Overexpression of the ornithine decarboxylase (ODC) gene may be important to the development and maintenance of colonic neoplasms, as well as tumors in general.
We have shown that expression levels of COXIII, a mitochondrial gene encoding one of the 13 subunits of cytochrome c oxidase, are abnormally low in colon tumors and colonic tissue at genetic risk for developing tumors but increase following in vitro treatment of HT29 human colonic adenocarcinoma cells with the fatty acid butyrate.
Using an IGF-II radioimmunoassay, we have now detected high levels of both 10-kDa and 7.5-kDa IGF-II species (2,370 ng/g) in a right colon tumor showing a 800-fold IGF-II gene over-expression in comparison to the normal adjacent tissue.
We have previously shown that O6-benzylguanine can be used to deplete cells of the DNA repair protein O6-alkylguanine-DNA alkyltransferase and to enhance the sensitivity of human glioma (SF767) and colon tumor (HT29) cells to the cytotoxic effects of alkylnitrosoureas.
These results suggest the following mechanisms for the development of colon tumors in patients with familial adenomatous polyposis: (a) the heterozygous mutant/wild-type condition at the APC gene causes formation of mild or moderate adenoma; (b) the loss of the normal allele in the APC gene leads to a change from moderate to severe adenoma; (c) LOH on chromosome 17p contributes to the conversion of adenoma to intramucosal carcinoma; (d) LOH on other chromosomes, such as 18 and 22q, are involved in the progression of intramucosal carcinoma to invasive carcinoma; and (e) K-ras mutation may also affect the development of moderate to severe adenoma.
In addition, nm23 expression was maintained in culture in each of 12 cell lines initiated from human colon neoplasms and did not differ between lines established from neoplasms of high or low metastatic capability.
In situ hybridization, using a biotinylated cDNA probe for the epidermal growth factor receptor (EGFR) gene, indicates that the amplified EGFR genes in the colon tumor cell line, DiFi, are localized in many small double minute chromosomes (dmin) of varying size and visibility.
These findings demonstrate that changes in versican gene methylation are specific for colonic neoplasms, that these changes may precede malignant transformation, and that inflammation and tissue remodelling alone are not enough to generate these changes in proteoglycan gene methylation and nuclease hypersensitivity.
In addition, reduced (approximately 10% of normal) ACY-1 expression was common in SCLC cell lines (14/29) and tumors (3/8), but not in NSCLC cell lines (1/19) or tumors (0/9), nor in other human cell lines (0/15) or colon tumors (0/8).
As the expression of histone H3 is restricted to the S phase of the cell cycle and therefore measures the growth fraction of a given population, we suggest that the increased expression of p53 observed in the large majority of colon tumors simply reflects the increased number of cycling cells frequently found in a neoplastic tissue.