Combined inhibition of CD73 and ZEB1 by Arg-Gly-Asp (RGD)-targeted nanoparticles inhibits tumor growth.

Abnormal expression of several macromolecules within tumor milieu helps the development of neoplasia and immune suppression in various cancers. ZEB-1 and CD73 are important factors in tumor progression, which their overexpression in tumor site enhances several cancer hallmarks, including proliferation, angiogenesis, metastasis, migration, and invasion. In this study, we decided to inhibit the expression of these factors in the tumor site by using RGD-conjugated chitosan lactate (RGD-CL) nanoparticles (NPs) encapsulating CD73/ZEB-1 siRNA molecules, in vitro and in vivo. The NPs were about 127 nm in size, non-toxic, and RGD conjugation to NPs could efficiently increase cell transfection through interaction with αvß3 integrins expressed on cancer cells and tumoral endothelial cells.Moreover, RGD-conjugated CL NPs containing siRNAs could significantly reduce the ZEB-1 and CD73 expression levels in cancer cells. Following transfection, cancer cells showed a significant reduction in migration and proliferation. Furthermore, the administration of these NPs into 4T1 and CT26 tumor-bearing mice resulted in tumor suppression and prolonged survival. These findings indicate the importance of targeting the CD73/ZEB1 axis in cancer cells, which could encourage their use in cancer patients in the near future.

Adenosine and adenosine receptors in colorectal cancer.

CD39 (nucleoside triphosphate diphosphohydrolase) and Ecto-5-nucleotidase (CD73) have been recognized as important factors mediating various pathological and physiological responses in the tumor microenvironment. Elevated expression of CD73 and CD39 is correlated with the over-production of adenosine in the tumor region. This increase is associated with an immunosuppressive state in the tumor site that enhances various tumor hallmarks such as metastasis, angiogenesis, and cell proliferation. Adenosine promotes these behaviors through interaction with four adenosine receptors, including A3R, A2BR, A2AR, and A1R. Signaling of these receptors reduces the function of immune effector cells and enhances the expansion and function of tumor-associated immune cells. Several studies have been shown the important role of adenosine/CD73/CD39/ARs axis in the immunopathogenesis of colorectal cancer. These findings imply that components of this axis can be considered as a worthy target for colorectal cancer immunotherapy. In this review, we summarized the role of CD73/CD39/adenosine/ARs in the immunopathogenesis of colorectal cancer.