CD44 Is Involved in Tumor Angiogenesis; an Activation Antigen on Human Endothelial Cells

Abstract

CD44 is described to be an activation molecule in a number of different cell types. We investigated the role of CD44 on human endothelial cells (EC) and in tumor angiogenesis. Using flow cytometry we showed that EC from the vasculature of human solid tumors display an enhanced expression of CD44 as compared to EC from normal tissue. This finding was confirmed by immunohistochemical studies on frozen tissue sections. Because tumors are dependent on angiogenesis, the role of angiogenic stimuli in the enhanced CD44 expression was investigated. We found that basic fibroblast growth factor (bFGF ) and vascular endothelial growth factor were able to efficiently upregulate CD44 expression on cultured human EC. The upregulation reached maximal levels after treatment for 3 days with 10 ng/mL bFGF. The physiological impact of this upregulation was shown by the enhanced binding of EC to hyaluronate after pretreatment with bFGF. In a next set of studies that were designed to unravel the regulation of CD44 expression on EC we concluded that CD44 is an activation antigen on human EC since (1) human umbilical vein derived endothelial cells, which in vivo do not express CD44, begin to express CD44 when plated and cultured, (2) CD44 expression is enhanced after subculture of confluent cultures, (3) CD44 is predominantly expressed on the BrdU incorporating subset of cultured EC. The specific expression of CD44 on activated and tumor EC prompted us to study the usefulness of CD44 as an endothelial target for therapy with immunotoxins. In vitro experiments showed that EC are efficiently killed after targeting immunotoxin to CD44.

The designer antiangiogenic peptide anginex targets tumor endothelial cells and inhibits tumor growth in animal models

“…The efficient migration inhibition by anginex suggests that the blockade of a matrix binding adhesion molecule may be important in its mechanism of action. Several these molecules are up-regulated in tumor vessels (30,31). In colocalization studies, however, using antibodies against anginex and EC adhesion molecules, we were unable to identify either αvβ3-, αvβ5-, or β1-integrins or CD44 as EC surface receptor for anginex.…”

Immunohistochemical study of microvessel density, CD44 (standard form), p53 protein and c‐erbB2 in gallbladder carcinoma

“…Angiogenic activity of a tumor depends on various factors, including p53 gene mutations, 12,13 c-erbB2 overexpression 14 and CD44 activation. 15 A few reports regarding angiogenesis in gallbladder carcinoma have recently appeared in the literature, sometimes with conflicting results. [16][17][18][19][20][21] None of these studies has investigated the relationship of angiogenesis in gallbladder carcinoma to p53, c-erbB2 and CD44 expression.…”

Engagement of CD44 modulates cyclooxygenase induction, VEGF generation, and cell proliferation in human vascular endothelial cells

“…Cell stimulation by monoclonal anti-CD44 antibody or natural CD44 ligands activate signaling pathways that culminate in cell proliferation, cytokine secretion, chemokine gene expression, and cytolytic effector functions. Normal endothelial cells (EC) express low levels of CD44, but expression is up-regulated by activation with, for example, cytokines, and by culturing of these cells (7). Expression is also increased on the vasculature of solid tumors (7,8).…”

“…Normal endothelial cells (EC) express low levels of CD44, but expression is up-regulated by activation with, for example, cytokines, and by culturing of these cells (7). Expression is also increased on the vasculature of solid tumors (7,8). Expression of CD44 on EC is associated with homing and migration of leukocytes (i.e., inflammation and migration).…”

“…Expression of CD44 on EC is associated with homing and migration of leukocytes (i.e., inflammation and migration). In addition, it has been demonstrated that CD44 plays some role in new blood vessel formation (angiogenesis), although its precise role in this process is not clear (7,9,10). EC proliferation is driven by the growth factor vascular endothelial growth factor (VEGF) that enhances vascular permeability (11) and stimulates angiogenesis in vivo (12).…”