Patterns of Mullerian Inhibiting Substance Type II and Candidate Type I Receptors in Epithelial Ovarian Cancer^†

Abstract

The MIS pathway is a potential therapeutic target in epithelial ovarian cancer (EOC): signaling requires both type II (T2R) and type I receptors (T1R), and results in growth inhibition. MISR2 is expressed in EOC, but the prevalence and relative contributions of candidate T1R remain unknown. We sought to: a) determine expression of T1R in EOC; b) assess impact of T1R expression with clinical outcomes; c) verify MIS-dependent Smad signaling and growth inhibition in primary EOC cell cultures. Tissue microarrays (TMA) were developed for analysis of T1Rs (ALK2/3/6) and MISR2 expression. Primary cell cultures were initiated from ascites harvested at surgery which were used to characterize response to MIS. TMA’s from 311 primary cancers demonstrated the most common receptor combinations were: MISR2+/ALK2+3+6+ (36%); MISR2+/ALK2+3+6- (34%); MISR2-/ALK2+3+6- (18%); and MISR2-/ALK2+3+6+ (6.8%). No differences in overall survival (OS) were noted between combinations. The ALK6 receptor was least often expressed T1R and was associated with lower OS in early stage disease only (p =0.03). Most primary cell cultures expressed MISR2 (14/22 (63.6%)): 95% of these express ALK 2 and ALK3, whereas 54.5% expressed ALK6. MIS-dependent Smad phosphorylation was seen in the majority of cultures (75%). Treatment with MIS led to reduced cell viability at an average of 71% (range: 57–87%) in primary cultures. MIS signaling is dependent upon the presence of both MISR2 and specific T1R. In the majority of EOC, the T1R required for MIS-dependent signaling are present and such cells demonstrate appropriate response to MIS.

Identification and validation of a five-lncRNA signature for predicting survival with targeted drug candidates in ovarian cancer

“…Expression of BMPR1B is highest in adult ovaries, and is the major gene identified for reproductive traits including folliculogenesis. While it was reported that OC patients with BMPR1B expression have an unfavorable prognosis [33], our results indicate that the lncRNA BMPR1B-DT predicts longer survival. Taken together, it is conceivable that lncRNA BMPR1B-DT is a competitor for the BMPR1B mRNA promoter.…”

Anti-Müllerian hormone concentration regulates activin receptor-like kinase-2/3 expression levels with opposing effects on ovarian cancer cell survival

“…Basal et al (25) analyzed the expression of AMHRII, ALK2, ALK3 and ALK6 by immunohistochemistry in 262 epithelial ovarian carcinoma samples; AMHRII was expressed in 73.4% of the samples, as previously reported (5,11,45,46). In the 235 samples in which all four receptors could be assessed, 36% expressed AMHRII/ALK2/ALK3/ALK6, 34% AMHRII/ALK2/ALK3, 18% ALK2/ALK3, and 7% ALK2/ALK3/ALK6, and these expression profiles were not associated with the disease stage, overall or disease-free survival (25). In the present study, using two ovarian cancer cell lines COV434-AMHRII and SKOV3-AMHRII, ALK3 was demonstrated to be the predominant AMHRI responsible for AMH signaling, resulting in the induction of apoptosis.…”

“…Although the roles of ALK2, ALK3 and ALK6 have been studied in several cell types during development and in other physiological conditions (18)(19)(20)(21)(22)(23)(24), limited data are available on their roles in cancer. Basal et al (25) have demonstrated that AMHRII, ALK2, ALK3 and ALK6 are expressed in epithelial ovarian cancer specimens, but have not assessed their functions.…”

The role of anti-Müllerian hormone (AMH) in ovarian disease and infertility

“…Though it is suggested that the majority of ovarian cancers within the Müllerian tract arise from the fimbriated end of the fallopian tube, there are certain types of tumours which derive from the secondary Müllerian system [98]. Knowing that AMH acts in the regression of Müllerian ducts during the male gender differentiation in the embryo, scientists have proposed the possibility of using AMH as a potential treatment agent in epithelial ovarian cancers [99]. It has been proven, that recombinant AMH affects certain ovarian cancer cell lines (OVCAR 8 and IGROV 1) and inhibits their growth [100].…”