Melatonin: A Rediscovered Antitumor Hormone? Its Relation to Surface Receptors; Sex Steroid Metabolism, Immunologic Response, and Chronobiologic Factors in Tumor Growth and Therapy

Estrogens are essential for bone mass accrual but their role before sexual maturation has remained elusive. Using in situ hybridization and immunohistochemistry, we investigated the expression of both estrogen receptor (ER) alpha and beta mRNA and protein as well as several mRNAs coding for enzymes involved in sex steroid metabolism (aromatase, type I and II 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), steroid sulfatase (STS) and type I 5 alpha-reductase) on sections of tibial metaphyses before (1- and 4-week-old), during (7-week-old) and after (16-week-old) sexual maturation in female and male rats. ER alpha and ER beta mRNA and protein were detected in metaphyseal bone in lining cells, osteoblasts, osteoclasts and some osteocytes with no apparent differences in expression during development or between the sexes. In contrast, aromatase, type I and II 17 beta-HSD and type I 5 alpha-reductase mRNAs were first detected in osteoblasts, osteoclasts and occasionally in osteocytes from sexual maturation (7-week-old rat) and onwards. Only STS was present before sexual maturation. To study the significance of ER alpha and beta expression in bone before sexual maturation when circulating sex steroid levels are low, 26-day-old female and male rats underwent gonadectomy or 17 beta-estradiol (E(2)) supplementation (0.5 mg/21 days) during 3 weeks. Following gonadectomy, trabecular bone volume (TBV) was lower in males (P=0.03) and there was a trend towards reduction in females (P=0.057). E(2) supplementation increased tibial TBV compared with controls in both genders as assessed by Masson-Goldner staining. These data suggest that the presence of ERs in bone cells before sex maturation might be of significance for bone mass accrual. Furthermore, based on the mRNA expression of the crucial enzymes aromatase and type I 17 beta-HSD, we suggest that bone cells in the tibial metaphysis acquire the intrinsic capacity to metabolize sex steroids from sexual maturation onwards. This process may contribute to the beneficial effects of estrogen on bone mass accrual, possibly by intracrinology.

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Possible genetic polymorphisms related to sex steroid metabolism and dementia in women

Hormones, Cognition and Dementia ◽

10.1017/cbo9780511635700.016 ◽

2010 ◽

pp. 143-152

Author(s):

Eef Hogervorst ◽

Stephan Bandelow ◽

Chris Talbot

Keyword(s):

Genetic Polymorphisms ◽

Steroid Metabolism ◽

Sex Steroid

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Joint Effects of Smoking and Gene Variants Involved in Sex Steroid Metabolism on Hot Flashes in Late Reproductive-Age Women

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-2216 ◽

2012 ◽

Vol 97 (6) ◽

pp. E1032-E1042 ◽

Cited By ~ 14

Author(s):

Samantha F. Butts ◽

Ellen W. Freeman ◽

Mary D. Sammel ◽

Kaila Queen ◽

Hui Lin ◽

...

Keyword(s):

Hot Flashes ◽

Reproductive Age ◽

Steroid Metabolism ◽

Sex Steroid ◽

Gene Variants ◽

Joint Effects ◽

Reproductive Age Women

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Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity

Clinical Endocrinology ◽

10.1111/j.1365-2265.2007.02755.x ◽

2007 ◽

Vol 66 (3) ◽

pp. 440-446 ◽

Cited By ~ 104

Author(s):

Deborah J. Wake ◽

Magnus Strand ◽

Eva Rask ◽

Jukka Westerbacka ◽

Dawn E. W. Livingstone ◽

...

Keyword(s):

Body Fat ◽

Fat Distribution ◽

Body Fat Distribution ◽

Steroid Metabolism ◽

Sex Steroid ◽

Human Obesity

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Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and innate antitumor immune responses

Science Translational Medicine ◽

10.1126/scitranslmed.aax6337 ◽

2020 ◽

Vol 12 (530) ◽

pp. eaax6337 ◽

Cited By ~ 17

Author(s):

Jesse M. Jaynes ◽

Rushikesh Sable ◽

Michael Ronzetti ◽

Wendy Bautista ◽

Zachary Knotts ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Tumor Growth ◽

Cancer Progression ◽

Selective Reduction ◽

Mannose Receptor ◽

Tumor Associated Macrophages ◽

Host Defense Peptides ◽

Surface Receptors ◽

Effective Combination

Solid tumors elicit a detectable immune response including the infiltration of tumor-associated macrophages (TAMs). Unfortunately, this immune response is co-opted into contributing toward tumor growth instead of preventing its progression. We seek to reestablish an antitumor immune response by selectively targeting surface receptors and endogenous signaling processes of the macrophage subtypes driving cancer progression. RP-182 is a synthetic 10-mer amphipathic analog of host defense peptides that selectively induces a conformational switch of the mannose receptor CD206 expressed on TAMs displaying an M2-like phenotype. RP-182–mediated activation of this receptor in human and murine M2-like macrophages elicits a program of endocytosis, phagosome-lysosome formation, and autophagy and reprograms M2-like TAMs to an antitumor M1-like phenotype. In syngeneic and autochthonous murine cancer models, RP-182 suppressed tumor growth, extended survival, and was an effective combination partner with chemo- or immune checkpoint therapy. Antitumor activity of RP-182 was also observed in CD206high patient-derived xenotransplantation models. Mechanistically, via selective reduction of immunosuppressive M2-like TAMs, RP-182 improved adaptive and innate antitumor immune responses, including increased cancer cell phagocytosis by reprogrammed TAMs.

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