Colorectal Cancer and Purinergic Signalling: An Overview

HIGHLIGHTS: What are the main findings? CD39-CD73 axis in tumor-associated immune cells promotes immune exhaustion, impairment of antitumor immune activity, and increased CRC progression. CD73 overexpression in cancer cells is associated with tumor growth, chemoresistance, and decreased patient survival. Extracellular ATP exhibits dual effects, either reducing tumor cell proliferation or favoring chemoresistance in a concentration-dependent fashion. Purinergic signaling components exhibit prognostic value and have the potential to be utilized as therapeutic targets. What is the implication of the main finding? CD73 induces colorectal cancer progression. CD39 contributes to immunosuppressive activity of T cells and poor prognosis. P2 and P1 purinoceptors were mainly associated with poor prognosis for patients. Ectonucleotidases and purinoceptors have potential as therapeutic targets in CRC. SIMPLE SUMMARY: Colorectal cancer is a leading cause of cancer-related death. Activated immune cells have the potential to eliminate tumor cells, but cancers gain the ability to suppress immune cell functions and escape immune attack. We explored one mechanism that cancers use to evade immune cells in colorectal cancer. This mechanism alters levels of molecules known as purines. Purines are key players in cellular energetics and many cellular processes and can also lead to immune suppression in cancer. In this study, we reviewed the literature that identified specific enzymes (ectonucleoetidases) and receptors (purinoceptors) which alter the levels of purines and contribute to immunosuppression in colorectal cancer. We hope that targeting these enzymes and receptors can activate the immune response against colorectal cancer and halt cancer growth and progression. ABSTRACT: Colorectal cancer (CRC) is among the most common cancers and exhibits a high fatality rate. Gut inflammation is related to CRC, with loss of homeostasis in immune cell activities. The cells of the innate and adaptive immune system, including macrophages, neutrophils, mast cells, and lymphocytes, are present in most solid tumors. Purinergic signaling allows for communication between immune cells within the tumor microenvironment (TME) and can alter the TME to promote tumor progression. This system is regulated by the availability of extracellular purines to activate purinoceptors (P1 and P2) and is tightly controlled by ectonucleotidases (E-NPP, CD73/CD39, ADA) and kinases, which interact with and modify nucleotides and nucleosides availability. In this review, we compiled articles detailing the relationship of the purinergic system with CRC progression. We found that increased expression of CD73 leads to the suppression of effector immune cell functions and tumor progression in CRC. The P1 family purinoceptors A1, A2A, and A2B were positively associated with tumor progression, but A2B resulted in increased cancer cell apoptosis. The P2 family purinoceptors P2X5, P2X7, P2Y(2), P2Y(6), and P2Y(12) were factors primarily associated with promoting CRC progression. In summary, CD39/CD73 axis and the purinergic receptors exhibit diagnostic and prognostic value and have potential as therapeutic targets in CRC.