High Expression of Ecto-Nucleotidases CD39 and CD73 in Human Endometrial Tumors

Abstract

One of the strategies used by tumors to evade immunosurveillance is the accumulation of extracellular adenosine, which has immunosupressive and tumor promoting effects. The study of the mechanisms leading to adenosine formation at the tumor interstitium are therefore of great interest in oncology. The dominant pathway generating extracellular adenosine in tumors is the dephosphorylation of ATP by ecto-nucleotidases. Two of these enzymes acting sequentially, CD39 and CD73, efficiently hydrolyze extracellular ATP to adenosine. They have been found to play a crucial role in a variety of tumors, but there were no data concerning endometrial cancer, the most frequent of the invasive tumors of the female genital tract. The aim of the present work is to study the expression of CD39 and CD73 in human endometrial cancer. We have analyzed protein and gene expression, as well as enzyme activity, in type I endometrioid adenocarcinomas and type II serous adenocarcinomas and their nonpathological endometrial counterparts. High levels of both enzymes were found in tumor samples, with significantly increased expression of CD39 in type II serous tumors, which also coincided with the higher tumor grade. Our results reinforce the involvement of the adenosinergic system in cancer, emphasizing the relevance of ecto-nucleotidases as emerging therapeutic targets in oncology.

Inhibition of CD39 Enzymatic Function at the Surface of Tumor Cells Alleviates Their Immunosuppressive Activity

“…This phenomenon suggests that, in some cases, tumor-associated stromal cells may potently hydrolyze ATP and, in concert with CD73, generate adenosine, thereby producing an "immunosuppressive environment" that favors tumor growth. This expression of CD39 by tumor-associated stromal cells has been detected previously in ovarian (33) and endometrial tumors (31) and requires further investigation.…”

“…CD39 promotes melanoma and colon cancer growth and metastasis in mice (12,13,30), and CD39 disruption or blockade facilitates NK cell-mediated tumor eradication in vivo (13). CD39 is also expressed by other cell types in the tumor environment, such as stromal cells (31) and endothelial cells (32), and may stimulate tumor progression. Furthermore, results from a recent study suggested that, similar to CD73, CD39 might be expressed by some tumor cells (33).…”

Consensus guidelines for the detection of immunogenic cell death

“…This expression pattern reflects the advantage that these enzymes confer to cancer cells by the degradative conversion of extracellular ATP, which promotes immunosurveillance, into adenosine, which exerts potent immunosuppressive effects. [191][192][193][194][195][196][197] Of note, autophagy is also important for the perception of cell death as immunogenic because it contributes to several aspects of cellular immune responses, including the differentiation, survival and activation of myeloid and lymphoid cells. [198][199][200] The release of HMGB1 from cells succumbing to ICD requires the permeabilization of both the nuclear and plasma membranes, de facto constituting a post-mortem event.…”

Immunohistochemical CD73 expression status in gastrointestinal neuroendocrine neoplasms: A retrospective study of 136�patients

“…CD73 expression is also associated with poor prognosis in several types of tumors (31), including colorectal cancer (32), gastric cancer (33), gallbladder cancer (34), serous ovarian cancer (35), triple negative breast cancer (36), and malignant melanoma (37). In endometrial tumors, no differences in the CD73 expression among tumors were observed with enzyme assays in either tissue slices or tissue homogenates (38). To the best of our knowledge, there has been no report on CD73 expression in GI-NENs.…”