Detection of CD39 and a Highly Glycosylated Isoform of Soluble CD73 in the Plasma of Patients with Cervical Cancer: Correlation with Disease Progression

Abstract

Persistent infection with high-risk human papillomavirus (HR-HPV) is the main factor in the development of cervical cancer (CC). The presence of immunosuppressive factors plays an important role in the development of this type of cancer. To determine whether CD39 and CD73, which participate in the production of immunosuppressive adenosine (Ado), are involved in the progression of CC, we compared the concentrations and hydrolytic activity of these ectonucleotidases in platelet-free plasma (PFP) samples between patients with low-grade squamous intraepithelial lesions (LSILs) ( n = 18 ), high-grade squamous intraepithelial lesions (HSILs) ( n = 12 ), and CC ( n = 19 ) and normal donors (NDs) ( n = 15 ). The concentrations of CD39 and CD73 in PFP increased with disease progression ( r = 0.5929 , p < 0.001 ). The PFP of patients with HSILs or CC showed the highest concentrations of CD39 (2.3 and 2.2 times that of the NDs, respectively) and CD73 (1.7 and 2.68 times that of the NDs, respectively), which were associated with a high capacity to generate Ado from the hydrolysis of adenosine diphosphate (ADP) and adenosine monophosphate (AMP). The addition of POM-1 and APCP, specific inhibitors of CD39 and CD73, respectively, inhibited the ADPase and AMPase activity of PFP by more than 90%. A high level of the 90 kD isoform of CD73 was detected in the PFP of patients with HSILs or CC. Digestion with endoglycosidase H and N-glycanase generated CD73 with weights of approximately 90 kD, 85 kD, 80 kD, and 70 kD. In addition, the levels of transforming grow factor-β (TGF-β) in the PFPs of patients with LSIL, HSIL and CC positively correlated with those of CD39 ( r = 0.4432 , p < 0.001 ) and CD73 ( r = 0.5786 , p < 0.001 ). These results suggest that persistent infection by HR-HPV and the concomitant production of TGF-β promote the expression of CD39 and CD73 to favor CC progression through Ado generation.

CD39 Regulation and Functions in T Cells

“…Tumor cells can overexpress CD39 compared with normal cells; however, elevated levels have been also reported in endothelial cells, cancer-associated fibroblasts (CAF) and several immune subpopulations, particularly, natural killer (NK) cells, tumor-associated-macrophages (TAM) and tumor-infiltrating lymphocytes (TILs) including Tregs and CD8 + T cells [ 23 , 24 , 25 , 26 , 27 , 28 ]. High CD39 expression is considered a marker of poor outcome and disease progression [ 29 , 30 , 31 ].…”

Potential roles of serum ATPase and AMPase in predicting diagnosis of colorectal cancer patients

“…ENTPDase and CD73 are required to maintain the stability of the tumor environment by hydrolyzing ATP and AMP. The critical roles of ENTPDase and CD73 in tumors have been confirmed in many studies [ 34–36 ]. For instance, the plasma concentrations and activity of CD39 (ENTPD1) in patients with cervical cancer play an important role in the progression of tumors and may be valuable markers.…”

The relationship between soluble CD73 and the incidence of septic shock in severe sepsis patients: a cross-sectional analysis of data from a prospective FINNAKI study

“…According to previous study, the circulating level of sCD73 is a predictor for the development and severity of acute pancreatitis (7). Studies showed CD73 promoted the proliferation and migration of breast cancer cells, hepatocellular carcinoma, and human cervical cancer through the activating 3-kinase (PI3K)/Akt signaling pathway (8)(9)(10) . Meanwhile, activation of PI3K/Akt signaling has been reported to be beneficial in sepsis (11)(12)(13)(14)(15).…”