CD44 Acts Both as a Growth‐ and Invasiveness‐Promoting Molecule and as a Tumor‐Suppressing Cofactor

Abstract

High‐molecular‐weight splice variants of the CD44 transmembrane protein family have been implicated in tumorigenesis and metastasis formation. By contrast, in certain tumors‐for example, Burkitt's lymphoma, neuroblastomas, and prostate cancer‐loss of CD44 expression seems to accompany transformation. Here we describe two modes of action of CD44 proteins. They can bind growth factors and present them to their authentic high‐affinity receptors, and thus promote proliferation and invasiveness of cells. Under these conditions the CD44 proteins recruit ERM proteins‐for example, ezrin or moesin‐to their cytoplasmic tails, thereby producing links to the cytoskeleton. This mode of action could account for the tumor‐promoting action of CD44 proteins. The second mode of action of CD44 proteins comes into play when cells reach confluent growth conditions. Under specific conditions, binding of another ligand, the ECM component hyaluronate, leads to the activation and binding to the CD44 cytoplasmic tail of the tumor suppressor protein merlin. The activation of merlin confers growth arrest, so‐called contact inhibition. This function of CD44 proteins defines them as tumor suppressors. The type of action of CD44 on a given cell will depend on the isoform pattern of CD44 expressed, on the cellular equipment with ERM protein members, on the nature of the ECM, and on yet‐unknown conditions.

Lipid rafts remodeling in estrogen receptor–negative breast cancer is reversed by histone deacetylase inhibitor

“…A number of functional associations between proteins that overexpress in mesenchymal cells have also been established. CD44/moesin and CD44/lyn interactions collaborate in triggering invasiveness and chemoresistance (23,24). Vimentin and fimbrin form functional complexes in macrophages (25).…”

Re-expression of DNA methylation-silenced CD44 gene in a resistant NB4 cell line: rescue of CD44-dependent cell death by cAMP

“…2,3 These surface molecules are involved in a fascinating number of distinct functions, including cell proliferation, cell survival, differentiation, cell adhesion and migration, angiogenesis. [4][5][6] While CD44 is important for the physiological behaviour of normal cells, it has rapidly been recognized that altered CD44 expression participates in the initiation or progression of tumour cells towards transformed phenotypes and metastasis. Importantly, in the case of myeloid leukaemia, 7,8 targeting CD44 by means of epitope-specific antibodies, cells undergo maturation and/or apoptosis, with anti-tumour features that can be exploited therapeutically.…”

CD44 Standard Isoform; Not a Good Marker for Colon Cancer

“…This interesting finding would be another explanation for discrepancies and controversies in the literature about the role of CD44 in cancer (26). HER2 as well as activating them; through this mechanism, CD44 can act as a tumor promoter molecule.…”