CD44

Hermes antigen (Goldstein L.A. et al., 1989)
Lymphocyte homing receptor
Pgp-1
MC56 (Cianfriglia M. et al., 1992)

Gene: maps to 11p13, has 20 exons of which up to 10 variant exons (v1-v10) are alternatively spliced (Günthert U. et al., 1995)
mRNA: size: kb
Protein: the standard CD44 isoform (CD44s) lacks exon sequences v1-v10. Variant isoforms (CD44v) contain segments encoded by various combinations of exons v1 through v10. All splice forms are heavily glycosylated to various degrees. CD44 thus embraces a whole family of cell surface transmembrane glycoproteins which differ in their extracellular part. Members of the family are expressed in a wide variety of tissues and cell types (Underhill C., 1992). CD44 proteins have been implicated in several cellular functions including cell-cell and cell-matrix adhesion, migration, and tumor metastasis (Naor D. et al., 1997).
Some CD44 variants are heparan-sulphate-modified and bind heparan-seaking cytokines. They then present these cytokines to their high-affinity receptors (Sherman L. et al., 1998). Based on antibody interference studies, this property is likely to be relevant for tumor colony formation and metastasis in certain cancers.
Cleavage of the extracellular portion of CD44 may occur. Such soluble CD44 proteins might prevent tumor formation (Yu Q. et al., 1997).

Cell lines:
- The phenotypic characteristics of 2 tumor cell lines (BC-H1 and BC-K1) established from bone marrow of patients with breast cancer were studied by immunocytochemistry, flow cytometry, and RT-PCR. Both cell lines expressed E-cadherin, vimentin, cytokeratins (including component 18), alpha 5-, alpha V-, beta 1-, and beta 3- integrin subunits, ICAM-1, MCAM, LFA-3 (CD58), and CD44s (but not CD44v5, v6, v7/8). BC-H1 also expressed ErbB2 (not found in BC-K1), and MAGE-4 (but not MAGE-1, -2, -3/6, -12; BC-K1 was not tested). The expressed molecules might be potential candidates for novel therapeutic targets (Putz E. et al., 1999).

Tumors:
- In a series including tumor samples of 91 patients, CD44 v3, v5, and v6 epitope expression was associated with poor breast cancer survival, while expression of CD44 v7/8 and v10 was found to be of no prognostic relevance (Kaufmann M. et al., 1995).

- In a study including samples of 227 patients, no significant associations with disease-free or overall survival were found for expression of total CD44 or variants carrying epitopes v6 or v9. CD44 isoform expression correlated with cellular differentiation and not with breast cancer prognosis (Friedrichs K. et al., 1995).

- A relationship of a poor prognosis with immunohistochemically assessed expression of v5, v6, and v7/8, has been reported in a study involving 115 breast cancer patients (Tempfer C. et al., 1996).

- A (non-significant) trend between v6 expression and poor survival has been reported in a study involving 55 patients (Schumacher U. et al., 1996).

- In a cohort of 38 tumor samples derived from node-negative patients, CD44 v6 expression was associated with improved survival (Guriec N. et al., 1997).

- A lack of significant association between CD44 v6 epitope expression and disease-free or overall survival has been reported in a study involving 338 patients (Jansen R.H.L. et al., 1998).

- A lack of significant association between CD44 v6 epitope expression and disease-free or overall survival has been reported in a study employing ELISA on 90 breast cancer cytosols. CD44 v5 expression was also found not to be related with relapse-free survival (Hefler L. et al., 1998).

- The expression of CD44 variants was evaluated by immunohistochemistry in primary breast cancer samples of 237 node-negative and 230 node-positive patients. The expression of CD44 v6 epitopes in tumors from node-negative patients was associated with a favorable prognosis, both upon univariate and multivariate analysis. The expression of CD44 v7/8, v9 or v10 epitopes was not significantly related with relapse-free survival. The v6 epitopes were expressed by a majority of tumors (>=65%). In addition, CD44-v6 epitopes were not found in normal duct epithelia but were strongly expressed by myoepithelial cells (Foekens J.A. et al., 1999).

Cianfriglia M. et al. (1992) The gene encoding for MC56 determinant (drug-sensitivity marker) is located on the short arm of human chromosome 11. Int. J. Cancer 52, 585-587.
Dougherty G.J. et al. (1991) Molecular cloning of CD44R1 and CD44R2, two novel isoforms of the human CD44 lymphocyte "homing" receptor expressed by hemopoietic cells. J. Exp. Med. 174, 1-5.
Foekens J.A. et al. (1999) Prognostic value of CD44 variant expression in primary breast cancer. Int. J. Cancer 84, 209-215.
Friedrichs K. et al. (1995) CD44 isoforms correlate with cellular differentiation but not with prognosis in human breast cancer. Cancer Res. 55, 5424-5433.
Goldstein L.A. et al. (1989) A human lymphocyte homing receptor, the hermes antigen, is related to cartilage proteoglycan core and link proteins. Cell 56, 1063-1072.
Günthert U. et al. (1995) Are CD44 variant isoforms involved in human tumor progression? Cancer Surv. 24, 19-42 (Review).
Guriec N. et al. (1997) CD44 isoforms with exon v6 and metastasis of primary NoMo breast carcinomas. Breast Cancer Res. Treat. 44, 261-268.
Hefler L. et al. (1998) Cytosol concentrations of CD44 isoforms in breast cancer tissues. Int. J. Cancer 79, 541-545.
Jansen R.H.L. et al. (1998) CD44v6 is not a prognostic factor in primary breast cancer. Ann. Oncol. 9, 109-111.
Kaufman M. et al. (1995) CD44 variant exon epitopes in primary breast cancer and length of survival. Lancet 345, 615-619.
Naor D. et al. (1997) CD44: structure, function, and association with the malignant process. Adv. Cancer Res. 71, 241-319 (Review).
Putz E. et al. (1999) Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: establishment of working models for human micrometastases. Cancer Res. 59, 241-248.
Screaton G.R. et al. (1992) Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc. Natl. Acad. Sci. USA 89, 12160-12164.
Schumacher U. et al. (1996) A CD44 variant epitope as a prognostic indicator in breast cancer. Eur. J. Surg. Oncol. 22, 259-261.
Sherman L. et al. (1998) A splice variant of CD44 expressed in the apical ectodermal ridge presents fibroblast growth factors to limb mesenchyme and is required for limb outgrowth. Genes Develop. 12, 1058-1071.
Tempfer C. et al. (1996) Prognostic value of immunohistochemically detected CD44 isoforms CD44v5, CD44v6 and CD44v7-8 in human breast cancer. Eur. J. Cancer 32A, 2023-2025.
Underhill C. (1992) CD44: the hyaluronan receptor. J. Cell Sci. 103, 293-298.
Yu Q. et al. (1997) Induction of apoptosis of metastatic mammary carcinoma cells in vivo by disruption of tumor cell surface CD44 function. J. Exp. Med. 186, 1985-1996.