Breakdown of the endothelial barrier function in tumor cell transmigration

¹ University of Erlangen-Nürnberg

^* To whom correspondence should be addressed. E-mail: claudia.mierke{at}t-online.de.

Submitted on June 11, 2007
Revised on July 26, 2007
Accepted on 6 November 2007

	Abstract

The poor prognosis of cancer is associated with the ability of tumor cells to metastasize. During the process of metastasis, tumor cells circulating in the blood or lymph vessels can adhere onto, and potentially transmigrate through, the endothelium and invade into the connective tissue. We studied the effectiveness of the endothelium as a barrier against the invasion of 51 tumor cell lines into a 3D collagen matrix. Only 9 tumor cell lines showed attenuated invasion in the presence of an endothelial cell monolayer, while 17 cell lines became invasive or showed a significantly increased invasion. Endothelial cells cocultured with invasive tumor cells increased chemokine gene expression of IL-8 and Gro-. Expression of the IL-8 and Gro- receptor, CXCR2, was upregulated in invasive tumor cells. Addition of IL-8 or Gro- increased tumor cell invasiveness by more than 2-fold. Tumor cell variants selected for high CXCR2 expression were 4-fold more invasive in the presence of an endothelial cell layer, while CXCR2 siRNA knock-down cells were 5-fold less invasive. We demonstrate that Gro- and IL-8 secreted by endothelial cells, together with CXCR2 receptor expression on invasive tumor cells, contribute to the breakdown of the endothelial barrier by enhancing tumor cell force generation and cytoskeletal remodeling dynamics.

Key Words: CXCR2, cell mechanics, endothelium, invasion, metastasis, transendothelial migration