Purinergic ecto-enzyme CD73 is a context-dependent tumor suppressor in colorectal cancer

Inhibition of purinergic signaling in cancer has recently received great attention. The purinergic ecto-enzyme CD73 represents a prominent candidate; however its intrinsic role in colorectal cancer (CRC) cells has not been fully investigated. Stable depletion of CD73 expression by using CRISPR/Cas9 in CRC cell lines led to increased cell proliferation, enhanced cell motility and the formation of larger xenograft tumors in mice. These observations may be explained by an exacerbation of the EMT process. In addition, acquired resistance to gefitinib, an EGFR inhibitor, in various CRC models is associated with the loss of CD73 expression. Overexpression of CD73 in CRC cells can revert some of these phenotypes, resulting in slower cell migration, forming smaller xenograft tumors, sensitizing gefitinib response and enhanced apoptosis. Further supporting the tumor suppressive roles of CD73, its overexpression in CRC cells increased vulnerability to cell death induced by multiple agents while its depletion provided protection. Moreover, our bioinformatic analyses with human patient samples supported our in vitro and in vivo results, indicating that the tumor suppressor function of CD73 depends on stromal content and infiltrating immune cell. Collectively, our data strongly reveal that CD73 can function as a tumor suppressor in CRC cells. Therefore, inhibition of CD73 in general may not bring the expected outcome in patient subgroups with poor immune cell infiltration highlighting the need for careful evaluation and personalized treatment based on histopathological features of tumors.