Study of different biochemical markers: bikunin, follistatin and activin significance in different types of ovarian cancer

OVARIAN CANCER HAS the second highest incidence in gynecologicalcancers
and is the fifth leading cause of cancer death among women in the world.
Characterizing the pathwaysthat regulate the growth of ovarian cells is necessary for
understanding the events that lead to development of ovarian cancer. The aim of the
present study was to evaluate the potential clinical implication of circulating Activin
A, follistatin, bikunin, ovarian tissue urokinase Plasminogen Activator (uPA) and
Smad-2 (fusion between Drosophila mothers against dpp (Mad) and C. elegans
Sma)expression for diagnosis and progression of ovarian cancer. Subjects: The study
was carried out on 75 women divided as follows: 15 women with serous ovarian
carcinoma, 15 women with mucinous ovarian carcinoma, 15 women with serous
ovarian cystadenoma, 15 fertile healthy women, 15 postmenopausal healthy women.
Methods:Serum levels of Activin A and Follistatin, and Plasma levels of
Bikunin were estimated using ELISA. Urokinase plasminogen activator (uPA) was
extracted from ovarian cancerous tissue and its levels estimated by ELISA. Detection
of Smad2 mRNA in ovarian tissue was performed by Reverse Transcription –
Polymerase Chain Reaction analysis (RT-PCR). Results: The levels of serum Activin
A and Follistatin were found to be significantly higher in serous and mucinous
ovarian carcinoma than in ovarian cystadenoma and controls (pre- and
postmenopausal). Plasma levels of Bikunin were estimated to be significantly lower in
patients with serous ovarian carcinoma and mucinous ovarian carcinoma than in
controls and than patients with ovarian cystadenoma. In the present study, levels of
uPA in ovarian tissue were significantly higher in serous ovarian carcinoma than in
ovarian cystadenoma and controls. Levels of uPA were significantly higher in
mucinous ovarian carcinoma than all other groups. Levels of uPA were found to be
increased with progression of the stage of ovarian tumor. Correlation studies showed
direct positive significant correlations between Activin A and Follistatin, Activin A
and uPA, Follistatin and uPA. Also, Bikunin was found to be inversely correlated to
Activin A, Follistatin and uPA. Smad-2 expression was detected in 75% of cases of
serous ovarian cystadenocarcinoma, in 90% of mucinous ovarian carcinoma.
Conclusions:In summary, activin A induces the proliferation of both serous and
mucinous ovarian carcinoma. Therefore, activin A may be regarded as both a
potentialgrowth factor and a tumor marker. The significantly elevated levels of serum
follistatin (Activin – binding protein) in ovarian carcinoma indicated that activin is
free and this modulated its signal transduction as illustrated by the expression of
Smad-2 in 90% of mucinous ovarian carcinoma and in 75% of serous
cystadenocarcinoma. The present study shows that the activin/Smad signaling
pathwayis functional in ovarian cancer cells which most probably promotes tumor
growth. It is proposed that Smad-2 increased the levels of uPA which is a proteolytic
enzyme that enhances tumor growth, progression, invasion and metastases. Plasma
bikunin concentration might be a strong and independent favorable prognostic
marker for ovarian cancer. It may be concluded that bikunin might attenuate Activin
A-elicited signaling cascades in ovarian cancer this probably suppresses uPA
expression. Treatment with bikuninmay be beneficial to delay the appearanceof
metastatic disease and/or combined with cytotoxic agents toimprove treatment
efficacy in advanced ovariancancers.