Inhibins and
activins are dimeric
proteins belonging to the
transforming growth factor-beta superfamily.
Follistatin is an
activin-binding protein that antagonizes the function of
activin via binding to its beta-subunits. Previously, we demonstrated that mice deficient in
inhibin develop ovarian and testicular
sex cord-stromal tumors of granulosa and Sertoli cell origin, with 100% penetrance as early as 4 weeks of age. Overproduction of
activins in the serum directly causes a
cachexia-like
wasting syndrome that results in lethality of these mice at an early stage after the onset of the
tumors. In an independent set of studies, overexpression of mouse
follistatin using the mouse
metallothionein I promoter in transgenic mice led to gonadal defects and eventual
infertility, primarily due to local effects of
follistatin in these tissues.
Activin has a positive growth effect on gonadal
tumor cells in culture and directly causes the
cancer cachexia-like syndrome in
inhibin-deficient mice via interaction with
activin receptor type IIA in livers and stomachs. We therefore hypothesized that an
activin antagonist such as
follistatin can act as a physiological modifier, either locally or via the serum, to block the
activin-mediated
cancer cachexia-like syndrome in
inhibin-deficient mice and/or slow the progression of gonadal
cancers in these mice. To test this hypothesis, we generated mice that are homozygous mutant for the
inhibin alpha null allele (i.e. inham1/inham1) and carry the mouse
metallothionein I follistatin (MT-FS) transgene. Our results show that gonadal
tumors that are histologically similar in most, but not all, cases to the
tumors in
inhibin-deficient mice develop in these inham1/inham1, MT-FS+ mice. However, inham1/inham1, MT-FS+ mice exhibit a less severe
wasting syndrome, lower serum
activin levels, and a statistically significant prolonged survival in a number of cases compared with mice deficient in
inhibin alone. Thus,
follistatin can act as a modulator of
tumor growth and the
activin-induced
cancer cachexia-like syndrome in
inhibin-deficient mice.