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Departments of Pathology (S.C.C., L.C., T.R.K., M.M.M.), Molecular and Cellular Biology (T.R.K., M.M.M.), and Molecular and Human Genetics (M.M.M.), Baylor College of Medicine, Houston, Texas 77030
Address all correspondence and requests for reprints to: Martin M. Matzuk, M.D., Ph.D., Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: mmatzuk{at}bcm.tmc.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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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. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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:ß
heterodimers (:ßA or :ßB), whereas activins are homodimers
(ßA:ßA; ßB:ßB) and heterodimers (ßA:ßB) that share a common
ß-subunit with inhibin. Inhibins are expressed in multiple tissues,
with the highest levels of expression in the Sertoli cells of the
testis, the granulosa cells of the ovary, and the pituitary (2). To study the roles of inhibins in mammalian reproduction and development, we previously generated inhibin knockout mice (7). These inhibin-deficient mice develop ovarian and testicular sex cord-stromal (Sertoli cell and/or granulosa cell) tumors with 100% penetrance, which were evident as early as 4 weeks of age in both sexes. Inhibin-deficient male mice developed testicular tumors that typically were bilateral, hemorrhagic, and multifocal (7), often resembling juvenile granulosa cell tumors found in young girls. Consistent with these histological findings, serum from these male mice demonstrated elevated estradiol levels (3). Female inhibin-deficient mice developed multifocal, hemorrhagic ovarian tumors that were often mixed granulosa and Sertoli cell tumors (7) and also showed elevated estradiol levels in most cases (3). As the tumors progressed, extensive destruction of the normal gonadal architecture by the focally invasive tumor occurred, leading to significant hemorrhage (7).
Gonadal tumor development in inhibin-deficient mice was accompanied by a severe progressive cancer cachexia-like wasting syndrome characterized by weight loss, lethargy, kyphoscoliosis, and a sunken eye appearance. The pathological findings of this wasting syndrome included anemia, hepatocellular necrosis around the central vein of the liver, and atrophy in the glandular stomach with a block in differentiation of multiple gastric lineages (8, 9). In addition to estradiol, serum levels of activin A and B and FSH were elevated in the inhibin-deficient mice after the tumors developed (3, 7, 8, 9). The above-mentioned effects of activins on the liver and stomach are due to direct effects of activins signaling through activin receptor type IIA (9, 10). Subsequently, using ovary transplantation techniques, we proved that absence of inhibin, rather than elevated levels of activin, caused the tumor development in these inhibin-deficient mice, thus defining inhibin as a tumor suppressor in the gonads (3). Inhibin also acts as a tumor suppressor in the adrenal glands; nearly 100% of inhibin-deficient mice developed adrenal cortical tumors after castration (7, 8). Although inhibin secretion from a contralateral ovary can suppress tumor development in an inhibin knockout ovary (3), and absence of activin receptor type IIA does not prevent ovarian or testicular tumor development (10), activin secretion from the tumor cells can stimulate the growth of these inhibin-deficient gonadal tumor cells in culture via an autocrine mechanism (11). In addition, follistatin added to the culture medium slows the growth rate of the tumor cells (11).
Follistatin is structurally unrelated to activins or inhibins. Follistatin binds to the ß-subunits of activin to prevent the interaction of activin with its type II receptors (12, 13). In vivo, this leads to inhibition of FSH synthesis and secretion (14). Follistatin may be important in regulating other factors besides activin, since it binds to other transforming growth factor-ß superfamily members such as bone morphogenic protein-4 (BMP-4), BMP-7, and inhibin (15, 16, 17). The affinities of follistatin for BMP-4 and BMP-7 are not known, but are presumed to be less than the affinity for activin (15, 16). Although follistatin is expressed in multiple tissues in mammalian development (2, 3, 12, 18, 19, 20, 21), the ovarian granulosa cells are the major site of its production (18, 21). We previously showed that follistatin knockout mice demonstrate widespread dermatopathological and musculoskeletal defects and growth delay (22). These defects are more diverse than those seen in activin receptor type IIA (ActRIIA)-, ActRIIB-, or activin-deficient mice (23, 24, 25). Follistatin-deficient mice die within hours of birth, preventing any further functional studies of follistatin in reproductive development and physiology. We subsequently generated a transgenic mouse model in which mouse follistatin (FS) was overexpressed using a mouse metallothionein (MT) I promoter (26). The presence of the follistatin transgene (MT-FS+) did not affect viability, but the transgenic mice had defects in fertility (26). MT-FS+ male mice exhibited Leydig cell hyperplasia, arrested spermatogenesis, and seminiferous tubule degeneration, which contributed to the infertility in these mice. MT-FS+ female mice had small ovaries, with blocks at different stages of folliculogenesis, and thin uteri and were infertile. Dermatological defects were present in both follistatin knockout and MT-FS+ transgenic mice, but there was no evidence of cancer.
