Cancer cell contact causes oscillatory and polarized rise of cytoplasmic ionized calcium concentration in human umbilical vein endothelial cells

The rise of cytoplasmic ionized Ca2+ concentration ([Ca2+]i) is an important factor in cellular signal transduction, which regulates a variety of cellular functions in vascular endothelial cells (vECs) such as morphological change, secretion of vaso-active molecules, or endothelial permeability. It is also known that the loss of vEC integrity plays pivotal roles in several physiological or pathological phenomena, such as inflammation or cancer metastasis. The aim of this study was to clarify the mode of cancer cell induced vEC retraction by cell to cell contact. Digital imaging analysis using Ca2+ indicator, fluo-3, cleary demonstrated an oscillatory intracellular and intercellular [Ca2+]i wave originated from the site of human breast cancer cell line MCF-7 cell contact in HUVECs, which was not inhibited by extracellular Ni2+ and was inhibited by pretreating the cells by paraformaldehyde. Although this phenomenon could be observed in malignant cells including murine malignant melanoma cell line, BL6, as well as benign cells including human fibroblast cell line, WI38, innert neutrophils did not cause vEC retraction nor [Ca2+]i oscillation. Thus, cancer cells could activate vECs by a cell to cell contact to cause retraction via common property of non-blood cells.