Obstet Gynecol Sci.  2014 Sep;57(5):343-357. 10.5468/ogs.2014.57.5.343.

Mullerian inhibiting substance/anti-Mullerian hormone: A novel treatment for gynecologic tumors

• Kim JH
• MacLaughlin DT
• Donahoe PK

• KMID: 2051715
• DOI: http://doi.org/10.5468/ogs.2014.57.5.343

Abstract

Mullerian inhibiting substance (MIS), also called anti-Mullerian hormone (AMH), is a member of the transforming growth factor-beta super-family of growth and differentiation response modifiers. It is produced in immature Sertoli cells in male embryos and binds to MIS/AMH receptors in primordial Mullerian ducts to cause regression of female reproductive structures that are the precursors to the fallopian tubes, the surface epithelium of the ovaries, the uterus, the cervix, and the upper third of the vagina. Because most gynecologic tumors originate from Mullerian duct-derived tissues, and since MIS/AMH causes regression of the Mullerian duct in male embryos, it is expected to inhibit the growth of gynecologic tumors. Purified recombinant human MIS/AMH causes growth inhibition of epithelial ovarian cancer cells and cell lines in vitro and in vitro via MIS receptor-mediated mechanism. Furthermore, several lines of evidence suggest that MIS/AMH inhibits proliferation in tissues and cell lines of other MIS/AMH receptor-expressing gynecologic tumors such as cervical, endometrial, breast, and in endometriosis as well. These findings indicate that bioactive MIS/AMH recombinant protein should be tested in patients against tumors expressing the MIS/AMH receptor complex, perhaps beginning with ovarian cancer because it has the worst prognosis. The molecular tools to identify MIS/AMH receptor expressing ovarian and other cancers are in place, thus, it is possible to select patients for treatment. An MIS/AMH ELISA exists to follow administered doses of MIS/AMH, as well. Clinical trials await the production of sufficient supplies of qualified recombinant human MIS/AMH for this purpose.

Keyword

Mullerian tumor; Mullerian inhibiting substance type II receptor; Mullerian inhibiting substance; Anti-Mullerian hormone; Ovarian neoplasms

MeSH Terms

Anti-Mullerian Hormone
Breast
Cell Line
Cervix Uteri
Embryonic Structures
Endometriosis
Enzyme-Linked Immunosorbent Assay
Epithelium
Equipment and Supplies
Fallopian Tubes
Female
Humans
Male
Mullerian Ducts
Ovarian Neoplasms
Ovary
Prognosis
Sertoli Cells
Uterus
Vagina
Anti-Mullerian Hormone

Figure

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  Fig. 1 MIS Expression is sexually dimorphic helpful in assessing of Intersex and gonadal tumor patients. Serum Müllerian inhibiting substance (MIS)/anti-Müllerian hormone (AMH) in humans varies with sex and age. MIS/AMH in males is high at birth and levels are maintained until puberty. MIS/AMH in females becomes measurable at puberty and is gone by the menopause. Elevated MIS in females (dashed line) is consistent with granulosa/sex cord tumors. MIS levels drop in response to therapy (Reproduced from MacLaughlin DT, et al. Future Oncol 2010;6:391-405, with permission of Future Medicine Ltd.) [28].

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  Fig. 2 The human Müllerian inhibiting substance (MIS)/anti-Müllerian hormone (AMH) gene has 5 exons and 4 introns and encodes a 70 kDa monomer with two N-linked glycosylation sites (circles). The disulfide-linked homodimer is activated by biosynthetic proteases to produce the 25-kDa carboxy-terminal dimer. This domain is responsible for its bioactivity. The 110-kDa amino-terminus stays associated with the carboxy-terminus via non-covalent forces (Reproduced from MacLaughlin DT, et al. Future Oncol 2010;6:391-405, with permission of Future Medicine Ltd.) [28].

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  Fig. 3 MIS signals via a heteromeric receptor system. The human Müllerian inhibiting substance (MIS)/anti-Müllerian hormone (AMH) type II receptor gene has 11 exons and the type I gene has 9. They share several features including extracellular ligand-binding domains, transmembrane spanning regions and intracellular serine-threonine kinase domains. Both types are required for MIS/AMH signaling and mutations in the type II receptor are associated with phenotypic changes in humans (Reproduced from MacLaughlin DT, et al. Future Oncol 2010;6:391-405, with permission of Future Medicine Ltd.) [28].

