Targeting Endothelial Connexin37 Reduces Angiogenesis and Decreases Tumor Growth

Abstract

Connexin37 (Cx37) and Cx40 form intercellular channels between endothelial cells (EC), which contribute to the regulation of the functions of vessels. We previously documented the participation of both Cx in developmental angiogenesis and have further shown that loss of Cx40 decreases the growth of different tumors. Here, we report that loss of Cx37 reduces (1) the in vitro proliferation of primary human EC; (2) the vascularization of subcutaneously implanted matrigel plugs in Cx37−/− mice or in WT using matrigel plugs supplemented with a peptide targeting Cx37 channels; (3) tumor angiogenesis; and (4) the growth of TC-1 and B16 tumors, resulting in a longer mice survival. We further document that Cx37 and Cx40 function in a collaborative manner to promote tumor growth, inasmuch as the injection of a peptide targeting Cx40 into Cx37−/− mice decreased the growth of TC-1 tumors to a larger extent than after loss of Cx37. This loss did not alter vessel perfusion, mural cells coverage and tumor hypoxia compared to tumors grown in WT mice. The data show that Cx37 is relevant for the control of EC proliferation and growth in different tumor models, suggesting that it may be a target, alone or in combination with Cx40, in the development of anti-tumoral treatments.

Connexins and angiogenesis: Functional aspects, pathogenesis, and emerging therapies (Review)

“…Moorby and Patel conducted extensive research on the GJ-dependent and-independent functions of cx43 and discovered that the carboxyl region of cx43 mainly governs the independent GJ function (19). It is increasingly accepted that the effects of GJIc-independent cxs on carcinogenesis extend beyond proliferation and migration, including angiogenesis and cell death (20)(21)(22)(23).…”

“…However, there appears to be a skewed association between Cxs and cancer, with evidence suggesting that Cxs may limit cancer cell development in certain instances while also promoting cancer cell motility, invasion, and metastatic dissemination in others ( 57 , 58 ). A key study revealed that inhibiting Cx37 decreases tumor angiogenesis; moreover, Cx37 and Cx40 work together to promote tumorigenesis ( 20 ). Consequently, the involvement of Cxs and GJs in cancer is more complex than previously thought.…”

Connexin37 Regulates Cell Cycle in the Vasculature

“…In humans, somatic mutations that impact the first transmembrane domain of Cx37 (and likely alter Cx37 gap junction channel function) have been linked to the development of hepatic hemangiomas, which are vascular malformations characterized by enlarged or excessive blood vessels [48, 49]. Surprisingly, however, Sathiyandan et al [50] found that in Cx37 −/− mice, tumor angiogenesis is impaired – not overaggressive, as would be predicted based on its developmental angiogenesis phenotype [10, 12] – leading to reduced tumor burden. This may be an indication that other antiproliferative pathways may have compensated for the loss of Cx37 in these mice with regard to preventing pathological tumor angiogenesis; certainly, more studies are needed to address this possibility.…”