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

Adriana Del Carmen Aguilar-Lemarroy,Benny Weiss-Steider,Jorge Hernández-Montes,Luis Vallejo-Castillo,Daniela Berenice Torres-Pineda,Alberto Monroy-García,Rommel Chacón-Salinas,Ricardo Muñóz-Godínez,Gabriela Molina-Castillo,Luis Roberto Ávila-Ibarra,María De Lourdes Mora-García,Giuseppe Valacchi,Juan José Montesinos-Montesinos,Sonia Mayra Pérez-Tapia,Rosario García-Rocha,Christian Azucena Don-López

doi:10.1155/2020/1678780

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.

Highlights

Cervical cancer (CC) is the fourth most common type of cancer in women and represents a major public health problem worldwide because more than 500,000 new cases and approximately 250,000 deaths are reported each year, more than 80% of which occur in developing countries [1]
We found that enzymatic digestion of the platelet-free plasma (PFP) samples using endoglycosidase H and N-glycanase resulted in products of 90, 85, 80, and 70 kD, which were observed mainly in the PFP samples of patients with HSILs or CC, suggesting that the highest degree of CD73 glycosylation in the plasma of these patients was associated with a higher AMPase capacity
We demonstrated that Ado generated by the enzymatic activity of CD73 induced the production of transforming grow factor-β (TGF-β) in tumor cells by interacting with A2AR and A2BR, suggesting an important connection between the adenosinergic pathway and the production of TGF-β in cells infected with HPV [35]

Summary

Introduction

Cervical cancer (CC) is the fourth most common type of cancer in women and represents a major public health problem worldwide because more than 500,000 new cases and approximately 250,000 deaths are reported each year, more than 80% of which occur in developing countries [1]. Persistent infection by high-risk human papillomavirus (HR-HPV). Is the main factor in the development of low-grade squamous intraepithelial lesions (LSILs), which can progress to highgrade lesions (HSILs) and eventually to CC [2]. The immune response against HPV antigens eliminates most infections and precursor lesions, some women exposed to HR-HPV will develop cancer, suggesting that other risk factors may be involved [5]. A growing number of studies have suggested that immunoregulation may play an important role in the development of CC. The adenosinergic pathway has been proposed to play an important role in essential signaling related to tumor growth, immunosuppression, and metastasis in cancer [6, 7]

Methods

Discussion

Conclusion