Evidence that cervical cancer cells cultured as tumorspheres maintain high CD73 expression and increase their protumor characteristics through TGF‐β production

Abstract

Recently, a link between the biological activity of CD73 and tumorigenicity in solid tumors has been proposed. We previously reported that the generation of adenosine (Ado) by the activity of CD73 in cervical cancer (CC) cells induces transforming growth factor‐beta 1 (TGF‐β1) production to maintain CD73 expression. In the present study, we analyzed the participation of TGF‐β1 in CD73 expression and the development of protumoral characteristics in CaSki CC cells cultured as tumorspheres (CaSki‐T) and in monolayers (CaSki‐M). Compared with those in CaSki‐M cells, CD73 expression and Ado generation ability were significantly increased in CaSki‐T cells. CaSki‐T cells exhibited enrichment in the CSC‐like phenotype due to increases in the expression levels of stem cell markers (CD49f, CK17, and P63; OCT4 and SOX2), greater sphere formation efficiency (SFE), and an increase in the percentage of side population (SP) cells. Interestingly, compared with CaSki‐M cells, CaSki‐T cells produced a greater amount of TGF‐β1 and presented a marked protumor phenotype characterized by a significant decrease in the expression of major histocompatibility complex class‐I (MHC‐I) molecules, an increase in the expression of multidrug resistance protein‐I (MRP‐I) and vimentin, and an increase in the protein expression levels of Snail‐1 and Twist, which was strongly reversed with TGF‐β1 inhibition. These results suggest that the presence of TGF‐β1−CD73–Ado feedback loop can promote protumoral characteristics in the CC tumor microenvironment.

Soluble galectin‐3 as a microenvironment‐relevant immunoregulator with prognostic and predictive value in lung adenocarcinoma

“…The evaluation of immune molecules' expression on tumor cells could provide the knowledge to comprehend better tumor immune evasion mechanisms. For this purpose, some studies have been focused on using tumorspheres, a 3D model system with outstanding applications for in vitro studies [34,35]. Recently, Bertolini et al reports that spheroid from cell lines are enriched in metastasis initiating cells with immunosuppressive potential [36].…”

Inhibition of CD73 expression or A2AR blockade reduces MRP1 expression and increases the sensitivity of cervical cancer cells to cisplatin

“…We have previously reported that HR‐HPV‐positive CC cells express high CD73 levels in the cell membrane and have a high capacity to generate ADO 40 . Furthermore, we reported that this pathway is important for increasing the protumorigenic characteristics of CC cells, including increased MRP1 expression 41 . Therefore, in this study, we examined the effect of CD73 and the interaction of ADO with ARs on MRP1 expression in CC cells.…”

“…40 Furthermore, we reported that this pathway is important for increasing the protumorigenic characteristics of CC cells, including increased MRP1 expression. 41 Therefore, in this study, we examined the effect of CD73 and the interaction of ADO with ARs on MRP1 expression in CC cells. We found that ADO induced an increase in MRP1 expression in CC cells by interacting with A2AR.…”

Adenosine Increases the Immunosuppressive Capacity of Cervical Cancer Cells by Increasing PD-L1 Expression and TGF-β Production through Its Interaction with A2AR/A2BR

“…For these reasons, adenosine signaling has emerged as a target in cancer immunotherapy due to its key role in the metabolic pathway that regulates tumor immunity [ 34 ]. In previous studies, we reported that Ado induces the production of TGF-β1 by CeCa cells by interacting with ARs, specifically A 2A R and A 2B R [ 35 ], and that this cytokine strongly contributes to enhancing protumoral characteristics related to tumor progression, such as migration and invasion, immune evasion, immunosuppression, and chemoresistance [ 36 ]. Considering these findings, in this study, we analyzed the role of Ado in the induction of PD-L1 expression in CeCa cells as well as the ability of these cells to inhibit the activation and cytotoxic activity of CD8+ T lymphocytes.…”