Human ovarian cancer cells from ascites express the human type II MIS receptor, bind labeled recombinant MIS and are growth inhibited

We continue to investigate the potential receptor-mediated, tumor-specific biological modifier, Mullerian Inhibiting Substance (MIS), a member of the TGF-P family that is responsible for regression of the Mullerian duct in ma le fetuses. MIS was chosen as a treatment for ovarian carcinomas because of their derivation from the coelomic epithelium that invaginates in the embr yo to form the Mullerian duct. We hypothesize that MIS binding to specific receptor can rapidly select potentially responsive tumors, that this can be visualized by flow cytometry, and that response to MIS in vivo can be pred icted by growth inhibition of the tumor cells in vitro. Samples of ascites cells from 27 patients with stage III or IV epithelial o varian carcinoma were studied to determine whether recombinant human Muller ian Inhibiting Substance (rhMIS) acts through its receptor in inhibiting tu mor colony growth in soft agar. We produced rhMIS in the laboratory, labele d it with biotin, cloned the human MIS type II receptor for mRNA detection in the tumor cells and raised antibodies to the receptor's extracellular do main peptide for protein detection. Ascites cells from 15/27 or 56% of pati ents tested bound biotinylated MIS (MIS-Biotin) and, of the 11 that grew in soft agarose, 9/11 or 82% showed statistically significant inhibition of c olony formation. Of the 15 patients who bound biotinylated MIS, mRNA was av ailable for analysis from nine, and 8/9 expressed MIS type 11 receptor mRNA by RT-PCR, showing a statistically significant correlation with binding by Chi(2) analysis (p=0.025). Solid ovarian cancers were positive for the MIS type II receptor protein by immunohistochemical staining which colocalized with staining for antibody to CA-125 (OC125). Thus, the detection of the M IS type II receptor by flow cytometry may be a useful predictor of therapeu tic response to MIS, and may be a modality to rapidly choose patients with late stage ovarian cancer for treatment with MIS.