Because of the contribution of activin to the liver and stomach
phenotypes in the inhibin-deficient mice and its stimulatory effect on
tumor cell growth in culture, we hypothesized that overexpression of
follistatin in the inhibin knockout background would antagonize
activin’s actions and possibly prevent the cancer cachexia-like
syndrome and/or alter the tumor growth rate. To test this, we generated
mice that were homozygous mutant for inhibin and carried the MT-FS
transgene
(inham1/inham1,
MT-FS+). Here, we demonstrate that overexpression
of follistatin slows the cachexia-like wasting syndrome and the
progression of tumor development in a number of inhibin-deficient
mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and MT-FS transgenic (line 5) male and
female mice were crossed to generate offspring that were homozygous
mutant for inhibin and carried the MT-FS transgene
(inham1/inham1,
MT-FS+). These mice were obtained at the expected
Mendelian ratio of 3:16.
Southern blot analysis
To determine the inhibin genotype of offspring, Southern
blot analyses were performed on tail DNA samples using
32P-labeled probes as previously described (7).
Detection of the MT-FS transgene using a 973-bp simian virus 40
3'-untranslated region/polyadenylated fragment as the probe was
described previously (26).
Morphological and histological analysis
Mice from each genotype were weighed once a week beginning at 4
weeks. Mouse ovaries, testes, stomachs, and livers were fixed in either
10% buffered formalin or Bouin’s fixative overnight. Bouin’s-fixed
tissues were then transferred to 70% ethanol saturated with lithium
carbonate and washed extensively. Tissue sections were dehydrated and
paraffin wax embedded, and 4-µm sections were cut and stained with
hematoxylin and eosin or periodic acid-Schiff. Gross and histological
analyses of the tissues were performed on at least six male and six
female mice.
Serum analysis
Mice were anesthetized using Metofane (Schering Plough Animal Health Corp., Union, NJ), and serum was collected using
either cardiac puncture or capillary eye bleed in Microtainer tubes
(Becton Dickinson and Co., Franklin Lakes, NJ). Serum
activin A levels were determined using an activin A enzyme-linked
immunosorbent assay kit from Serotec (Kidlington, Oxford,
UK). The standard used was bovine follicular fluid. This assay measures
total activin A levels in serum (both free and bound). The sensitivity
of this assay is 3.8 pg/ml. The Serotec assay has been
validated for mouse serum (Dr. Teresa K. Woodruff, personal
communication). FSH levels were determined using a
[125I]hormone labeling method as previously
described (27). Serum samples used for FSH analysis were obtained from
the same group of mice as that previously used for activin A serum
analysis. FSH values are represented as the mean ±
SEM. The sensitivity of the FSH assay is 10 ng/ml, and the
NIDDK standard used was rat FSH I-9.
Statistical analysis
A confidence interval test was used to determine the
significance of the survival rates. One-way ANOVA was used to determine
the statistical significance of serum samples. Microsoft Corp. Excel (Redmond, WA) was used for
both of these analyses. P < 0.05 was considered
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Before
this time, the weight gain of these mice is indistinguishable from that
of their wild-type littermate controls as are the serum activin A and B
levels (8). In the present study we show that in contrast to
inhibin-deficient mice or transgenic mice carrying only the MT-FS
transgene, growth curves of male (Fig. 1A) and female (Fig. 1B) mice
overexpressing the follistatin transgene and lacking inhibin
(inham1/inham1,
MT-FS+) were intermediate between those of the
cachectic-prone
inham1/inham1
mice and the healthy MT-FS+ mice. Although the
inham1/inham1,
MT-FS+ mice did exhibit some weight loss, this
cachexia was less dramatic, and there were minimal other symptoms
[e.g. less of a hunchback appearance (kyphoscoliosis)]
during the 20-week period compared to mice lacking only inhibin. One
hundred percent of MT-FS+ control male and female
mice were alive after 20 weeks (Fig. 2, A
and B). This correlates with normal weight gain in the
MT-FS+ mice over this time period (Fig. 1, A and
B). At 13 weeks of age, 97% of the
inham1/inham1
males were dead, in contrast to 40% of the
inham1/inham1
MT-FS+ mice (Fig. 2A). At 17 weeks of age, 95%
of the
inham1/inham1
female mice were dead, whereas 38% of the
inham1/inham1,
MT-FS+ female mice were still alive. Even at 20
weeks, there was a statistically significant number of the
inham1/inham1,
MT-FS+ female mice that were still alive (21%, 5
of 24) compared with
inham1/inham1
female mice (2%, 1 of 52; confidence interval, 0.189 ± 0.085;
P < 0.001). Similarly, after 20 weeks of age, a
statistically significant number of
inham1/inham1,
MT-FS+ male mice were alive (20%, 4 of 20)
compared with
inham1/inham1
male mice (0%, 0 of 38; confidence interval, 0.2 ± 0.089;
P < 0.002).
