen-expressing tumor cells did not grow ex vivo in the presence of the TGF-beta antibody, suggesting autocrine TGF-beta is a survival signal in these cells. Radiation failed to enhance lung metastases in mice bearing tumors that lack the type II TGF-beta receptor, suggesting that the increase in metastases was due, at least in part, to a direct effect of TGF-beta on the cancer cells. These data implicate TGF-beta induced by anticancer therapy as a pro-metastatic signal in tumor cells and provide a rationale for the simultaneous use of these therapies in combination with TGF-beta inhibitors.
Biswas
Swati
S
Department of Cancer Biology, Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.
Guix
Marta
M
Rinehart
Cammie
C
Dugger
Teresa C
TC
Chytil
Anna
A
Moses
Harold L
HL
Freeman
Michael L
ML
Arteaga
Carlos L
CL
D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy*; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009381:Neoplasms, Radiation-Induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009360:Neoplastic Cells, Circulating / Q000276:immunology / Q000473:pathology; D012192:Retroviridae Infections / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000276:immunology*; D014412:Tumor Virus Infections / Q000473:pathology / Q000517:prevention & control
D019138:Antibodies, Blocking; D000952:Antigens, Polyomavirus Transforming; D016212:Transforming Growth Factor beta