Abstract
CD44 is a cell surface adhesion receptor that is highly expressed in many cancers and regulates metastasis via recruitment of CD44 to the cell surface. Its interaction with appropriate extracellular matrix ligands promotes the migration and invasion processes involved in metastases. It was originally identified as a receptor for hyaluronan or hyaluronic acid and later to several other ligands including, osteopontin (OPN), collagens, and matrix metalloproteinases. CD44 has also been identified as a marker for stem cells of several types. Beside standard CD44 (sCD44), variant (vCD44) isoforms of CD44 have been shown to be created by alternate splicing of the mRNA in several cancer. Addition of new exons into the extracellular domain near the transmembrane of sCD44 increases the tendency for expressing larger size vCD44 isoforms. Expression of certain vCD44 isoforms was linked with progression and metastasis of cancer cells as well as patient prognosis. The expression of CD44 isoforms can be correlated with tumor subtypes and be a marker of cancer stem cells. CD44 cleavage, shedding, and elevated levels of soluble CD44 in the serum of patients is a marker of tumor burden and metastasis in several cancers including colon and gastric cancer. Recent observations have shown that CD44 intracellular domain (CD44-ICD) is related to the metastatic potential of breast cancer cells. However, the underlying mechanisms need further elucidation.
Highlights
Migration and InvasionCD44 receptor has the potential to integrate adhesive and signaling activities to modulate migration/invasion processes during cancer progression (Lokeshwar et al, 1995)
Reviewed by: Sumit Sahni, University of Illinois at Chicago, USA Sigrid A
The multifunctional glycoprotein CD44 can undergo alternative splicing events to produce CD44 variant isoforms that are more restricted in their distribution as compared to the standard CD44 isoforms (Rall and Rustgi, 1995)
Summary
CD44 receptor has the potential to integrate adhesive and signaling activities to modulate migration/invasion processes during cancer progression (Lokeshwar et al, 1995). The surface expression of CD44 along with its interaction with matrix metalloproteinase 9 (MMP9) on the surface of the cell results in secretion of active MMP9, migration, and invasion of PC3 cells (Desai et al, 2007, 2008; Gupta et al, 2013a). CD44v3 has been shown to upregulate the function of cytoskeleton through ankyrin to activate the actomyosin contractile complex in order to mediate cell migration in head and neck squamous carcinoma cell line. The formation of new blood vessels (angiogenesis) is required for tumor cell to disseminate and migrate to distant organs. Adhesion of cancer cells to vasculature and enhanced expression of CD44 (CD44s and/or CD44v) by angiogenic factors (e.g., VEGF) produced by tumor cells might lead to facilitated extravasation via angiogenesis. It was suggested that an increase in micro vessel number and expression of CD44 might be useful diagnostic markers of metastasis of breast cancer (Ozer et al, 1997)
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