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).
However, as mentioned above, nine
inham1/inham1,
MT-FS+ mice were still alive at 20 weeks of age.
Furthermore, we observed six
inham1/inham1,
MT-FS+ mice that survived between 6 and 8 months
of age.
The inham1/inham1,
MT-FS+ mice develop ovarian and testicular
tumors histologically similar to those in
inham1/inham1mice
As might be expected from the weight loss and survival curves
(Figs. 1 and 2),
inham1/inham1,
MT-FS+ mice do develop gonadal tumors. Tumor
formation in the
inham1/inham1,
MT-FS+ male and female mice was first evident in
some mice at 7 weeks of age, and by 12 weeks of age, tumors were
grossly evident in a number of these mice (Fig. 3, A and B). Histological analysis
revealed that
inham1/inham1,
MT-FS+ male and female mice developed multifocal
undifferentiated Sertoli and/or granulosa cell tumorigenic lesions
(Fig. 3, C and D). As mentioned above, our original reports of mice
lacking only inhibin (3, 7, 10, 27) demonstrated that the testicular
tumors typically resembled human juvenile granulosa cell tumors of
young females and produced high levels of estradiol. Interestingly, the
tumors in the
inham1/inham1,
MT-FS+ male mice also had components that
resembled Sertoli cell tumors, which were never seen in mice lacking
only inhibin (3, 7, 10, 27) (Matzuk and colleagues) and which
were more typical of human and mouse mixed granulosa/Sertoli cell
tumors (see Fig. 3F). Female mice lacking inhibin and carrying the
MT-FS transgene also predominantly showed mixed granulosa/Sertoli cell
tumors with distinct areas of mitotically active granulosa cells (Fig. 3D). The extent of hemorrhage within the tumor tissue of both male and
female
inham1/inham1,
MT-FS+ mice did not correlate with a specific
tumor cell type. We noted, however, that in contrast to
inhibin-deficient mice, only sparse areas of focal hemorrhage
were present in the ovaries of
inham1/inham1,
MT-FS+ female mice. Thus, the presence of the
MT-FS transgene in the inhibin-deficient background appears to somehow
alter the tumorigenic process in both male mice (i.e.
increased Sertoli cell tumor component) and female mice
(i.e. less hemorrhage noted; see
Discussion).
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) to the granulosa cell tumor component
seen in some
inham1/inham1,
MT-FS+ females (Fig. 3D) and more typical of
testicular tumors from male mice lacking only inhibin (3, 7, 10, 27).
The bilateral tumors from one of the 8-month-old
inham1/inham1,
MT-FS+ females were grossly larger than the
tumors taken from an
inham1/inham1,
MT-FS+ 12-week-old mouse (Fig. 3B).
Histologically, these tumors were mixed granulosa/Sertoli cell tumors.
However, the Sertoli cell component of these tumors (Fig. 3F), which
was histologically similar to the testis tumors (Fig. 3C), predominated
and was a major portion of the tumor. Interestingly, the gross (Fig. 3A) and histological (Fig. 3, E and F, and data not shown) analysis of
the two tumors from these older female and male
inham1/inham1,
MT-FS+ mice demonstrated only sparse hemorrhage,
suggesting that the tumors were less aggressive locally. In addition,
all of the 6- to 8-month-old male and female mice failed to develop any
cachexia-like symptoms (see next section).
The inham1/inham1,
MT-FS+ mice have reduced serum activin A levels
compared with
inham1/inham1mice
Gonadal tumors from inhibin-deficient male and female mice secrete
activin A and B into the serum at high levels (8, 9, 10). These
circulating activins cause a cachexia-like wasting syndrome. To address
whether the decreased weight loss and prolonged survival of the
inham1/inham1,
MT-FS+ mice could be due to reduced serum activin
levels, we performed activin A ELISAs. We used serum from 14- to
25-week-old
inham1/inham1,
MT-FS+ mice and 13- to 18-week-old
inham1/inham1
mice. These time points correlated with periods of decreased survival
and weight loss. The highest levels of serum activin A were detected in
inham1/inham1
male and female mice (Fig. 4, A and B,
respectively). For males and females, serum activin A levels in
inham1/inham1,
MT-FS+ mice were statistically lower than those
in
inham1/inham1
mice, although they continued to be elevated compared with levels in
control MT-FS+ mice (Fig. 4; P <
0.05). Serum activin A levels in MT-FS+ male and
female control mice were essentially undetectable (Fig. 4, A and B;
males, 0.16 ± 0.01 ng/ml; females 0.25 ± 0.02 ng/ml).
