Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer

Abstract

Despite improvements in prevention and management of colorectal cancer (CRC), uncontrolled tumor growth with metastatic spread to distant organs remains an important clinical concern. Genetic deletion of CD39, the dominant vascular and immune cell ectonucleotidase, has been shown to delay tumor growth and blunt angiogenesis in mouse models of melanoma, lung and colonic malignancy. Here, we tested the influence of CD39 on CRC tumor progression and metastasis by investigating orthotopic transplanted and metastatic cancer models in wild-type BALB/c, human CD39 transgenic and CD39 deficient mice. We also investigated CD39 and P2 receptor expression patterns in human CRC biopsies. Murine CD39 was expressed by endothelium, stromal and mononuclear cells infiltrating the experimental MC-26 tumors. In the primary CRC model, volumes of tumors in the subserosa of the colon and/or rectum did not differ amongst the treatment groups at day 10, albeit these tumors rarely metastasized to the liver. In the dissemination model, MC-26 cell line-derived hepatic metastases grew significantly faster in CD39 over-expressing transgenics, when compared to CD39 deficient mice. Murine P2Y2 was significantly elevated at both mRNA and protein levels, within the larger liver metastases obtained from CD39 transgenic mice where changes in P2X7 levels were also noted. In clinical samples, lower levels of CD39 mRNA in malignant CRC tissues appeared associated with longer duration of survival and could be linked to less invasive tumors. The modulatory effects of CD39 on tumor dissemination and differential levels of CD39, P2Y2 and P2X7 expression in tumors suggest involvement of purinergic signalling in these processes. Our studies also suggest potential roles for purinergicbased therapies in clinical CRC.

Purines, Purinergic Receptors, and Cancer

“…The main enzymes responsible are the CD39 and CD73 ectonucleotidases, which are upregulated by the hypoxiainduced transcription factors Sp1 and HIF-1, respectively (34,35). Expression of E-NTPDase1 (CD39) or E-NTPDase2 by vascular endothelium or by tumor cells accelerates tumor growth and metastasis of rat glioma, mouse colorectal cancer, and mouse melanoma (36,37), whereas on the contrary, CD39 gene deletion causes reduced growth of transplanted tumors in mice (38). Stagg and coworkers have shown in a series of elegant studies that AMP hydrolysis by CD73, the final step in the chain of reaction leading to adenosine generation, is crucial for tumor progression (39-41) because neutralization or deletion of CD73 inhibits tumor growth and prevents metastasis, supporting a major role for adenosine as a key component of the tumor-suppressive microenvironment.…”

CD73 promotes tumor growth and metastasis

“…Similar to CD73, a recent series of studies investigated the role of host-derived CD39, [25][26][27] A 2A R 14 and A 2B R 28 on tumor growth and metastasis. In fact, all 4 adenosine receptor subtypes participate in controlling tumor progression.…”

Inhibition of CD39 Enzymatic Function at the Surface of Tumor Cells Alleviates Their Immunosuppressive Activity

“…The number of CD39 þ Tregs is increased in human cancers, and these cells participate in immunosuppression by generating adenosine (25)(26)(27)(28)(29). CD39 promotes melanoma and colon cancer growth and metastasis in mice (12,13,30), and CD39 disruption or blockade facilitates NK cell-mediated tumor eradication in vivo (13). CD39 is also expressed by other cell types in the tumor environment, such as stromal cells (31) and endothelial cells (32), and may stimulate tumor progression.…”