CD44 integrates signaling in normal stem cell, cancer stem cell and (pre)metastatic niches

Abstract

The stem cell niche provides a regulatory microenvironment for cells as diverse as totipotent embryonic stem cells to cancer stem cells (CSCs) which exhibit stem cell-like characteristics and have the capability of regenerating the bulk of tumor cells while maintaining self-renewal potential. The transmembrane glycoprotein CD44 is a common component of the stem cell niche and exists as a standard isoform (CD44s) and a range of variant isoforms (CD44v) generated though alternative splicing. CD44 modulates signal transduction through post-translational modifications as well as interactions with hyaluronan, extracellular matrix molecules and growth factors and their cognate receptor tyrosine kinases. While the function of CD44 in hematopoietic stem cells has been studied in considerable detail, our knowledge of CD44 function in tissue-derived stem cell niches remains limited. Here we review CD44s and CD44v in both hematopoietic and tissue-derived stem cell niches, focusing on their roles in regulating stem cell behavior including self-renewal and differentiation in addition to cell-matrix interactions and signal transduction during cell migration and tumor progression. Determining the role of CD44 and CD44v in normal stem cell, CSC and (pre)metastatic niches and elucidating their unique functions could provide tools and therapeutic strategies for treating diseases as diverse as fibrosis during injury repair to cancer progression.

Figure 1

Diagrammatic representations of the CD44 gene and protein structure. (a) Schematic of the genomic structure of CD44. CD44 standard, CD44s; epithelial CD44, CD44E; CD44 variant 10, CD44v10; soluble CD44, CD44RC; shortened-tail CD44, CD44-st. (b) CD44 structural domains and their corresponding amino acid sequences. The modified CD44 molecule line drawing was adapted from Ponta et al.

Figure 2

CD44s and CD44v function in discrete stem cell niches. (a) Embryonic stem cell (ESC) niche. The standard CD44 (CD44s) appears to be the primary CD44 isoform in the ESC niche. (b) Mesenchymal stem cell (MSC) niche. In this niche, the two primary isoforms are CD44s and the homing receptor Hematopoietic Cell E-/L-selectin Ligand (HCELL). (c–e) Hematopoietic stem cell niches. These niches represent the functions of (c) CD44s and (d) CD44v in bone marrow and (e) of CD44v in the developing fetal thymus. (f) Overview of extracellular matrix components which modulate HA/CD44s and CD44v/RTK function in the stem cell-like niche. (g) Cancer stem cell (CSC) niche. Both CD44s and CD44v promote tumor progression through similar and unique mechanisms (discussed in more detail in the text). HA, hyaluronan; NK cell, natural killer cells; MW, molecular weight; CS-A, chondroitin sulfate A; ND, ligand not determined; HS, heparan sulfate; RTK, receptor tyrosine kinase; HGF, hepatocyte growth factor; FGF2, fibroblast growth factor 2; HB-EGF, heparin-binding EGF-like growth factor; MEK, mitogen activated kinase kinase; ERK, extracellular signal-regulated kinase