Ecto-5′-nucleotidase expression is associated with the progression of renal cell carcinoma

Yu, Yi; Wang, Wei; Song, Lei; Hu, Wentao; Dong, Chen; Pei, Hailong; Zhou, Guangming; Yue, Zhongjin

doi:10.3892/ol.2015.3138

Cited by 31 publications

(16 citation statements)

References 49 publications

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“…In this study, we identified CD73 as a specific cell surface biomarker of ccRCC CSCs basing on our previous studies [ 26 , 27 ] and discovered the association of CD73 intensive expression levels with ccRCC tumor formation by using siRNA technology. To the best of our knowledge, this represents the first identification of CD73 as a cell surface biomarker for ccRCC CSCs and also the first demonstration of the involvement of CD73 in ccRCC progression.…”

Section: Discussionmentioning

confidence: 99%

“…Our group has recently identified, with rhodamine-123 (Rho) staining and cell sorting from human RCC cell line 786-O, that a small subset of Rho high cells have stem-like characteristics [ 26 ]. Also, we found that the level of Ecto-5′-nucleotidase (CD73) expression in clinical specimens was associated with the aggressiveness of ccRCC [ 27 ]. So, in this study, we verified that CD73 expression was highly associated with positive Rho staining, and it may be a specific biomarker of ccRCC CSCs.…”

Section: Introductionmentioning

confidence: 99%

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Ecto-5′-nucleotidase (CD73) is a biomarker for clear cell renal carcinoma stem-like cells

Song

Cui

et al. 2017

Oncotarget

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Identification of a specific biomarker for cancer stem cells (CSCs) is of potential applications in the development of effective therapeutic strategies for renal cell carcinoma (RCC). In this study, both the RCC cell line 786-O and surgically removed clear cell RCC (ccRCC) tissues were implemented to grew as spheroids in serum-free medium supplemented with mitogens. This subpopulation possessed key characteristics defining CSCs. We also identified that surgically removed ccRCC tissues were heterogenic and there was a subpopulation of cells that was highly stained with rhodamine-123. Based on membrane-proteomic analyses, CD73 was identified as a candidate biomarker. We further found that CD73high cells were highly tumorigenic. As few as 100 CD73high cells were capable of forming xenograft tumors in non obese diabetic/severe combined immunodeficiency disease mice, whereas 1 × 105 CD73low cells did not initiate tumor formation. During successive culture, the CD73high population regenerated both CD73high and CD73low cells, whereas the CD73low population remained low expression level of CD73. Furthermore, the CD73high cells were more resistant to radiation and DNA-damaging agents than the CD73low cells, and expressed a panel of ‘stemness’ genes at a higher level than the CD73low cells. These findings suggest that a high level of CD73 expression is a bona fide biomarker of ccRCC stem-like cells. Future research will aim at the elucidation of the underlying mechanisms of CD73 in RCC development and the distinct aspects of ccRCC stem-like cells from other tumor types.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ecto-5′-nucleotidase (CD73) is a biomarker for clear cell renal carcinoma stem-like cells

Song

Cui

et al. 2017

Oncotarget

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“…Yu et al analyzed CD73 expression by IHC in patients with ccRCC, the majority of whom had localized Open access (T1-4, N0, M0) disease. 22 Nearly half of tumors (48%) expressed CD73, which was associated with high tumor grade and T stage. In our prior work in RCC, we observed CD73 expression in 19% of primary tumors and that expression was significantly more common in metastatic tumor samples (67%).…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma

