Alternative splicing of ten different variant exons (v1-v10) is responsible for the creation of a large number of different CD44 surface proteins. Some of these proteins play decisive roles in the metastatic spread of rat tumours. Also in human cancers, CD44 splice variants are frequently expressed in advanced states of tumorigenesis. In breast cancer and in non-Hodgkin's lymphomas expression of exon v6 is correlated with poor prognosis of patient survival. In colorectal carcinogenesis, expression of exon v5 is an early tumour marker since it is already detectable on small dysplastic polyps (but not on normal colon epithelium). In contrast, exon v6 expression occurred with increased frequency with tumour progression, and its expression on colorectal tumours indicated reduced survival probability. Most likely, tumours carrying the CD44 v6 epitope acquire selective advantage during tumour progression and metastasis formation. This could be a proliferative advantage since mice transgenic for the CD44 isoform CD44v4-v7 on T lymphocytes show an accelerated T-dependent immune response as compared with non-transgenic siblings.

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Radiation and mutagen inducible mammalian genes.

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Radiation-induced signal transduction. Mechanisms and consequences.

Over a dose range up to 50 Gy of low-LET (linear energy transfer) ionizing radiation and up to 5 kJ/m2 UVB, mammalian cells convert molecular damage into productive response (mostly gain of function). By inactivation of negative regulatory components, such as protein tyrosine phosphatases as one mechanism discovered, the balance between restraining and stimulating influences is disturbed and an increase in signal flow results. Also DNA damage causing transcriptional arrest produces a signalling cascade of as yet unknown details. Such stimulation of the intracellular communication network can lead to apoptosis, elevated cell cycling and differentiation processes possibly including repair and recombination. The outcome likely depends on integration of all signals received which is as yet ill-understood. Although accurate determinations of low-dose inductions have not been achieved for technical reasons, the dose-response curves of induced signal transduction likely show threshold characteristics, in contrast to the direct consequences of DNA damage.

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CD44 splice variants; expression on lymphocytes and in neoplasia.

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CD44 isoforms in metastatic cancer.

CD44 designates a large family of proteins generated from one gene by alternative splicing. Variants of CD44 (CD44v) differ from the standard form (CD44s) by usage of ten variant exons in various combinations. Some variants have been causally related to the metastatic spread of rat tumor cells. In human mammary carcinomas and colorectal carcinomas, the expression of CD44v has also been correlated with more progressed tumor stages. Moreover, the expression of CD44v on mammary and colorectal carcinomas correlates with a bad prognosis for patient survival. The biochemical features of these CD44 isoforms that may account for both their normal functions and their roles in tumor progression are discussed.

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