Müllerian inhibiting substance preferentially inhibits stem/progenitors in human ovarian cancer cell lines compared with chemotherapeutics

Abstract

Cancer stem cells are proposed to be tumor-initiating cells capable of tumorigenesis, recurrence, metastasis, and drug resistance, and, like somatic stem cells, are thought to be capable of unlimited selfrenewal and, when stimulated, proliferation and differentiation. Here we select cells by expression of a panel of markers to enrich for a population with stem cell-like characteristics. A panel of eight was initially selected from 95 human cell surface antigens as each was shared among human ovarian primary cancers, ovarian cancer cell lines, and normal fimbria. A total of 150 combinations of markers were reduced to a panel of three-CD44, CD24, and Epcam-which selected, in three ovarian cancer cell lines, those cells which best formed colonies. Cells expressing CD44, CD24, and Epcam exhibited stem cell characteristics of shorter tumor-free intervals in vivo after limiting dilution, and enhanced migration in invasion assays in vitro. Also, doxorubicin, cisplatin, and paclitaxel increased this enriched population which, conversely, was significantly inhibited by Mülle-rian inhibiting substance (MIS) or the MIS mimetic SP600125. These findings demonstrate that flow cytometry can be used to detect a population which shows differential drug sensitivity, and imply that treatment of patients can be individualized to target both stem/progenitor cell enriched and nonenriched subpopulations. The findings also suggest that this population, amenable to isolation by flow cytometry, can be used to screen for novel treatment paradigms, including biologic agents such as MIS, which will improve outcomes for patients with ovarian cancer.anthrapyrazolone | chemotherapy resistance | stem/progenitor cell-enriched populations A s evidence is accumulating to indicate that cancer could be a stem cell disease (1-4), it is becoming increasingly important to be able to identify cancer stem/progenitor cells and to develop treatment modalities that specifically target the stem cell enriched population, coupled with treatments effective against the larger population not enriched for stem cells. The concept of cancer stem cells has opened new areas of research in carcinogenesis, but has the more immediate translational potential of uncovering new treatment targets.We previously identified somatic label-retaining cells with stem cell features in ovarian surface epithelium (5), and with others (6, 7), postulate that somatic stem cells or their immediate progenitors can revert to cancer stem cells (8). It is also possible that the stem cells may remain the same, but that signals which control the stem/progenitor cell activity may change. Several recent studies have demonstrated that cancer stem cells may confer chemotherapeutic resistant ovarian tumor growth and metastasis (2, 9).Ovarian cancer is diagnosed in approximately 25,000 new cases per year in the United States and is associated with a 50% mortality rate (10, 11); more than 90% of cases are epithelial in origin (12, 13). Epithelial ovarian cancers fall into four main subtypes: mucinous,...

Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance

“…We recently identified a CD44+, CD24+, Epcam+ (3+) population, selectable by flow cytometry, which is enriched for stem/progenitor cells (5). When combined with negative selection for Ecadherin (3+Ecad−), the resulting smaller population consistently formed more and larger colonies [ Fig.…”

Anti-Müllerian hormone inhibits growth of AMH type II receptor-positive human ovarian granulosa cell tumor cells by activating apoptosis

“…The production of purified, fully cleaved AMH has been achieved only recently, 51 and with this AMH one would need only 1:1000 of the dose compared with partially cleaved AMH. Targeting AMHRII with activating antibodies 62 or small molecule agonists 23,59 presents another attractive option for supplementary treatment of AMHRII-positive advanced or recurrent GCTs. Nevertheless, the observed activation of apoptosis in GCTs may not necessarily involve AMHRII, given that the doses used in this study are more robust than implicated by the reported K d for AMH to AMHRII.…”

“…19,20 Ovarian epithelial carcinoma cells, originating from the coelomic epithelium/Müllerian duct, express AMHRII 17 and AMHRII positivity is also associated with prolonged overall survival. 19 AMH has been indicated as a growth inhibitor of AMHRII-positive ovarian cancer cells in vitro [20][21][22][23] and in vivo, [24][25][26][27] and this growth-inhibitory effect is characterized by a block in the cell cycle progression and subsequent apoptosis. 20,22 Although AMH has been indicated as a tissue marker for GCTs, 28 AMH immunoreactivity in a series of 80 primary GCTs was low or negative in the tumors larger than 10 cm in diameter.…”

Cancer Stem Cells in Tumor Heterogeneity

“…Cancer stem cells differ from their non-stem cancer cell counterparts in a wide variety of measurable properties, some of which include: proliferation rate (Moore and Lyle, 2011), migratory and invasive behavior (Wei et al, 2010), metastatic potential , and DNA repair activation/mechanisms (Bao et al, 2006a).…”