Tripathi

Lin

Xie

et al. 2020

J Immunother Cancer

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BackgroundCD73–adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5′-nucleotidase (NT5E), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)) and A2 adenosine receptor (A2AR; ADORA2A) transcript levels with markers of angiogenesis and antitumor immune response.MethodsPatients with RCC with available archived nephrectomy samples were eligible for inclusion. Tumor CD73 protein expression was assessed by immunohistochemistry and quantified using a combined score (CS: % positive cells×intensity). Samples were categorized as CD73negative (CS=0), CD73low or CD73high (< and ≥median CS, respectively). Multivariable Cox regression analysis compared disease-free survival (DFS) and overall survival (OS) between CD73 expression groups. In the TCGA dataset, samples were categorized as low, intermediate and high NT5E, ENTPD1 and ADORA2A gene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared between NT5E, ENTPD1 and ADORA2A expression groups.ResultsAmong the 138 patients eligible for inclusion, ‘any’ CD73 expression was observed in 30% of primary tumor samples. High CD73 expression was more frequent in patients with M1 RCC (29% vs 12% M0), grade 4 tumors (27% vs 13% grade 3 vs 15% grades 1 and 2), advanced T-stage (≥T3: 22% vs T2: 19% vs T1: 12%) and tumors with sarcomatoid histology (50% vs 12%). In the M0 cohort (n=107), patients with CD73high tumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73negative group (DFS: 75%, adjusted HR: 2.7, 95% CI 1.3 to 5.9, p=0.01; OS: 64%, adjusted HR: 2.6, 95% CI 1.2 to 5.8, p=0.02) independent of tumor stage and grade. In the TCGA analysis, high NT5E expression was associated with significantly worse 5-year OS (p=0.008). NT5E and ENTPD1 expression correlated with higher regulatory T cell (Treg) signature, while ADORA2A expression was associated with increased Treg and angiogenesis signatures.ConclusionsHigh CD73 expression portends significantly worse survival outcomes independent of stage and grade. Our findings provide compelling support for targeting the immunosuppressive and proangiogenic CD73–adenosine pathway in RCC.

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“…Consistently, Lu et al reported that high CD73 expression was found in 45.60% of patients with gastric cancer [ 11 ]. Yu and colleagues also found that 47.20% of renal cell carcinoma highly expressed CD73 [ 22 ]. Of note, Hoon et al collected 167 patients with epithelial ovarian cancer and found that 70.1% of patients showed positive expression for CD73 while data from Oncomine showed that ovarian cancer had low CD73 expression level.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive evaluation of NT5E/CD73 expression and its prognostic significance in distinct types of cancers

et al. 2018

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BackgroundCD73 is one of the critical component in the formation of immunosuppressive microenvironment in cancers. We aimed to provide an overview of the current status of CD73 expression and its relationship with clinicopathlogical features and prognosis in different cancers.MethodsPubMed, Web of Science, EMBASE and Cochrane library were searched to identify the relevant studies. CD73 expression level in distinct cancers and its relationship with clinicopathlogical characteristics and prognosis were investigated using online database. Meta-analyses were conducted using RevMan v5.0 and STATA v12.0.ResultsFourteen publications with 2951 cases were included. The incidence of high CD73 expression was 0.50 (95% CI: 0.36–0.63). Data from Oncomine validated that median CD73 expression level in tumor tissues was markedly higher than that in normal tissues in most kinds of cancers except cecum adenocarcinoma and ovarian cancer (P < 0.05). High CD73 expression was significantly correlated with shorter overall survival (OS) in various cancers (high risk [HR] = 1.48; P < 0.05). Subgroup analysis using online database demonstrated that high CD73 expression was significantly correlated with poor OS in breast (HR = 1.23; P < 0.05) and ovarian cancer (HR = 1.14; P < 0.05), but favorable OS in lung (HR = 0.80; P < 0.05) and gastric cancer (HR = 0.71; P < 0.05). High CD73 expression was dramatically associated with lymph node metastases (OR = 2.61; P = 0.05).ConclusionHigh CD73 expression was significantly associated with lymph node metastases and a promising prognostic factor in different types of cancers.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4073-7) contains supplementary material, which is available to authorized users.

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Ecto-5′-nucleotidase expression is associated with the progression of renal cell carcinoma

Cited by 31 publications

References 49 publications

Ecto-5′-nucleotidase (CD73) is a biomarker for clear cell renal carcinoma stem-like cells

Ecto-5′-nucleotidase (CD73) is a biomarker for clear cell renal carcinoma stem-like cells

Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma

Comprehensive evaluation of NT5E/CD73 expression and its prognostic significance in distinct types of cancers

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