Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium

Abstract

Background: The modulation of gap junctional communication between tumor cells and between tumor and vascular endothelial cells during tumorigenesis and metastasis is complex. The notion of a role for loss of gap junctional intercellular communication in tumorigenesis and metastasis has been controversial. While some of the stages of tumorigenesis and metastasis, such as uncontrolled cell division and cellular detachment, would necessitate the loss of intercellular junctions, other stages, such as intravasation, endothelial attachment, and vascularization, likely require increased cell-cell contact. We hypothesized that, in this multi-stage scheme, connexin-43 is centrally involved as a cell adhesion molecule mediating metastatic tumor attachment to the pulmonary endothelium.

Connexins: a junctional crossroad to breast cancer

“…In fact, increased Cx43 expression was detected in tumor cell/endothelial cell contact areas in vitro and in vivo, where it marked the sites of micrometastases to the lungs. Moreover, a GJIC via Cx43 increased the adhesion of breast cancer cells to lung endothelial cells, whereas such adhesion was reduced in breast cancer cells with a dominant-negative Cx43 mutation, known to exhibit non-functional GJIC, highlighting the importance of Cx43 and GJIC in metastatic homing of breast cancer cells (Elzarrad et al, 2008). Other studies have correlated Cx26 expression to an increased lymphatic vessel invasion, large tumor size and poor prognosis in breast cancer patients (Naoi et al, 2007).…”

Involvement of epithelial-mesenchymal transition in adenoid cystic carcinoma metastasis

“…The role of connexin 43 in metastasis is also supported by its ability to mediate heterocellular gap junctional communication, which enhances cancer cell diapedesis, the migration of fibroblasts and vascular endothelial cells through mesenchymal tissues, and the extravasation of cancer cells (28,29). In addition, connexin 43 is also up-regulated in micrometastasis and tumor vasculature, and markedly so in tumor cell-endothelial cell contact areas, whether in pre-existing vessels or in newly formed tumor vessels (30). These studies strongly suggest that connexin 43 accelerates tumor extravasation and adhesion to endothelial cells at distant sites.…”

Intercellular Communication, a Missing Link in Endometriosis Peritoneal Invasiveness

“…Gap junctions are clusters of transmembrane channels formed by connexin molecules, which connect the cytoplasm of adjacent cells and mediate exchanges of ions, metabolites and signaling molecules [6]. They have been directly implicated in both extravasation [7,8] and metastasis [5,9], as well as embryonic implantation into the endometrium [10].…”