Erythropoietin and erythropoietin receptor system in a large uterine myoma of a patient with myomatous erythrocytosis syndrome: possible relationship with the pathogenesis of unusual tumor size

Pollio, Fabrizio; Staibano, Stefania; Mansueto, Gelsomina; Rosa, Gaetano De; Persico, Francesco; Falco, Massimo De; Lieto, Andrea Di

doi:10.1016/j.humpath.2004.10.009

Cited by 25 publications

(15 citation statements)

References 43 publications

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“…Other studies have shown the ectopic synthesis and secretion of Epo by uterine leiomyoma cells 27, 28. Interestingly, concomitant expression of EpoR within leiomyoma tissue and increased levels of ectopic Epo production have been associated with unusually large myomas, suggesting that an autocrine/paracrine Epo‐EpoR system may be regulating the proliferation of these cells 29. Additionally, concomitant expression of Epo and EpoR in cervical intraepithelial neoplasia,10 and cervical tumours10, 11, 30 seem to indicate that an Epo‐EpoR loop may contribute to the development of cervical cancer.…”

Section: Discussionmentioning

confidence: 92%

Autocrine/paracrine erythropoietin signalling promotes JAK/STAT‐dependent proliferation of human cervical cancer cells

López

Lappin

Maxwell

et al. 2011

Intl Journal of Cancer

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Erythropoietin (Epo) regulates erythropoiesis by binding to its receptor (EpoR) and promoting cell proliferation, differentiation and inhibition of apoptosis. Epo is widely used to treat cervical cancer-related anaemia. However, there are data suggesting that administration of Epo is associated with an increment in recurrence rate, and decreased disease-free and overall survival. In the present study, we investigated the expression of Epo and EpoR on cervical cancer cell lines. We observed that both EpoR and extracellular Epo are constitutively expressed in cervical cancer cells. Inhibition of either Epo or EpoR expression with siRNA attenuated cell proliferation, whereas addition of exogenous Epo led to a significant increase in cell growth, both in vitro and in vivo. Epo-induced proliferation was associated with the activation of JAK2, JAK3, STAT3 and STAT5 but not JAK1 and STAT1. Our results are consistent with the existence of a functional, endogenous Epo/EpoR system in cervical cancer with the capacity to activate the transduction of signals resulting in an increased proliferation potential.Erythropoietin (Epo) is a glycoprotein hormone that binds to the homodimer Epo receptor (EpoR) on the surface of the erythroid precursor cells promoting proliferation, differentiation and protecting erythroid progenitors from apoptosis.

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Section: Discussionmentioning

confidence: 92%

Autocrine/paracrine erythropoietin signalling promotes JAK/STAT‐dependent proliferation of human cervical cancer cells

López

Lappin

Maxwell

et al. 2011

Intl Journal of Cancer

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“…3 Epo-activated signaling pathways also are well studied, 4 yet gaps in knowledge persist concerning the nature of key signals for EpoR biofunction. Interest in this basic problem also is provoked by apparent EpoR cytoprotection of injured myocardial, neuronal, endothelial, and renal cells, 5 and by the association of EpoR action with angiogenesis, 5 VHL carcinomas, 6 melanoma, 7 and myoma 8 formation. To better elucidate core signals for erythroid progenitor cells, we presently have performed first-time analyses of the signaling capacities of minimal knocked-in murine EpoR alleles in primary bone marrow-derived erythroblasts.…”