Interestingly, when the serum activin A levels were analyzed in the
8-month-old female and the 6-month-old male
inham1/inham1,
MT-FS+ mice, the levels of activin A were
extremely low (5.23 ng/ml and undetectable, respectively). Thus,
despite the presence of gross tumors in these two mice, activin levels
were not dramatically elevated and may have caused the prolonged
survival of these mice (see Discussion).
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The inham1/inham1,
MT-FS+ mice have less severe stomach and liver
pathology compared with
inham1/inham1 mice
The cachexia-like wasting syndrome in the
inham1/inham1 mice is due
to increased activin secretion from the gonadal tumors (8, 10). This
syndrome results in increased signaling through ActRIIA, which results
in liver and stomach pathology in these mice (8, 9, 10). To confirm that
the wasting syndrome in many of the
inham1/inham1,
MT-FS+ mice was due to a similar pathological
process, we examined these tissues histologically. Indeed, compared
with the essentially normal glandular stomach of
inham1/inham1,
MT-FS+ mice at 7 weeks (Fig. 5A), parietal cells were mildly depleted
in the glandular stomach of a cachectic
inham1/inham1,
MT-FS+ mouse at 12 weeks (Fig. 5B). The pathology
in these mice was milder than the complete and marked atrophy seen in
the stomachs of
inham1/inham1
mice (i.e. nearly complete disappearance of parietal cells
and other lineages, as determined by light and immunohistochemical
analysis) (8, 9). The stomachs of the 8-month-old female and
6-month-old male were also analyzed. In the 8-month-old female (Fig. 5C) and 6-month-old male (data not shown)
inham1/inham1,
MT-FS+ mice, stomach histology appeared
completely normal with no obvious depletion of parietal cells,
consistent with the low serum activin A levels.
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, D and E). However, the livers of the
8-month-old female (Fig. 5F) and 6-month-old male (data not shown)
inham1/inham1
MT-FS+ mice failed to show any signs of
hepatocellular necrosis or inflammation. Thus, although tumors occurred
in the older male and female
inham1/inham1,
MT-FS+ mice, these mice lived longer because of
the low activin levels and the lack of resultant liver and stomach
pathology. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study we show that overexpressing follistatin in the
absence of inhibin did not prevent initial gonadal tumor growth in
mice. Sex cord-stromal tumors continued to develop in 100% of the
inham1/inham1,
MT-FS+ male and female mice. However, we show
that follistatin in the absence of inhibin is an important modulator of
gonadal tumor progression and/or cachexia in the inhibin-deficient
mice. The presence of the MT-FS transgene resulted in prolonged
survival despite intermediate weight loss and a significant tumor
burden. A higher proportion (
20%) of both male and female
inham1/inham1,
MT-FS+ mice survived longer than 20 weeks of age
compared with inhibin-deficient male mice, which never survived past 17
weeks, and inhibin-deficient females, of which only one rare female
survived past 20 weeks of age. In addition, a total of six
inham1/inham1,
MT-FS+ mice lived to 6–8 months of age, further
confirming the important role of follistatin as a modulator in these
mice.
How is follistatin exerting its effects to increase the survival of these inhibin-deficient mice? It appears that follistatin is likely working via several mechanisms in these mice. First, at least in the case of the male inham1/inham1, MT-FS+ mice, there appears to be altered tumor differentiation. We observed sex cord-stromal tumors with an increased Sertoli cell tumor component in these transgene-carrying male mice, a finding that was never seen in males lacking only inhibin (7) (Matzuk and colleagues). Second, activin levels from both the male and female inham1/inham1, MT-FS+ mice were reduced compared with those in inham1/inham1 mice, leading to less dramatic wasting effects (i.e. reduced stomach pathology) in these mice. This could be due to differences in the secretion of activin from the tumors (e.g. because of tumor differentiation), because local follistatin in the tumor is preventing the release of activin into the circulation (e.g. increased surface-bound follistatin binding the activin), or because follistatin-bound activin is cleared more rapidly from the circulation. This mechanism is likely the reason for the prolonged survival of the 6- to 8-month-old inham1/inham1, MT-FS+ mice, which have very low levels of activin in the serum. Third, although we were unable to previously detect free follistatin in the circulation of MT-FS transgenic mice (26), this does not rule out the possibility that much of the activin in the circulation of inham1/inham1, MT-FS+ mice is bound to follistatin and that this is reducing the overall positive effects of the circulating activins. This is possibly true for several reasons, including the lower FSH levels in these mice [compared with our previously published findings for inhibin-deficient mice (7) (see below)] and the mild effects in the stomachs of the transgene carriers [in contrast to the nearly complete atrophy in mice lacking only inhibin, as observed at the histological and immunohistochemical levels (8, 9)]. We believe that all three of these mechanisms are having an effect in our mice, with some mechanisms being more prominent than others.
