CD44: A Multifunctional Cell Surface Adhesion Receptor Is a Regulator of Progression and Metastasis of Cancer Cells

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.

Keywords: CD44; CD44-ICD; angiogenesis; cancer; hyaluronic acid; invasion; metastasis; migration.

Figure 1

CD44 transmembrane receptor function. CD44, a multifunctional receptor can control biological functions involved in cancer cell dissemination and metastasis. CD44 can be sequentially cleaved by membrane type 1 matrix metalloprotease (MT1-MMP) and then presenilin-1/γ secretase induced by ligands [osteopontin (OPN), hyaluronic acid (HA), etc] binding. Cleavage produces (1) extracellular domain (ECD) fragment. (2) CD44β like peptide or transmembrane domain (TMD), and (3) CD44 intracellular domain (ICD) fragment. CD44—ICD translocates into the nucleus to activate transcription of genes important in metastasis and cell survival. Adapted from Thorne et al., .