Section: Introductionmentioning

confidence: 99%

Core erythropoietin receptor signals for late erythroblast development

Menon

Fang

Wojchowski

2006

Blood

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IntroductionSignals provided by Epo and its single transmembrane receptor (EpoR) are essential for erythroblast formation. 1 Physicochemical studies have revealed unique mechanisms for Epo binding 2 and conformation-dependent activation of EpoR-Jak2 kinase complexes. 3 Epo-activated signaling pathways also are well studied, 4 yet gaps in knowledge persist concerning the nature of key signals for EpoR biofunction. Interest in this basic problem also is provoked by apparent EpoR cytoprotection of injured myocardial, neuronal, endothelial, and renal cells, 5 and by the association of EpoR action with angiogenesis, 5 VHL carcinomas, 6 melanoma, 7 and myoma 8 formation. To better elucidate core signals for erythroid progenitor cells, we presently have performed first-time analyses of the signaling capacities of minimal knocked-in murine EpoR alleles in primary bone marrow-derived erythroblasts.Epo binding occurs via Epo high-affinity A, B, D helix site-1, and low-affinity A, C helix site-2 interactions with bipartite 7 beta-strand ligand binding sites in appositioned EpoR dimers. 2 Via a cytoplasmic juxtamembrane box-1 domain, the EpoR also preassembles with Jak2 kinase. 9 Epo-EpoR interactions stimulate Jak2 phosphorylation at Y1007/Y1008 sites, 10 and Jak2 (potentially in concert with Src, Btk, STK, and/or Kit tyrosine kinases) 11-15 then mediates the phosphorylation of multiple EpoR cytoplasmic tyrosine motifs. In particular, within the EpoR of mouse, human, and zebra fish, 16 8 distal phosphotyrosine motifs are conserved that possess established binding specificities for SH2-domain-encoding effectors. These include the following: PY343 binding of Stat5 17 ; PY401 binding of cytokine-inducible SH2-domain-containing protein Cis-1, SH2 inositol 5-phosphatase, SHIP-1, Gab-2, SOCS-3, and/or Syp/SH2-PTP2 18-22 ; PY429 and PY431 binding of SOCS-3 and/or SHP-1 23,24 ; PY460 binding of CrkL 25 and regulation of intracellular calcium flux 26 ; PY464 and/or PY479 binding of Lyn 27 ; and PY479 binding of alpha-p85/PI3 kinase. 28 In the human EpoR, an additional juxtamembrane cytoplasmic PY285 site also exists and has been demonstrated in 32D cells to modulate Stat5 and Stat1 activation. 29 Based on the evolutionary conservation of these EpoR PY sites and their demonstrated role as an assembling scaffold for downstream effectors, 4 EpoR phosphotyrosine motifs are predicted to be important for Epo's actions. The extent to which these EpoR regions (and linked pathways) act in central or perhaps only modulatory capacities, however, is controversial. This point is highlighted by the ability of PY-deficient EpoR alleles to support steady-state erythropoiesis in vivo. 30 Specifically, steady-state erythropoiesis in mice expressing a knocked-in PY-null EpoR-HM allele is affected to the extent that hematocrits are decreased approximately 8 points on average, and red blood cell (RBC) counts are decreased approximately 15%. 30 Unexpectedly, this suggests that core signals provided by Jak2 (in the absence of EpoR PY signals) efficiently...

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“…Apart from confirming erythropoietin production by myomatous tissue, Fabrizio Pollio and colleagues found a strong Epo-R expression in myoma endothelial cells, leading to the theory that erythropoietin production from uterine myoma not only contributes to erythrocytosis, but also stimulates proliferation and differentiation of myoblasts through autocrine and paracrine mechanisms leading to the large myomatous size almost always seen in this condition [12]. Similarly, in our case, we were able to detect elevated erythropoietin secretion in the myomatous tissue with elevated erythropoietin level in the blood that normalized after surgical resection of the leiomyoma.…”

Section: Discussionmentioning

confidence: 99%

Myomatous Erythrocytosis Syndrome: Case Report and Review of the Literature

Suresh¹,

Rizk²

2020

Cureus

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Myomatous Erythrocytosis Syndrome is defined as erythrocytosis, myomatous uterus, and the return of normal hematologic values following surgical resection. The exact role of erythropoietin in disease pathogenesis is unknown. In this study we report the case of a 49 year old premenopausal woman who was found to have an enlarged heterogeneous mass arising from the uterus concerning for malignancy. Her RBC count was 5.75 T/L, hemoglobin was 17.6 g/dL and hematocrit was 54.3%. Pre-operative erythropoietin levels were 24.6 mIU/mL and JAK2 mutation was not detected. She underwent Total Abdominal Hysterectomy and Bilateral Salpingo-Oophorectomy. The pathology was consistent with a uterine leiomyoma. Laboratory evaluation performed eight weeks after surgery showed a RBC count of 4.5 T/L, hemoglobin of 13.6 g/dL, hematocrit of 40.5%. Post-operative erythropoietin level was 5.4 mIU/mL. The tissue showed diffuse moderate to strong cytoplasmic immunopositive for Erythropoietin. Erythropoietin plays an important role in this condition, however the exact mechanism is still under investigation. The theory of erythropoietin secreting tumor autonomously without negative feedback is the most credible so far. However, further studies with use of blood erythropoietin level, tissue erythropoietin detection using immune-stain and new molecular biology techniques need to be done and compared to uterine myoma patients with no erythrocytosis. Usually, no further treatment is required following surgical removal.

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Erythropoietin and erythropoietin receptor system in a large uterine myoma of a patient with myomatous erythrocytosis syndrome: possible relationship with the pathogenesis of unusual tumor size

Cited by 25 publications

References 43 publications

Autocrine/paracrine erythropoietin signalling promotes JAK/STAT‐dependent proliferation of human cervical cancer cells

Autocrine/paracrine erythropoietin signalling promotes JAK/STAT‐dependent proliferation of human cervical cancer cells

Core erythropoietin receptor signals for late erythroblast development

Myomatous Erythrocytosis Syndrome: Case Report and Review of the Literature

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