The role of connexin-43 in breast cancer metastasis to the lung
The role of gap junctional intercellular communication in tumorigenesis and metastasis is controversial. While some of the stages of tumorigenesis and metastasis, such as uncontrolled cell division and cellular detachment, are associated with loss of intercellular junctions, other stages, such as intravasation, endothelial attachment, and vascularization, demand increased cell-cell contact. A role for connexins in facilitation of tumor growth, metastatic potential, and tumor vascularization has been documented recently. A simplistic notion of loss of cellular communication cannot fully characterize the status of the cellular interaction between tumor cells or between endothelial and tumor cells during the whole metastatic process. Our initial observation was of endothelial cells embedded within metastatic lung tumors, not as organized vessels but as sporadic individual cells embedded side by side and with shared borders with the tumor cells. That observation of shared borders between the endothelial cells and tumors cells highlighted the need for communication and co-ordination between the adjacent cells. Since the role of gap junctions in tumorigenesis and metastasis has been controversial, we formed the following hypothesis in this work: Connexin-43 facilitates metastatic breast cancer cell arrest in the pulmonary vasculature and promotes metastatic tumor growth. To address this hypothesis we first aimed to (1) evaluate the role of connexin-43 in gap junctional communication between pulmonary microvascular endothelial cells (PMVECs) and 4T1-GFP mammary adenocarcinoma cells. We have determined that Cx-43 is present in both cell types and its expression induced and redistributed at the contact regions between the tumor cells and the endothelium. In addition, our results indicated that functional gap junctions are present between the tumor and endothelial cells. After confirming the presence of functional gap junctions we aimed to (2) determine the role of Cx-43 in breast cancer metastasis to the lung. To address the second aim in this work we evaluated the role of Cx-43 in the arrest of metastatic breast cancer in the pulmonary endothelium and metastatic tumor growth in the lung. Our results show that in a syngeneic mouse breast cancer experimental metastasis model, Cx-43 facilitates metastatic 'homing' by increasing the arrest of cancer cells to the pulmonary vasculature. The marked upregulation of connexin 43 in tumor cell-endothelial cell contact areas, whether in preexisting 'homing' vessels or in newly formed tumor vessels, indicate that connexin 43 can serve as a marker of micrometastases and tumor vasculogenesis.