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Abnormal CD44 Gene Expression in Neoplasia: Biological and Clinical Implications

  • David Tarin

Summary

The CD44 gene is one of the most interesting and promising new candidate markers for early cancer detection and for the analysis of genetic disturbances involved in neoplasia. It a large gene that under normal circumstances produces a variety of heavily glycosylated cell surface proteins by alternative splicing of its exons. Severe abnormalities have been observed in its patterns of expression in many types of common human tumors by both protein and RNA analyses. They are manifested by markedly increased levels of unusual CD44 transcripts and proteins in many tumors compared to corresponding normal tissues. Also, inappropriate expression patterns of the alternatively spliced exons have been linked to both tumor growth and metastatic potential. A unique manifestation of aberrant CD44 gene expression is the retention of introns in mature mRNA transcripts in the nucleus and cytoplasm of tumor cells but not in their normal counterparts. This phenomenon would naturally result in abnormal or truncated protein products. The clinical relevance of these observations is demonstrated by the frequent detection of all these abnormalities in fresh tissue samples from tumors of many organs and by their presence in preinvasive and high risk precancerous lesions. It has also been possible to achieve noninvasive detection of malignancy by identifying aberrant CD44 expression in exfoliated cells in body fluids and waste products. This chapter reviews the molecular mechanisms that result in such profound misregulation of the expression of this gene in neoplasia and the biological and clinical implications of these changes for tumors of the gastrointestinal tract.

This chapter is an account of current ideas and information on one of the most interesting and mysterious components in the mammalian genetic repertoire. It is still known only by the code name CD44, indicating that its products and functions are largely unknown, although it has leapt to the forefront of attention and curiosity because its expression is so strikingly unusual in many common types of cancer, including those of the gastrointestinal tract and because it appears to be involved in a large variety of biological processes that are unrelated to each other.

The group of proteins encoded by this locus first attracted interest as a result of efforts by several research laboratories to identify and characterize cell surface molecules on white blood cells that might be important in cell-mediated immunity. These investigations included studies to isolate molecules involved in organizing the recirculatory traffic of lymphocytes as they patrol the organs of the body on surveillance missions [1]. The work resulted in the raising of a number of monoclonal antibodies (mAbs), which were eventually recognized to bind to different epitopes on a family of structurally related proteins assigned the designation CD (cluster of differentiation) 44 by the Human Leukocyte Workshop.

Subsequent studies [2, 3] with these antibodies rapidly made it clear that the CD44 family of proteins are not confined to the surfaces of white blood cells, and that some of them appear to be ubiquitously distributed on all cell types. It also emerged almost simultaneously that they are involved not just in immunological activities but in a surprising diversity of biological processes [4, 5], although their exact role in these processes remains unclear. Some of the functions in which they have been implicated include the following.

  • Lymphocyte recirculation

  • T lymphocyte activation

  • Adhesion to other cells and to the intercellular matrix

  • Embryonic development

  • Hyaluronan metabolism

  • Signal transduction across the cell membrane

  • Growth factor secretion

Shortly afterward various parts of the gene were cloned and sequenced by several groups [6–11], and it became evident that by alternative splicing of its exons it can produce a large variety of protein isoforms. It appears to be one of the most alternatively spliced genes yet found.

The human CD44 gene has now been mapped to the chromosomal locus 11p13 and confirmed to encode a family of large transmembrane glycoproteins. It is composed of a stretch of approximately 60 kb comprising at least 21 exons, 10 of which (exons 1–5 and 16–20) are constantly expressed on all cell types as the standard form (CD44s). The remaining 11 can be alternatively spliced with the constant ones (Fig. 1) to generate a number of variant protein isoforms (CD44v), which can be further modified by differential post-translational glycosylation.

The complexity of the processes in which this gene is involved in cell and tissue function was further revealed when it became apparent that its expression is characteristically and severely changed in many common types of neoplasia, and that such dysfunction is involved in the acquisition of metastatic ability in some circumstances. The following account summarizes current knowledge of the unusual patterns of CD44 expression in cancer and considers their clinical and biological implications.

Keywords

CD44 Gene CD44 Protein Early Cancer Detection CD44 Isoforms CD44 Gene Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Japan 1997

Authors and Affiliations

  • David Tarin
    • 1
  1. 1.Nuffield Department of Pathology and Bacteriology, John Radcliffe HospitalOxford UniversityHeadington, OxfordUK

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