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.