Activin-beta(c) reduces reproductive tumour progression and abolishes cancer-associated cachexia in inhibin-deficient mice

Elspeth Gold, Francesco E Marino, Craig Harrison, Yogeshwar Makanji, Gail P Risbridger

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24 Citations (Scopus)

Abstract

Activins are involved in the regulation of a diverse range of physiological processes including development, reproduction and fertility and have been implicated in the progression of cancers. Bioactivity is regulated by the inhibin alpha-subunit and by an activin binding protein, follistatin. The activin-beta(C) subunit was not considered functionally significant in this regard due to an absence of phenotype in knockout mice. However, activin-beta(C) forms heterodimers with activin-beta(A) and activin C antagonizes activin A in vitro. Thus, it is proposed that over-expression, rather than loss of activin-beta(C) , regulates activin A bioactivity. In order to prove biological efficacy, inhibin alpha-subunit knockout mice (alpha-KO) were crossed with mice over-expressing activin-beta(C) (ActC + +). Deletion of inhibin leads to Sertoli and Granulosa Cell Tumours, increased activin A and cancer-associated cachexia. Therefore, cachexia and reproductive tumour development should be modulated in alpha-KO/ActC + + mice, where excessive activin A is the underlying cause. Accordingly, a reduction in activin A, no significant weight loss and reduced incidence of reproductive tumours was evident in alpha-KO/ActC + + mice. Over-expression of activin-beta(C) antagonised the activin signaling cascade thus, the tumourigenic effects of activin A were abrogated. This study provides proof of the biological relevance of activin-beta(C) . Being a regulator of activin A it is able to abolish cachexia and modulate reproductive tumour development in alpha-KO mice.
Original languageEnglish
Pages (from-to)599 - 607
Number of pages9
JournalJournal of Pathology
Volume229
Issue number4
DOIs
Publication statusPublished - 2013

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