A preliminary study of the role of extracellular -5′- nucleotidase in breast cancer stem cells and epithelial-mesenchymal transition

Yu, Jiangang; Liao, Xiaohong; Li, Luying; Zhi, Xiuling; Yu, Jerry; Zhou, Ping

doi:10.1007/s11626-016-0089-y

Cited by 22 publications

(21 citation statements)

References 48 publications

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“…The coexpression of both CD73, which generates adenosine, and A2BR, which is activated in response to adenosine binding, constitutes an autocrine signaling pathway leading to STAT3dependent expression of NANOG, a pluripotency factor that specifies the BCSC phenotype. These findings may explain previous studies reporting that CD73 activity promoted the BCSC phenotype (60). We previously reported that hypoxia induces HIF-dependent demethylation of N 6 -methyladenosine residues leading to stabilization of NANOG mRNA, thereby stimulating BCSC accumulation (61,62).…”

Section: Discussionsupporting

confidence: 70%

Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment

Lan

Samanta

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

112

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Breast cancer stem cells (BCSCs), which are characterized by a capacity for unlimited self-renewal and for generation of the bulk cancer cell population, play a critical role in cancer relapse and metastasis. Hypoxia is a common feature of the cancer microenvironment that stimulates the specification and maintenance of BCSCs. In this study, we found that hypoxia increased expression of adenosine receptor 2B (A2BR) in human breast cancer cells through the transcriptional activity of hypoxia-inducible factor 1. The binding of adenosine to A2BR promoted BCSC enrichment by activating protein kinase C-δ, which phosphorylated and activated the transcription factor STAT3, leading to increased expression of interleukin 6 and NANOG, two key mediators of the BCSC phenotype. Genetic or pharmacological inhibition of A2BR expression or activity decreased hypoxia- or adenosine-induced BCSC enrichment in vitro, and dramatically impaired tumor initiation and lung metastasis after implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice. These data provide evidence that targeting A2BR might be an effective strategy to eradicate BCSCs.

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Section: Discussionsupporting

confidence: 70%

Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment

Lan

Samanta

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

112

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“…Indeed, increased CD73 levels were detected in cell lines of breast carcinoma undergoing EMT-induced by TGF-β. [52,53] While EMT is a hallmark of a more aggressive phenotype and is also induced by HIF-1, TGF-β is secreted by tumors and has an immunosuppressive role similar to that of CD73. [54][55][56].…”

Section: Discussionmentioning

confidence: 99%

CD73 expression in normal and pathological human hepatobiliopancreatic tissues

Sciarra

Monteiro

Ménétrier‐Caux

et al. 2019

Cancer Immunol Immunother

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Background: the tumor-expressed CD73 ectonucleotidase generates immune tolerance and promotes invasiveness via adenosine production from degradation of AMP. While anti-CD73 blockade treatment is a promising tool in cancer immunotherapy, a characterization of CD73 expression in human hepatobiliopancreatic system is lacking. Patients and methods: CD73 expression was investigated by immunohistochemistry in a variety of non-neoplastic and neoplastic conditions of the liver, pancreas and biliary tract. Results: CD73 was expressed in normal hepatobiliopancreatic tissues with subcellularspecific patterns of staining: canalicular in hepatocytes, and apical in cholangiocytes and pancreatic ducts. CD73 was present in all hepatocellular carcinoma (HCC), in all pancreatic ductal adenocarcinoma (PDAC), and in the majority of intra and extrahepatic cholangiocellular carcinomas, whereas it was detected only in a subset of pancreatic neuroendocrine neoplasms and almost absent in acinar cell carcinoma. In addition to the canonical pattern of staining, an aberrant membranous and/or cytoplasmic expression was observed in invasive lesions, especially in HCC and PDAC. These two entities were also characterized by a higher extent and intensity of staining as compared to other hepatobiliopancreatic neoplasms. In PDAC, aberrant CD73 expression was inversely correlated with differentiation (p<0.01) and was helpful to identify isolated discohesive tumor cells. Additionally, increased CD73 expression was associated with reduced overall survival (HR 1.013) and loss of E-Cadherin. Conclusions: consistent CD73 expression supports the rationale for testing anti-CD73 therapies in patients with hepatobiliopancreatic malignancies. Specific patterns of expression could also be of help in the routine diagnostic workup.

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“…However, little is known about the expression and function of CD73 in other types of stem cells, in particular in CICs. In fact, to our knowledge, the functional contribution of CD73 to CICs has been reported only in cell lines from pancreatic neuroendocrine ( Katsuta et al., 2016 ) and mammary tumors ( Yu et al., 2017 ). The role of CD73 in OCIC function is consistent with previous reports on the expression and the biological activity of CD73 in OC.…”

Section: Discussionmentioning

confidence: 96%

CD73 Regulates Stemness and Epithelial-Mesenchymal Transition in Ovarian Cancer-Initiating Cells

et al. 2018

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SummaryCancer-initiating cells (CICs) have been implicated in tumor development and aggressiveness. In ovarian carcinoma (OC), CICs drive tumor formation, dissemination, and recurrence, as well as drug resistance, thus accounting for the high death-to-incidence ratio of this neoplasm. However, the molecular mechanisms that underlie such a pathogenic role of ovarian CICs (OCICs) remain elusive. Here, we have capitalized on primary cells either from OC or from its tissues of origin to obtain the transcriptomic profile associated with OCICs. Among the genes differentially expressed in OCICs, we focused on CD73, which encodes the membrane-associated 5′-ectonucleotidase. The genetic inactivation of CD73 in OC cells revealed that this molecule is causally involved in sphere formation and tumor initiation, thus emerging as a driver of OCIC function. Furthermore, functional inhibition of CD73 via either a chemical compound or a neutralizing antibody reduced sphere formation and tumorigenesis, highlighting the druggability of CD73 in the context of OCIC-directed therapies. The biological function of CD73 in OCICs required its enzymatic activity and involved adenosine signaling. Mechanistically, CD73 promotes the expression of stemness and epithelial-mesenchymal transition-associated genes, implying a regulation of OCIC function at the transcriptional level. CD73, therefore, is involved in OCIC biology and may represent a therapeutic target for innovative treatments aimed at OC eradication.

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A preliminary study of the role of extracellular -5′- nucleotidase in breast cancer stem cells and epithelial-mesenchymal transition

Cited by 22 publications

References 48 publications

Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment

Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment

CD73 expression in normal and pathological human hepatobiliopancreatic tissues

CD73 Regulates Stemness and Epithelial-Mesenchymal Transition in Ovarian Cancer-Initiating Cells

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