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  Fig. 4 Recombinant human Müllerian inhibiting substance (MIS)/anti-Mü hormone (AMH) inhibits MOVCAR cell lines in vitro in a dose dependent manner (A). (B) shows the mean level of inhibition of MOVCAR cells by 71 nM MIS/AMH in six different experiments; approximately 95% compared to controls in a colorimetric cell count assay (From Pieretti-Vanmarcke R, et al. Clin Cancer Res 2006;12:1593-8, with permission from American Association for Cancer Research) [110].

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  Fig. 5 Recombinant human Müllerian inhibiting substance (MIS)/anti-Müllerian hormone (AMH) decreases growth of MOVCAR allografts in nude mice. Cells were injected in the dorsal fat pad (A) or the left leg (B) and animals treated with PBS or MIS/AMH. Tumor volumes (+/- SEM) 35 to 82 days after injection are shown (From Pieretti-Vanmarcke R, et al. Clin Cancer Res 2006;12:1593-8, with permission from American Association for Cancer Research) [110]. *Significant from control.

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  Fig. 6 Müllerian inhibiting substance (MIS)/anti-Müllerian hormone given intraperitoneally for 38 days to a mouse after a dorsal fat pad tumor had formed ablated the mass. (A) shows the treated animal (top) and the control animal (bottom) with its tumor (arrow). Tumor volume measurements are given in (B) (From Jakowlew SB, editor. Transforming growth factor-[beta] in cancer therapy. 1st ed. Totowa: Humana Press; 2008, with permission from Springer) [111].

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  Fig. 7 In vitro dose responses for MOVCAR7 cells for Müllerian inhibiting substance (MIS)/anti-Müllerian hormone (AMH) and rapamycin, paclitaxel, cisplatin and doxorubicin alone (A-E) and results of combination treatments (bar graphs, bottom) are shown. Rapamycin and doxorubicin were synergistic with MIS/AMH Ⓢ; Paclitaxel and cisplatin were additive Ⓐ. Significant inhibition relative to controls is indicated by an asterisk (*); MIS/AMH alone was always significantly different from combination treatment (**) (From Pieretti-Vanmarcke R, et al. Proc Natl Acad Sci U S A 2006;103:17426-31, with permission from National Academy of Sciences) [113].

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  Fig. 8 (A) Inhibition of cervical cancer cell growth by Müllerian inhibiting substance (MIS)/anti-Müllerian hormone (AMH) for C33A and CaSki cells, after 4 days of MIS/AMH treatment (P<0.001). (B) C33A cells stably transfected with empty vector, an inactive MIS/AMH (K1), or bioactive MIS/AMH (K2). K1 had little effect, whereas active MIS/AMH inhibited to over 90% (From Barbie TU, et al. Proc Natl Acad Sci U S A 2003;100:15601-6, with permission from National Academy of Sciences) [100].

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  Fig. 9 RT-PCR of Müllerian inhibiting substance type II receptor mRNA from human cervix and cervical cancers. Bands of 361 bp are detected in normal cervix (a,b), squamous cell carcinoma of cervix (c), and adenocarcinoma of cervix (d). Lane (e) is the DNA ladder [114].

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  Fig. 10 Müllerian inhibiting substance/anti-Müllerian hormone type II receptor protein expression in the rat uterus. Pregnant (A) and non-pregnant (B) uteri and ovary are positive for the receptor but not intestine by western assay. Receptor expression may increase with pregnancy (From Renaud EJ, et al. Proc Natl Acad Sci U S A 2005;102:111-6, with permission from National Academy of Sciences) [70].

• 

  Fig. 11 71 nM recombinant human Müllerian inhibiting substance (MIS)/anti-Müllerian hormone (AMH) significantly inhibits proliferation of human endometrial cancer cell lines AN3CA (by 67%) and KLE (by 52%) compared with cells treated with buffer control. MIS/AMH did not inhibit the growth of COS 7 cells, which do not express the MIS/AMH type II receptor (From Renaud EJ, et al. Proc Natl Acad Sci U S A 2005;102:111-6, with permission from National Academy of Sciences) [70].

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  Fig. 12 Induction of early and late apoptosis by Müllerian inhibiting substance (MIS) in endometrial stromal cells. Cells were treated with 71 nM MIS for 72 hours. For apoptosis, the externalization of phosphatidylserine was assessed by measuring annexin-V-FITC binding using propidium iodide as a counterstain. Quadrant rectangular dot grams from a representative of 3 independent experiments are shown (From Namkung J, et al. J Clin Endocrinol Metab 2012;97:3224-30, with permission from The Endocrine Society) [118].

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