CD44 isoforms in intestinal cancer Identity and functions

Colorectal cancer derives from epithelial cells lining the crypts and develops through a series of genetic modifications that transforms normal epithelium to an adenoma and then ultimately adenocarcinoma. Active Wnt signaling in the intestinal crypt compartment is crucial to maintain a proliferating and multipotent pool of intestinal stem cells. CD44 is a prominent Wnt-responsive gene in these cells. CD44 comprises a versatile family of transmembrane adhesion receptors capable of binding extracellular matrix components. The occurrence of variable exons, mainly involving the extracellular domain, allows for the expression of various isoforms. Importantly, certain CD44 isoforms function as a coreceptor for growth factors that are present in the ISC microenvironment. It’s involvement in sensing, integrating and transducing microenvironmental signals makes CD44 a putative factor in regulating ISC fate decisions and in promoting intestinal tumorigenesis. These concepts are strengthened by the sustained expression of CD44 on colon cancer cells with stem-cell like properties. Aberrant CD44 expression in invasive CRC is associated with increased tumorigenic and metastatic potential, indicating a functional role throughout disease. The elucidation of tumor-specific CD44 isoforms, or signaling pathways affected by these isoforms, may contribute to the development of targeted treatment strategies. However, the functional contribution of CD44, and in particular individual splice variants of CD44, to the onset and progression of intestinal cancer has remained elusive. This thesis investigates the contribution of CD44 and variant isoforms to intestinal tumorigenesis and focuses on its role in affecting signaling cascades that regulate cell fate, cancer growth and progression.