Expression of Follicle-Stimulating Hormone Receptor in Tumor Blood Vessels

Radu, Aurelian; Pichon, Christophe; Camparo, Philippe; Antoine, Martine; Allory, Yves; Couvelard, Anne; Fromont, Gaëlle; Hai, M. T. Vu; Ghinea, Nicolae

doi:10.1056/nejmoa1001283

Cited by 271 publications

(258 citation statements)

References 18 publications

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“…The possible role in pregnancy duration remains intriguing. Other studies described the association of the FSHR and its variants with an increasing number of noncanonical and nonobviously FSH-related pathophysiological events, such as osteoporosis (45), vasculogenesis (86), hypertension (33), ovarian cancer (87), and testis cancer (88). All these suggestions would question the dogma of the unique action of FSH at the gonadal level.…”

Section: Discussionmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Genetics of FSH action: a 2014-and-beyond view

Simoni

Casarini

2014

European Journal of Endocrinology

117

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Objective: To assess the pharmacogenetic potential of FSH for infertility treatment. Design: Review of the literature and genomic databases. Methods: Single-nucleotide polymorphism (SNP) assessed: rs6166 (c.2039AOG, p.N680S), rs6165 (c.919AOG, p.T307A), rs1394205 (c.K29GOA) in FSHR, and rs10835638 (c.K211GOT) in FSHB. Literature search via PubMed. Blast analysis of genomic information available in the NCBI nucleotide database. Comparison of allele frequency and haplotype distribution using the http://spsmart.cesga.estool. Results: All these SNPs appear first in Homo, result in reduced FSH action, and are present with variable frequencies and combinations worldwide. Stringent clinical studies demonstrate that the FSHR genotype influences serum FSH levels and gonadal response in both sexes. Serum FSH levels depend on the K211GOT SNP, influencing transcriptional activity of the FSHB promoter. Genotypes reducing FSH action are overrepresented in infertile subjects. Conclusions: Although the clinical relevance of the FSHR polymorphisms alone is limited, the combination of FSHR and FSHB genotypes has a much stronger impact than either one alone in both sexes. About 20% of people are carriers of the alleles associated with lower serum FSH levels/reduced FSHR expression or activity, possibly less favorable for reproduction. Prospective studies need to investigate whether stratification of infertile patients according to their FSHR-FSHB genotypes improves clinical efficacy of FSH treatment compared with the current, naïve approach. A relative enrichment of less favorable FSHR-FSHB genotypes may be related to changes in human reproductive strategies and be a marker of some health-related advantage at the cost of reduced fertility.

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Section: Discussionmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Genetics of FSH action: a 2014-and-beyond view

Simoni

Casarini

2014

European Journal of Endocrinology

117

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“…GnRH antagonists are also associated with a more profound and sustained suppression of follicle-stimulating hormone levels compared with GnRH agonists [14]. This observation is of interest as evidence is accumulating that follicle-stimulating hormone may have a direct role in the pathogenesis and progression of PrCa [26,27,28,29,30]. Together, such effects could in theory contribute to a more rapid and/or more pronounced shrinkage of prostate tumours during treatment with degarelix as compared with G+B.…”

Section: Discussionmentioning

confidence: 99%

Degarelix versus Goserelin (+ Antiandrogen Flare Protection) in the Relief of Lower Urinary Tract Symptoms Secondary to Prostate Cancer: Results from a Phase IIIb Study (NCT00831233)

et al. 2012

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Introduction: No studies to date have assessed the efficacy/tolerability of degarelix in the relief of lower urinary tract symptoms (LUTS) secondary to prostate cancer (PrCa). Methods: Patients were randomised to degarelix 240/80 mg or goserelin 3.6 mg + bicalutamide flare protection (G+B); both treatments were administered for 3 months. The primary endpoint was change in International Prostate Symptom Score (IPSS) at week 12 compared with baseline. Results: This study was stopped early due to recruitment difficulties. 40 patients received treatment (degarelix n = 27; G+B n = 13); most had locally advanced disease and were highly symptomatic. Degarelix was non-inferior to G+B in reducing IPSS at week 12 in the full analysis set (p = 0.20); the significantly larger IPSS reduction in the per-protocol analysis (p = 0.04) was suggestive of superior reductions with degarelix. Significantly more degarelix patients had improved quality of life (IPSS question) at week 12 (85 vs. 46%; p = 0.01). Mean prostate size reductions at week 12 were 42 versus 25% for patients receiving degarelix versus G+B, respectively (p = 0.04; post hoc analysis). Most adverse events were mild/moderate; more degarelix patients experienced injection site reactions whereas more G+B patients had urinary tract infections/cystitis. Conclusion: In 40 men with predominantly locally advanced PrCa and highly symptomatic LUTS, degarelix was at least non-inferior to G+B in reducing IPSS at week 12.

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“…This happened basically because of the ease of availability of granulosa cells for research compared with the OSE cells. We need to acknowledge the large body of the available literature (Table 2) at both protein and transcript levels suggesting the presence of FSHR on OSE in normal and cancerous states (Bose 2008), 20-fold higher in oocytes compared with granulosa cells (Meduri et al 2002), in blood vessels of normal gonads (Vu Hai et al 2004) as well associated with various metastatic tumors Radu et al 2010).…”

Section: Referencesmentioning

confidence: 99%

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

Bhartiya

Singh

2015

Reproduction

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Despite extensive research, genetic basis of premature ovarian failure (POF) and ovarian cancer still remains elusive. It is indeed paradoxical that scientists searched for mutations in FSH receptor (FSHR) expressed on granulosa cells, whereas more than 90% of cancers arise in ovary surface epithelium (OSE). Two distinct populations of stem cells including very small embryonic-like stem cells (VSELs) and ovarian stem cells (OSCs) exist in OSE, are responsible for neo-oogenesis and primordial follicle assembly in adult life, and are modulated by FSH via its alternatively spliced receptor variant FSHR3 (growth factor type 1 receptor acting via calcium signaling and the ERK/MAPK pathway). Any defect in FSH-FSHR3-stem cell interaction in OSE may affect folliculogenesis and thus result in POF. Ovarian aging is associated with a compromised microenvironment that does not support stem cell differentiation into oocytes and further folliculogenesis. FSH exerts a mitogenic effect on OSE and elevated FSH levels associated with advanced age may provide a continuous trigger for stem cells to proliferate resulting in cancer, thus supporting gonadotropin theory for ovarian cancer. Present review is an attempt to put adult ovarian biology, POF, aging, and cancer in the perspective of FSH-FSHR3-stem cell network that functions in OSE. This hypothesis is further supported by the recent understanding that: i) cancer is a stem cell disease and OSE is the niche for ovarian cancer stem cells; ii) ovarian OCT4-positive stem cells are regulated by FSH; and iii) OCT4 along with LIN28 and BMP4 are highly expressed in ovarian cancers.Reproduction (2015) 149 R35-R48

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Expression of Follicle-Stimulating Hormone Receptor in Tumor Blood Vessels

Abstract: FSH receptor is selectively expressed on the surface of the blood vessels of a wide range of tumors. (Funded by INSERM.).

Cited by 271 publications

References 18 publications

MECHANISMS IN ENDOCRINOLOGY: Genetics of FSH action: a 2014-and-beyond view

MECHANISMS IN ENDOCRINOLOGY: Genetics of FSH action: a 2014-and-beyond view

Degarelix versus Goserelin (+ Antiandrogen Flare Protection) in the Relief of Lower Urinary Tract Symptoms Secondary to Prostate Cancer: Results from a Phase IIIb Study (NCT00831233)

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

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