Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1996-05-28
1999-03-30
Scheiner, Toni R.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
53038885, 5303877, 435 71, 435 72, 435 723, 435330, 435331, C07K 1630, C12N 512, G01N 3353, G01N 33577
Patent
active
058891595
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to proteins that serve as tumor markers for human carcinoma and to methods of isolating differentially expressed genes.
BACKGROUND OF THE INVENTION
Tumor markers for human tumor cells have been largely limited to activated oncogenes and their products, for example, the myc, ras, fos, and erbB2 genes and their encoded oncoproteins. In addition, activated anti-oncogenes, such as RB, p53, and DCC, have been identified in normal cells but do not appear to be present in tumor cells. Oncogene and anti-oncogene products have proven difficult to use as consistent predictors of tumor and normal tissue, respectively, due to the relatively low level of expression of the genes encoding these proteins. Thus, there is a need in the art for a tumor marker which is not only differentially expressed in tumor and normal tissue, but also consistently detectable in human tumor tissue and consistently absent in the corresponding normal tissue.
A common method used to identify genes differentially or uniquely expressed in tumors, in cells responding to growth factors, and in differentiated cell types such as, among others, T cells, adipocytes, neurons, and hepatocytes is the subtractive hybridization technique (S. W. Lee et al., Proc. Natl. Acad. Sci. U.S.A. 80:4699, 1983). A method of differential display of eukaryotic mRNA by means of the polymerase chain reaction (PCR) has recently been developed (P. Liang et al., Science 257:967, 1992). This method utilizes oligo dT linked to two additional bases as the primer for reverse transcription driven by reverse transcriptase. cDNA fragments are then amplified by Taq DNA polymerase-based PCR using an oligo dT primer along with one additional primer. The amplified cDNAs are then resolved by DNA sequencing gels. There is a need in the art for a streamlined and simplified process for isolating cDNAs corresponding to differentially expressed mRNAs.
SUMMARY OF THE INVENTION
The invention is based on the discovery of a novel protein, TC1 (SEQ ID NO:4), which is a tumor marker, particularly for invasive and metastatic tumors, and the gene encoding this protein.
The invention thus encompasses the TC1 protein (SEQ ID NO:4), which is useful as a tumor marker for tumor diagnosis and therapy, particularly for colorectal, breast, and gastrointestinal tumors, and for metastatic tumors emanating from these tumor types. TC1 is also a useful marker in general for tumor cell invasion and metastasis. mRNA encoding TC1 is not expressed in most cultured tumor cells, i.e., in vitro, but is expressed once these cells are grown in vivo. Because later stage and deeply invasive tumors contain higher levels of TC1 protein than other tumor tissues, TC1 appears to be a particularly useful marker for later stage cancers.
TC1 protein may also serve as a target in tumor targeted therapy to prevent tumor cell metastasis and thus invasion of additional organs. For example, a polypeptide fragment of the TC1 protein may be used as an antagonist of TC1 biological activity; e.g., where TC1 biological activity includes invasion and metastasis, the polypeptide fragment may be administered to a patient afflicted with the tumor in order to inhibit the spread of the tumor to other tissues. Alternatively, a truncated portion of TC1 which retains the invasive and metastatic biological activities of the full-length molecule will be useful for screening for antagonists of TC1 activity. Potentially useful polypeptides are described herein.
The invention also encompasses nucleotide probes based on the TC1 nucleotide sequence; e.g., 10, 20, 30, 40, etc. nucleotides in length. Such probes are useful for PCR-based tumor detection and in situ hybridization of tumor tissue sections. In addition, probes whose nucleotide sequences are based on homologies with other genes or proteins having sequences related to TC1, i.e., genes of the TC1 family, two of which are described herein, are useful for detecting additional genes belonging to the TC1 family of genes.
The invention thus also enc
REFERENCES:
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Bao Shideng
Chen Lan Bo
Liu Yuan
Dana-Farber Cancer Institute Inc.
Johnson Nancy A.
Scheiner Toni R.
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