Müllerian inhibiting substance/anti-Müllerian hormone: a potential therapeutic agent for human ovarian and other cancers

Abstract

According to the 2008 American Cancer Society statistics, cancer remains the second leading cause of death in American today. Early detection, innovative surgery, new drugs and increased public education regarding avoidable risk factors, such as smoking, have had significant impact on the incidence and survival rates of many cancers, while overall death rates from all cancers have declined a modest 5% over the past 50 years. Ovarian cancer statistics, however, have not been as encouraging. Despite recent advances in the management of this disease, 5-year survival has not improved, and the search continues for rationally designed new treatments. Müllerian Inhibiting Substance is a strong candidate because it addresses many of the deficiencies of existing treatments. Namely, Müllerian Inhibiting Substance has little demonstrated toxicity, it complements the activity of known anticancer drugs, it is highly specific against cancers expressing its receptor and it inhibits the proliferation of drug-resistant tumors.

Figure 1. The pattern of MIS in human serum is sexually dimorphic and varies with age

MIS in males is high at birth and, after a transient drop at approximately 2 years of age, levels are maintained until puberty. Serum MIS in females becomes measurable in the prepubertal period and is sustained until the menopause, after which it is no longer produced. The shaded bar demonstrates why serum MIS is useful in the perinatal period for evaluating cases of ambiguous genitalia. MIS is absent in genetic females and positive in cases with testicular tissue. The higher the values, the more normal the tissue. Serum testosterone is undetectable in normal males at this time. Rising serum MIS over normal limits in adult females (dotted line) is consistent with granulosa or sex cord tumors. MIS: Müllerian Inhibiting Substance.

Figure 2. The human MIS gene has five exons and four introns and encodes a monomer of 70 kDa with two N-linked glycosylation sites (circles)

The monomer forms a homodimer via disulfide bond formation and is activated by biosynthetic kex-like proteases to produce the 25-kDa carboxy terminal dimer, which is the bioactive domain of the molecule. The 110-kDa amino terminus stays associated with the carboxy terminus via noncovalent forces. MIS: Müllerian Inhibiting Substance.

Figure 3. The human MIS type II receptor gene, with its 11 exons, is larger than the nine-exon type I gene

They share several similar but not identical features, hence the different shadings, including extracellular ligand binding domains, transmembrane spanning regions and intracellular S/T kinase domains. Both types are required for MIS signaling, and mutations in the type II receptor are associated with phenotypic changes in humans. MIS: Müllerian Inhibiting Substance; S/T: Serine/threonine.

Figure 4. Müllerian Inhibiting Substance type II receptor expression in benign ovarian epithelium and epithelial ovarian cancers

Immunohistochemical analysis shows no receptor expression in benign postmenopausal ovary and strong staining in serous epithelial ovarian cancer. (A) Postmenopausal ovary and (B) surface epithelium. Serous epithelial ovarian cancers at (C) 1.25× and (D) 20×. Reprinted with permission from [113].

Figure 5. Müllerian Inhibiting Substance type II receptor expression in normal ovarian tissues

(A) PCR of Müllerian Inhibiting Substance type II receptor (arrow) in human ovary; lane A: secretory phase; lane B: follicular cyst; lane C: luteal cyst; lane D: borderline mucinous cystadenoma; lane E: borderline malignant cystadenoma; lane F: serous adenocarcinoma; lane G: endometrioid adenocarcinoma. (B) Light microscopy of a proliferative phase human ovary. Granulosa cells of the small antral follicle show expression of the Müllerian Inhibiting Substance type II receptor mRNA (400×). Adapted from [114].

Figure 6. Mouse ovarian carcinoma (MOVCAR) tumor-initiating cells, also known as SP cells, which can be separated from less tumorigenic NSP cells, respond to MIS in vitro (SP: 86%; NSP: 93%)

SP cells are moderately resistant to doxorubicin (30% inhibition) but are still nearly completely inhibited by MIS. ^†p < 0.001. ^‡p < 0.0005. MIS: Müllerian Inhibiting Substance; NSP: Non-side population; SP: Side population.