Prevention of cachexia-like syndrome development and reduction of tumor progression in inhibin-deficient mice following administration of a chimeric activin receptor type II-murine Fc protein.
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Inhibin is a secreted tumor suppressor, and inhibin alpha null mice develop gonadal sex cord-stromal tumors with 100% penetrance at an early age. Inhibin-deficient mice die of a severe wasting syndrome due to increased activin signaling through activin receptor type II. The current study was designed to assess the in vivo effects of an activin antagonist, a chimeric activin receptor type II fused to the Fc region of a murine IgG2a (ActRII-mFc), administered transiently to the inhibin-deficient mice. Results showed that the severe weight loss was prevented in the ActRII-mFc-treated mice, FSH levels were reduced, and an extended life span was observed for these mice compared with phosphate-buffered saline-treated controls. Although ActRII-mFc treatment did not seem to prevent the formation of gonadal tumors, tumors were smaller in the majority of experimentally treated mice and were characterized by the presence of variable numbers and sizes of cysts in contrast to the solid hemorrhagic tumors that typically developed in the controls. Moreover, the ActRII-mFc-treated mice were less anemic, and their livers and stomachs were histologically normal. In summary, this study demonstrated that in vivo administration of the activin antagonist, ActRII-mFc, not only prevents the cachexia-like symptoms in the inhibin-deficient mouse model, but also reduces tumor progression. These results support an essential role of activins in the cachexia-like syndrome development and implicate activins as growth-promoting factors in gonadal tumor progression. The current findings have potential implications in the design of new drugs or strategies for the treatment of ovarian and testicular tumors and other conditions where ligands signal through ActRII.
author list (cited authors)
Li, Q., Kumar, R., Underwood, K., O'Connor, A. E., Loveland, K. L., Seehra, J. S., & Matzuk, M. M.
complete list of authors
Li, Qinglei||Kumar, Ravi||Underwood, Kathryn||O'Connor, Anne E||Loveland, Kate L||Seehra, Jasbir S||Matzuk, Martin M