P2X7 a new therapeutic target to block vesicle-dependent metastasis in colon carcinoma: role of the A2A/CD39/CD73 axis

Abstract

Extracellular vesicle-driven cancer metastasis represents a therapeutic challenge due to the lack of effective blocking drugs. This study reveals a unique mechanism involving the P2X7 receptor and the A2A/CD39/CD73 axis, which affects ATP and adenosine levels in cancer via vesicular release, thereby enhancing metastasis. It also introduces a novel P2X7-based therapeutic approach to target tumor vesicular release. Indeed, activation of P2X7 on colon carcinoma cells induced the release of extracellular vesicles carrying P2X7, A2A, CD39, and CD73, resulting in significantly elevated ATP and adenosine levels within the tumor microenvironment. These vesicles enhanced colon carcinoma metastatic potential and systemic IL-17 production when administered in vivo, effects that were successfully mitigated through P2X7 antagonism, which also reduced A2A levels in the metastatic niche. Treatment with P2X7 and A2A antagonists (AZ10606120 and SCH58261) markedly inhibited cancer growth and prevented tumor dissemination in an immune response-dependent manner. Finally, expression levels of P2X7, CD39, CD73, and A2A mRNAs were significantly higher in stage IV metastatic colon carcinoma patients. Furthermore, P2X7 and A2A expression increased in APC-mutated tumors and in spontaneous neoplasias within the colon mucosa of APC-mutated PIRC rats. Our study highlights the close interconnection between P2X7, A2A, CD39, and CD73 in colon carcinoma metastases. It identifies P2X7-dependent vesicle secretion as a new mechanism that favors metastatic dissemination and offers an innovative immunotherapeutic approach that targets vesicular release. Furthermore, we establish a first-time association between P2X7 and A2A overexpression and APC oncogene mutations, suggesting that these receptors could serve as potential biomarkers for advanced colon carcinoma.