Ecto-5′-nucleotidase (CD73) promotes tumor angiogenesis

Abstract

Angiogenesis is essential for tumor growth, progression and metastasis. Studies indicate that expression and activity of ecto-5'-nucleotidase (CD73) are elevated in metastatic carcinomas. Our previous studies found that angiogenesis of tumor xenografts was decreased when the activity of CD73 in cancer cells was inhibited, implying that this enzyme is involved in tumor angiogenesis. To elucidate the mechanism, we investigated CD73 influence on tumor angiogenesis in both in vitro assays and in tumor bearing mice. We found that capillary-like structures were formed more in CD73(+/+) pulmonary microvascular endothelial cells (PMECs) than CD73(-/-) PMECs, and this was more pronounced when the cells were cultured in cancer-conditioned medium. Meanwhile, CD73 decreased endothelial cells adhesion to collagen IV and promoted migration. Additionally, the extent of tumor angiogenesis and the size of tumors were greater in CD73(+/+) mice than in CD73(-/-) mice. Thus, we concluded that CD73 can promote endothelial cells forming new vessels in cancer condition, facilitating tumor growth and hematogenous metastasis.

Increased efficacy of a dendritic cell–based therapeutic cancer vaccine with adenosine receptor antagonist and CD73 inhibitor

“…48 Another study showed that CD73 causes endothelial cells to form tube-like structures and facilitates tumor angiogenesis. 11 It has been shown that targeted blockade of CD73 with a mAb significantly decreased tumor VEGF levels and suppressed tumor angiogenesis. 49 In our study, inhibition of adenosine combined with a DC-based vaccine reduced VEGF production.…”

Inhibition of CD73 stimulates the migration and invasion of B16F10 melanoma cells in vitro, but results in impaired angiogenesis and reduced melanoma growth in vivo

“…Adenosine is regarded as an important hypoxia-counteracting mediator (41,42) which exerts a mitogenic effect on the endothelium and regulates the synthesis of pro-and anti-angiogenic factors (such as VEGF through the A 3 receptor in melanoma cells) (6,43). Experiments performed on human breast cancer xenografts in a nude mouse model have demonstrated that both the chemical inhibition of CD73 and systemic CD73-deficiency can decrease angiogenesis not only in vitro (in isolated pulmonary microvascular endothelial cells) but also in vivo by contributing to an increase in the necrotic area of the tumor (17,18). The regulatory role of adenosine produced extracellularly by the grafted B16F10 cells could be variable.…”

“…Recently, it was reported that both CD73-deficiency in transgenic mice and pharmacological inhibition of CD73 in wild-type mice significantly slows the development of subcutaneous tumors, experimental lung metastases (9,15,16) and human xenograft tumors (17,18). CD73 was further suggested to be a potential negative prognostic marker in certain cancer types, such as human colorectal cancer (19).…”

“…CD73 overexpression in some human breast cancer cell lines increased their ability to invade, migrate and adhere to ECM proteins, thus Inhibition of CD73 stimulates the migration and invasion of B16F10 melanoma cells in vitro, but results in impaired angiogenesis and reduced melanoma growth in vivo increasing their metastatic potential. Furthermore, inhibition of CD73 activity reversed those effects (18,20). Nonetheless, some clinical studies have shown that CD73 exhibits low activity in breast cancer cells when compared to the adjacent non-involved tissue (21,22) and that elevated CD73 expression in tumor cells was a positive prognostic marker for disease-free survival in stage I-III breast cancer patients (23).…”

Human induced pluripotent stem cells derived endothelial cells mimicking vascular inflammatory response under flow

“…26 Following the manufacturer's instructions, the thin gel method was used for plating the ECs on top of the gel. Briefly, Matrigel (354234, Corning Inc., USA) was thoroughly thawed at 4 C. After mixing the Matrigel using cooled pipets on ice, we added 50 ll/cm 2 to the growth surface in 24 well plates that were placed on ice.…”