The normal structure and function of CD44 and its role in neoplasia

Abstract

CD44 is a transmembrane glycoprotein, the variant isoforms of which are coded for by alternative splicing, with the most prolific isoform being CD44 standard. CD44 is found in a wide variety of tissues including the central nervous system, lung, epidermis, liver, and pancreas, whereas variant isoforms of CD44 (CD44v) appear to have a much more restricted distribution. Variants of CD44 are expressed in tissues during development, including embryonic epithelia. Known functions of CD44 are cellular adhesion (aggregation and migration), hyaluronate degradation, lymphocyte activation, lymph node homing, myelopoiesis and lymphopoiesis, angiogenesis, and release of cytokines. The functions of CD44 are principally dependant on cellular adhesion in one setting or another. The role of CD44 in neoplasia is less well defined, although metastatic potential can be conferred on non-metastasising cell lines by transfection with a variant of CD44 and high levels of CD44 are associated with several types of malignant tumours. The physiological functions of CD44 indicate that the molecule could be involved in the metastatic spread of tumours. Many studies have investigated the pattern of CD44 distribution in tumours and some observations suggest that certain cells do not use CD44 in tumorigenesis or in the production of metastases. However, the data are extremely conflicting, and further studies are needed to establish the prognostic value of CD44 and its variant isoforms. The precise function of CD44 in the metastatic process and the degree of involvement in human malignancies has yet to be established fully.

Molecular mechanisms regulating the tumor-targeting potential of splice-activated gene expression

“…7 While CD44 H is expressed primarily on resting normal cells, CD44R1 is generally restricted to a subset of transformed cells and certain activated normal cells. 7,9,10 Importantly, striking correlations have been noted between the expression of CD44R1 on tumor cells and both enhanced metastatic propensity and poor patient prognosis. 7,8,10 While the precise molecular mechanisms that underlie this relationship remain to be fully defined, studies from our group have shown that unlike CD44 H, CD44R1 can promote cell-cell adhesion via the recognition of chondroitin sulfate side chains, particularly if these are presented on the surface of opposing cells in association with other CD44R1 molecules.…”

“…7,9,10 Importantly, striking correlations have been noted between the expression of CD44R1 on tumor cells and both enhanced metastatic propensity and poor patient prognosis. 7,8,10 While the precise molecular mechanisms that underlie this relationship remain to be fully defined, studies from our group have shown that unlike CD44 H, CD44R1 can promote cell-cell adhesion via the recognition of chondroitin sulfate side chains, particularly if these are presented on the surface of opposing cells in association with other CD44R1 molecules. 11 Recently, we have extended these studies and demonstrated that differential alternative splicing of CD44 can also be exploited in the context of tumor-targeted gene therapy.…”

Expression of Standard CD44 in Advanced Gastric Cancer: Relationship with Metastasis to Lymph Nodes

“…In malignant tumors originating from various organs, there is some controversy as to whether CD44s acts as a growth / invasion-promoting molecule or tumor suppression cofactor. While a number of studies have shown that CD44s expression is associated with metastasis and a poor patient prognosis 21 , others have shown that down-regulation of CD44s expression is correlated with an adverse patient outcome. For example, reduced CD44s expression has been shown to be associated with a high incidence of lymphatic or vascular in ltration in endometrial carcinoma 26 and breast carcinoma 24 , and a poor prognosis in patients with pancreatic carcinoma, thyroid carcinoma, and squamous cell carcinoma of the head and neck 27,28 .…”

“…The clinical signi cance of CD44s expression in gastric cancer, however, remains unclear. Various studies have reported an association of CD44s expression with an advanced stages of gastric cancer and a poor prognosis [20][21][22][23] , with one study reporting adverse correlation between CD44s expression and tumor progression [24][25][26][27][28][29] .…”

Épissage alternatif, pathologie et thérapeutique moléculaire

“…Cet EA est favorisé en pré-sence de la protéine PTB (polypyrimidine tract binding protein) dont le taux est augmenté. Le gène CD44 est impliqué dans l'adhérence et la migration cellulaires et peut coder pour des formes variantes de CD44, CD44v, associées à de nombreux cancers [22]. Le gène suppresseur de tumeur BRCA1 code pour une protéine nucléaire, mais, dans certains cancers du sein, un variant d'épissage dépourvu de l'exon 11 code pour une protéine dépourvue de signal de localisation nucléaire, suggérant la possibilité d'une perte de fonction de la protéine [23].…”