Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1995-04-07
1998-11-03
Degen, Nancy
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
436 64, 536 231, 536 241, 536 2431, 536 2433, C12Q 168, C07H 2104, G01N 33483
Patent
active
058306463
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND
The present invention is concerned with using expression of the CD44 gene or part of the CD44 gene to investigate neoplasia. Such investigation includes taking a tissue, body fluid or other sample from a patient to perform diagnosis, to give a prognosis or to evaluate therapy that is already being carried out. In particular, the invention provides a simple method for carrying out routine screening for neoplasia using body fluid samples or other samples which can be obtained non-invasively.
The usual way to diagnose a tumour at present is by looking at cells or thin slices of tissue down a microscope, a method which is often very effective but has some important limitations. With a small sample, diagnosis can be very difficult and often a large number of cells will not be available, or it is not desirable or possible to obtain a large sample from the patient. In as many as 50% of cases a reliable diagnosis cannot be given; it may be that there is no positive evidence of carcinoma but also no certainty that the patient is actually free from carcinoma. More invasive investigation is then required to establish a diagnosis.
Judgment of prognosis also relies on the appearance of cells when viewed under a microscope. Generally, the more bizarre-looking the cells in a primary tumour, the more likely they are to metastasise later on but the correlation is by no means absolute. It would clearly be an advantage to be able to predict more accurately whether or not metastasis is likely to occur in order to judge what will be the most effective treatment.
The human CD44 gene codes for a family of variably glycosylated cell surface proteins of different sizes, the numerous functions of which are not yet fully established, but which share epitopes recognised by the CD44 monoclonal antibody (mAb). It is known to consist of a standard portion which is expressed in haemopoietic cells and many other cell types and into which the products of additional exons may be spliced in various combinations to produce different proteins. This is a well recognised mechanism in eukaryotes for producing several often functionally unrelated proteins from the same gene, and is known as alternative splicing.
Two common CD44 isoforms have so far been purified and characterised (Stamenkovic et al. 1989), namely i) a 90 kD form consisting of a central 37 kD core which is heavily glycosylated and ii) a 180 kD form which has 135 extra amino acids inserted into the proximal extra-membrane domain and is even more heavily glycosylated. Immuno-cytochemical and immuno-precipitation studies have shown that both are widely distributed in many different cells and tissues. The former is known as the haemopoietic or standard form which is present on circulating leukocytes, bone marrow cells and numerous other cell types. The other, known as the epithelial variant, is detectable on several epithelial cell types. Both are believed to function as receptors mediating homotypic and heterotypic adhesive interactions, attaching cells to each other or to adjacent extracellular scaffolding.
Some time ago, some of the CD44 epitopes recognised by the mAb Hermes-3 were identified as constituting the peripheral lymph node receptor enabling circulating lymphocytes to recognise and traffic through peripheral lymph nodes. Further mAbs to this antigen later became available and Stamenkovic et al. (1989) used one of them to clone a cDNA sequence coding for the standard form of the molecule from an expression library in COS cells. They additionally found, by Northern blotting, that this gene was expressed not only by lymphoid cells, but also by a variety of carcinoma cell lines and a representative sample of solid carcinomas, amongst which two colonic carcinomas appeared to express more than normal colonic epithelium.
Birch and colleagues (1991) reported that melanoma cell clones which strongly expressed the 80-90 kD form of the CD44 antigen, recognised by the Hermes-3 antibody, were substantially more metastatic in nude mice than clones which expressed it weakly.
REFERENCES:
patent: 5506119 (1996-04-01), Herrlich et al.
G.R. Screaton et al. "Genomic structure of DNA . . . " Chemical Abstracts #184829m. vol 118, No. 19 May 10, 1993 (Columbus, Ohio USA), p. 253.
D.L. Cooper et al. "The complex CD44 transcriptional . . . " Chemical Abstracts #122543e vol 118 No. 13, Mar. 29, 1993 (Columbus, Ohio USA), p. 619.
M. Hoffman et al. "CD44 splice variantes . . . " Chemical Abstracts #206116k, vol 117 No. 21, Nov. 23, 1992 (Columbus, Ohio USA), p. 203.
H.J. Harn et al. "The multi-specific cell adhesion . . . " Chemical Abstracts #229300j, vol 116 No. 23, Jun. 8, 1992 (Columbus, Ohio USA), p. 202.
Jackson et al. J. Biol. Chem 26(7) 4732-4739 1992 "Multiple Variants of the Human Lymphocyte Homing Receptor CD44 . . . ".
Gunthet et al. Cell 65 13-24 1991 "A New Variant of Glycoprotein CD44 Confers Metastatic Potential to Rat Carcinoma Cells".
Janabe et al. Lancet 341 725-726 1993 "Expression of CD44R1 Adhesion Molecule in Colon Carcinomer & Metastases".
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Matsumura Yasuhiro
Tarin David
Degen Nancy
Isis Innovation Limited
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