The Expression of Anti-Müllerian Hormone Type II Receptor (AMHRII) in Non-Gynecological Solid Tumors Offers Potential for Broad Therapeutic Intervention in Cancer.

Jean-Marc Barret,Isabelle Ray-Coquard,Olivier Dubreuil,Charles Dumontet,André Nicolas,Emilie Duchalais,Tilda Passat,Emeline Perrial,Didier Meseure,Sergio Roman-Roman,Solenne Gaillard,Mehdi Lahmar,Anne Jarry,Gabriel Champenois,Céline Bossard,Cécile Deleine,Jean-François Prost,Jaafar Bennouna

doi:10.3390/biology10040305

Abstract

Simple SummaryUntil now, only a few studies have examined the AMHRII expression in tumors. Here, with more than 1000 tumor samples and using several complementary techniques we confirmed AMHRII expression in gynecological cancer and demonstrated AMHRII expression in certain non-gynecological cancers such as colorectal cancers. These findings open the way for new therapeutic approaches targeting AMHRII and emphasize the need to better understand the role of AMH/AMHRII in cancer.The anti-Müllerian hormone (AMH) belongs to the TGF-β family and plays a key role during fetal sexual development. Various reports have described the expression of AMH type II receptor (AMHRII) in human gynecological cancers including ovarian tumors. According to qRT-PCR results confirmed by specific In-Situ Hybridization (ISH) experiments, AMHRII mRNA is expressed in an extremely restricted number of normal tissues. By performing ISH on tissue microarray of solid tumor samples AMHRII mRNA was unexpectedly detected in several non-gynecological primary cancers including lung, breast, head and neck, and colorectal cancers. AMHRII protein expression, evaluated by immunohistochemistry (IHC) was detected in approximately 70% of epithelial ovarian cancers. Using the same IHC protocol on more than 900 frozen samples covering 18 different cancer types we detected AMHRII expression in more than 50% of hepato-carcinomas, colorectal, lung, and renal cancer samples. AMHRII expression was not observed in neuroendocrine lung tumor samples nor in non-Hodgkin lymphoma samples. Complementary analyses by immunofluorescence and flow cytometry confirmed the detection of AMHRII on a panel of ovarian and colorectal cancers displaying comparable expression levels with mean values of 39,000 and 50,000 AMHRII receptors per cell, respectively. Overall, our results suggest that this embryonic receptor could be a suitable target for treating AMHRII-expressing tumors with an anti-AMHRII selective agent such as murlentamab, also named 3C23K or GM102. This potential therapeutic intervention was confirmed in vivo by showing antitumor activity of murlentamab against AMHRII-expressing colorectal cancer and hepatocarcinoma Patient-Derived tumor Xenografts (PDX) models.

Highlights

IntroductionAnti-Müllerian hormone type II receptor (AMHRII) binds the anti-Müllerian hormone (AMH or Müllerian inhibiting substance or MIS for Müllerian inhibiting substance) [3] and plays a major role in male fetus sexual differentiation by inducing the regression of Müllerian ducts, precursors of female reproductive organs (uterus, fallopian tubes, and upper vagina) [4]
The Anti-Müllerian hormone type II receptor (AMHRII), known as MIS type II receptor (MISRII or MISIIR), is a member of the transforming growth factor beta (TGFβ) receptor superfamily and was discovered in 1994 by two independent teams [1,2].AMHRII binds the anti-Müllerian hormone (AMH or Müllerian inhibiting substance or MIS for Müllerian inhibiting substance) [3] and plays a major role in male fetus sexual differentiation by inducing the regression of Müllerian ducts, precursors of female reproductive organs [4]
Using flow cytometry on fresh tissues to quantify AMHRII expression at the plasma membrane, we showed that AMHRII is aberrantly expressed in CRC cells as compared to normal colonic epithelial cells in 70% of CRC with a mean receptor density of 50,000, a level even slightly higher than that found in ovarian cancers (39,000)

Summary

Introduction

AMHRII binds the anti-Müllerian hormone (AMH or Müllerian inhibiting substance or MIS for Müllerian inhibiting substance) [3] and plays a major role in male fetus sexual differentiation by inducing the regression of Müllerian ducts, precursors of female reproductive organs (uterus, fallopian tubes, and upper vagina) [4]. AMHRII has been described to be expressed in Sertoli and Leydig cells and is involved in the regulation of androgen biosynthesis [6]; Inactivating mutations of AMHRII result in Leydig cell hyperplasia [7]. AMHRII expression has been described in the brain but its role (neurogenesis, neuroprotection, and/or regulator of sex-linked bias) [8]. Mutated forms of AMHRII do not appear to be associated with a neurological or behavioral impact [10]

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