Why doesn’t the presence of MT-FS transgene have the same effect in all inhibin-deficient mice? All mice lacking inhibin do not die at the same age (3, 7, 8). This is due to genetic differences in the mice, the timing of the oncogenic "hits," and differences in aggressiveness of the various tumors. Likewise and similar to other transgenic studies, all transgenes are not expressed the same in different mice even within a line. This difference in expressivity between the transgenic mice is one possible reason for the early death of some mice relative to others.
Our laboratory has generated several compound mutants to study gonadal
tumor growth and differentiation. We previously generated double
homozygous mutant mice deficient in both inhibin and ActRIIA (10).
Gonadal sex cord-stromal tumors developed in these compound
homozygotes; however, the mice suffered no unusual weight loss, and the
livers and stomachs were histologically normal (9, 10). These results
demonstrated that the wasting syndrome in the inhibin-deficient mice
was due to increased levels of activin signaling through the ActRIIA in
hepatocytes and the glandular stomach. Several lines of evidence have
also shown an important role of gonadotropins in regulating
steroidogenesis and gonadal tumor development. Mice that lack both
inhibin and GnRH and have suppressed LH and FSH levels (27) do not
develop gonadal or adrenal tumors or a wasting syndrome and can survive
for more than 1 yr. These studies identified FSH and LH as modifying
factors of tumor development in these mice. In confirmation of these
studies, double mutant mice lacking both inhibin and FSH develop sex
cord-stromal tumors, yet 70% of the males are still alive by 1 yr of
age and have minimal cachexia, and double mutant females live twice as
long as female mice deficient in only inhibin (28). In these
studies activin secretion from these tumors in the absence of FSH was
dramatically decreased, suggesting that FSH acts in part as a modifier
to reduce the cachexia-like symptoms. In the present studies both
activin and FSH levels in the male
inham1/inham1,
MT-FS+ mice are lower than the levels in the
female mice, and as might be anticipated, levels of FSH are lower in
these same males relative to those in females. The lower FSH levels in
the
inham1/inham1,
MT-FS+ male mice, compared with those in female
mice of the same genotype, could also be acting as an additional
modifier of gonadal tumor development. Thus, gonadal tumor development
and the cancer cachexia-like syndrome involve an extremely complex
network of circulating and local factors, with inhibins, activins,
follistatin, and gonadotropins playing key roles in these
processes.
In human patients with advanced stage tumors and hematological malignancies, free follistatin levels were elevated (29). S1-Nuclease assays showed follistatin messenger RNA to be expressed in the testes, ovary, kidney, cerebral cortex, pituitary, adrenal, pancreas, heart, uterus, lung, and skeletal muscle of the rat (21, 30). Ovarian neoplasms account for only 4% of all cancers among women (31). However, the lack of early symptoms accounts for a 5-yr survival rate of only 46% for all stages and the highest mortality rate of cancers of the female reproductive system (31). Testicular cancers represent only 1% of all tumors in males, but is the most common malignancy in males between the ages of 15 and 34 yr (31, 32). Our present findings demonstrate a modulating role for follistatin in mouse gonadal tumorigenesis. Other hormonal factors may also influence initial tumor development and/or survival. For example, it will be interesting to determine whether signaling through estrogen receptors and/or LH receptor will influence gonadal tumor development and progression in inhibin mutant mice. The inham1/inham1, MT-FS+ mice may be an important in vivo model for furthering our understanding of the roles of follistatin in gonadal tumor development and the study and testing of markers for granulosa cell tumors.
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Acknowledgments |
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Footnotes |
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Received September 21, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-Inhibin is a tumour-suppressor gene with gonadal
specificity in mice. Nature 360:313–319.2[CrossRef][Medline]
and p53-deficient mice:
the role of activin as an autocrine growth factor. Mol Endocrinol 8:983–995[Abstract]
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