CD44 in Cancer Progression: Adhesion, Migration and Growth Regulation

Abstract

It is well established that the large array of functions that a tumour cell has to fulfil to settle as a metastasis in a distant organ requires cooperative activities between the tumour and the surrounding tissue and that several classes of molecules are involved, such as cell-cell and cell-matrix adhesion molecules and matrix degrading enzymes, to name only a few. Furthermore, metastasis formation requires concerted activities between tumour cells and surrounding cells as well as matrix elements and possibly concerted activities between individual molecules of the tumour cell itself. Adhesion molecules have originally been thought to be essential for the formation of multicellular organisms and to tether cells to the extracellular matrix or to neighbouring cells. CD44 transmembrane glycoproteins belong to the families of adhesion molecules and have originally been described to mediate lymphocyte homing to peripheral lymphoid tissues. It was soon recognized that the molecules, under selective conditions, may suffice to initiate metastatic spread of tumour cells. The question remained as to how a single adhesion molecule can fulfil that task. This review outlines that adhesion is by no means a passive task. Rather, ligand binding, as exemplified for CD44 and other similar adhesion molecules, initiates a cascade of events that can be started by adherence to the extracellular matrix. This leads to activation of the molecule itself, binding to additional ligands, such as growth factors and matrix degrading enzymes, complex formation with additional transmembrane molecules and association with cytoskeletal elements and signal transducing molecules. Thus, through the interplay of CD44 with its ligands and associating molecules CD44 modulates adhesiveness, motility, matrix degradation, proliferation and cell survival, features that together may well allow a tumour cell to proceed through all steps of the metastatic cascade.

Macrophage Migration Inhibitory Factor: a Potential Marker for Cancer Diagnosis and Therapy

“…CD44 is a co receptor of MIF which upon binding starts a downstream signaling pathway involving the ERK1/2 pathway and AKT pathway (Shi et al, 2006). It is speculated that CD44 plays a role in invasion and its being considered as a metastasis promoting molecule (Marhaba & Zoller, 2004;Jang et al, 2011). CD44 helps in the attachment of stem cells and circulation of the tumor cells to the bone marrow endothelial cells (Lapidot et al, 2005).…”

In vivo CD44‐CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance

“…Several isoforms exist that differ by glycosylation and the insertion of so-called variant exon products. The CD44 standard (CD44s) isoform is expressed in most hematopoietic cells while expression of CD44 variant isoforms (CD44v) is largely restricted to hematopoiesis and leukocyte activation (reviewed in [1,2]). …”

“…CD44 also interacts with transmembrane proteins devoid of catalytic activity. It associates with tetraspanin, EpCAM, ICAM and integrins like avb3 via osteopontins, or a3b1 likely via CD9 (reviewed in [1,2]) as well as with a4b1 [9].…”

CD44v7 ligation downregulates the inflammatory immune response in Crohn's disease patients by apoptosis induction in mononuclear cells from the lamina propria

“…22 These apparent discrepancies may be due to the fact that the antibodies have different functional activities (blocking or activating) and that CD44 exists in multiple variant isoforms that are upregulated under highly restricted conditions during inflammation and tumorigenesis 23,24 where they provide a pro-survival capacity to the cells. 7 In most of the reports, the isoforms were not distinguished.…”