Erythropoietin and Its Receptor in Breast Cancer: Putting Together the Pieces of the Puzzle

Mannello, Ferdinando; Tonti, Gaetana A.

doi:10.1634/theoncologist.2008-0110

Cited by 10 publications

(5 citation statements)

References 52 publications

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“…Thus, cells can circumvent JAK2-dependent pathway for the JAK2-independent pathway (ERK1/2). Mannello and other previously reported about a JAK2-independent pathway [60]. …”

Section: Discussionmentioning

confidence: 99%

Erythropoietin is a JAK2 and ERK1/2 effector that can promote renal tumor cell proliferation under hypoxic conditions

Miyake¹,

Goodison

Lawton

et al. 2013

J Hematol Oncol

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BackgroundErythropoietin (EPO) provides an alternative to transfusion for increasing red blood cell mass and treating anemia in cancer patients. However, recent studies have reported increased adverse events and/or reduced survival in patients receiving both EPO and chemotherapy, potentially related to EPO-induced cancer progression. Additional preclinical studies that elucidate the possible mechanism underlying EPO cellular growth stimulation are needed.MethodsUsing commercial tissue microarray (TMA) of a variety of cancers and benign tissues, EPO and EPO receptor immunohistochemical staining was performed. Furthermore using a panel of human renal cells (Caki-1, 786-O, 769-P, RPTEC), in vitro and in vivo experiments were performed with the addition of EPO in normoxic and hypoxic states to note phenotypic and genotypic changes.ResultsEPO expression score was significantly elevated in lung cancer and lymphoma (compared to benign tissues), while EPOR expression score was significantly elevated in lymphoma, thyroid, uterine, lung and prostate cancers (compared to benign tissues). EPO and EPOR expression scores in RCC and benign renal tissue were not significantly different. Experimentally, we show that exposure of human renal cells to recombinant EPO (rhEPO) induces cellular proliferation, which we report for the first time, is further enhanced in a hypoxic state. Mechanistic investigations revealed that EPO stimulates the expression of cyclin D1 while inhibiting the expression of p21cip1 and p27kip1 through the phosphorylation of JAK2 and ERK1/2, leading to a more rapid progression through the cell cycle. We also demonstrate an increase in the growth of renal cell carcinoma xenograft tumors when systemic rhEPO is administered.ConclusionsIn summary, we elucidated a previously unidentified mechanism by which EPO administration regulates progression through the cell cycle, and show that EPO effects are significantly enhanced under hypoxic conditions.

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“…Thus, cells can circumvent JAK2-dependent pathway for the JAK2-independent pathway (ERK1/2). Mannello and other previously reported about a JAK2-independent pathway [60]. …”

Section: Discussionmentioning

confidence: 99%

Erythropoietin is a JAK2 and ERK1/2 effector that can promote renal tumor cell proliferation under hypoxic conditions

Miyake¹,

Goodison

Lawton

et al. 2013

J Hematol Oncol

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“…Ras/Raf, may contribute in the EPO-mediated, JAK2-dependent, activation of MAPKs after CLI. Although tyrosine phosphorylation of STATs with JAK kinase is found in most cells, some reports demonstrated the existence of JAK2-independent phosphorylation of STAT5 [ 47 , 48 ]. To clarify this issue, we combined EPO and AG490 to treat rat CLI and found that STAT5 activation in ischemic quadriceps was in a JAK2-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

AG490 suppresses EPO-mediated activation of JAK2-STAT but enhances blood flow recovery in rats with critical limb ischemia

et al. 2016

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BackgroundErythropoietin (EPO) has been demonstrated to enhance recovery in ischemic organs through enhancing angiogenesis. In this study, we used an experimental critical limb ischemia (CLI) rat model to reveal the underlying mechanisms and directly examine the benefits of the anti-apoptotic capacity of EPO in the acute phase of limb ischemia and following blood flow recovery.MethodsTo determine the role of the JAK2/STAT pathway in EPO-enhanced recovery after CLI, male Sprague-Dawley rats (n = 8 for each group) were divided into group 1 (normal control), group 2 (CLI treated with normal saline), group 3 (CLI treated with EPO), group 4 (CLI treated with AG490, a JAK2 inhibitor), and group 5 (CLI treated with EPO and AG490). Animals were sacrificed either at day 1 or day 14 and biochemical and histopathological examination of ischemic quadriceps were conducted.ResultsAt day 1, EPO administration reduced expression levels of apoptotic indices and activated the JAK2/STAT pathway; this activation was inhibited by additional AG490 treatment. Furthermore, the decrease in the size of the infarcted area, as well as activation of ERK1/2 and JNK showed similar regulatory trends with EPO or AG490 treatment. Of Interest, EPO and AG490 in combination showed a synergistic effect, increasing expression levels of antioxidants (GR, GPx, NQO-1) and decreasing transcriptional levels of pro-inflammatory factors (TNF-α, NF-kB). At day 14, laser Doppler analysis showed that the blood flow recovery was enhanced by EPO, AG490, or combined treatment.ConclusionAlthough inhibition of the JAK2/STAT pathways reduces the anti-apoptotic effects of EPO in the early phase of CLI, the benefits of AG490 in anti-inflammation and anti-oxidation still play a positive role in enhancing blood flow recovery after CLI.

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“…[31][32][33][34][35][36][37] The present essay is aimed to review the structural and functional aspects of expression of erythropoietin receptors (EPOR) in tumor cells and their possible influence on tumour growth. Along with, that further analysis has been to drawn regarding clinical significance of these receptors and effect of recombinant EPO on various tumors expressing these receptors.…”

Section: Epor In Tumour Tissuesmentioning

confidence: 99%

A Systematic Review on the Erythropoietin Receptors Expression in Various Cancers and Importance of Recombinant Erythropoietin in Chemotherapy Induced Anaemia

Kumar¹

2017

HTIJ

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Erythropoietin (EPO) is the primary and influential mediator of red cell synthesis. Its action is mediated by various pathways as JAK2-STAT5, Ras-Raf-MAP kinase, PI-3K-Akt and protein kinase C and adaptor protein CrkL following interaction between EPO and erythropoietin receptors (EPOR) in the various cells. Apart from erythropoiesis it also regulates neuronal functioning and angiogenesis etc. Nevertheless, the pathological presence of these EPOR receptors is seen in various tumour cells that have raised concerns regarding enhanced tumour growth and impaired overall survival.

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Erythropoietin and Its Receptor in Breast Cancer: Putting Together the Pieces of the Puzzle

Cited by 10 publications

References 52 publications

Erythropoietin is a JAK2 and ERK1/2 effector that can promote renal tumor cell proliferation under hypoxic conditions

Erythropoietin is a JAK2 and ERK1/2 effector that can promote renal tumor cell proliferation under hypoxic conditions

AG490 suppresses EPO-mediated activation of JAK2-STAT but enhances blood flow recovery in rats with critical limb ischemia

A Systematic Review on the Erythropoietin Receptors Expression in Various Cancers and Importance of Recombinant Erythropoietin in Chemotherapy Induced Anaemia

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