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In this study, we examined the relationship between the histopathological grade and immunohistochemical localization of six genetically distinct type IV collagen α chains, the major component of basement membrane (BM), in normal and neoplastic colorectal tissues. In the normal colorectal mucosa, α1/α2(IV) and α5/α6(IV) chains were stained in all epithelial BM. However, α3/α4(IV) chains were restrictively immunostained in the BM of the apical surface epithelium. Similar immunostaining profiles for α1/α2(IV) and α5/α6(IV) chains were observed in tubular adenomas with mild/moderate atypia. However, in intramucosal carcinomas, both α1/α2(IV) chains were linearly stained in the BM of cancer cell nests, while the assembly of α5/α6(IV) chains into the BM was inhibited in a discontinuous or negatively stained pattern. The normal colorectal mucosa forms a second network of BM composed of α5/α6(IV), partly α3/α4(IV) chains, in addition to the classic network of α1/α2(IV) chains. The differential immunohistochemical localization of the type IV collagen α5/α6 chains could be one diagnostic marker for the invasiveness of colorectal cancer. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Our previous studies have demonstrated the significant role of brain-type glycogen phosphorylase (BGP) in the carcinogenesis of gastric carcinoma. The aims of the present study were to investigate the expression of BGP in colorectal carcinoma as well as the timing of this expression in the adenoma-carcinoma sequence (ACS), in comparison with the overexpression of p53 protein. We also sought to identify this marker in the particular colorectal mucosa bearing de novo carcinoma. METHODS: The expression of BGP and p53 protein in colorectal carcinoma using affinity purified specific anti-human BGP antibody (Ab) and anti-p53 Ab was studied using 96 resected specimens. Further investigation to examine the timing of BGP expression in comparison with p53 overexpression was carried out using 13, 18, eight, and 16 specimens of adenoma with mild, moderate, and severe dysplasia, and carcinoma in adenoma, respectively. The BGP immunohistochemistry in whole resected human colorectal mucosa (two with carcinoma and one with ulcer) was carried out using specific anti-BGP and anti-p53 Ab. RESULTS: The BGP visualized by immunohistochemistry was commonly present in colorectal carcinoma (83.3%). The expression of this molecule during ACS showed excellent correlation with the increased dysplasia and was found before p53 overexpression, whereas no BGP expression was seen in the normal human large intestine remote from the cancer foci. Positive staining in overtly normal-looking colonic mucosa was observed mainly around carcinomas without any adenoma component. CONCLUSIONS: The present study is the first to localize the BGP molecule in colorectal carcinoma, adenoma, and normal mucosa. It is suggested that BGP is a novel biomarker for carcinogenesis in both the pathways of ACS and the de novo colorectal carcinoma. [ABSTRACT FROM AUTHOR]

Recently, differences in histological diagnosis of colonic neoplasms between Japan and Western countries have been noted. We examined the relationship between the histopathology and immunohistochemical localization of six genetically distinct type IV collagen α chains, the major component of basement membrane (BM), in normal and neoplastic colonic tissues. α1/α2(IV) and α5/α6(IV) chains were observed in normal mucosa and tubular adenomas with mild/moderate atypia. In non-invasive cancers, both α1/α2(IV) chains were linearly stained in the BM of cancer cell nests, while the assembly of α5/α6(IV) chains into the BM was inhibited in a discontinuous or negatively stained pattern. The differential expressions of the type IV collagen α5/α6 chains could be one of the diagnostic markers of the invasiveness of colon cancer. [Copyright &y& Elsevier]

Our recent study has demonstrated that brain (fetal)-type glycogen phosphorylase (BGP) positive foci (BGP foci) have a vital role in the de novo colorectal carcinogenesis. This paper reviewed the investigation on the genetic alternations in the BGP foci and the clarification of the mechanisms of de novo colorectal carcinogenesis. De novo colorectal carcinomas with invasion into submucosa or superficial muscularis propria were selected from resected specimens. Investigations of the p53, K-ras and APC mutations were performed in the BGP foci, BGP negative colorectal mucosa and de novo colorectal carcinoma. No K-ras mutation was observed in all of the cases. Mutations of p53 and APC were 14 (50.0%) and 9 (32.1%) in de novo colorectal carcinomas, and 11 (39.3%) and 1 (3.6%) in BGP foci, respectively. Both p53 and APC mutations were detected in 8 and 1, p53 mutation alone in 6 and 10, APC mutation alone in 1 and 0 out of 28 de novo colorectal carcinomas and BGP foci, respectively. Our sequential studies propose that the two major pathways, i.e., the p53–APC pathway and the p53 alone pathway in the de novo colorectal carcinogenesis. [Copyright &y& Elsevier]

The presence of RON and its variant isoform in malignant and non-malignant human colonic tissues was investigated by immunohistochemistry using paraffin-embedded sections and RT-PCR analysis followed by direct sequencing of PCR product using RNAs isolated from frozen tissues. In normal colonic mucosa of both human fetus and adult, RON was uniformly expressed in cript cells, especially in the bottom of cripta. On the other hand, the expression was distributed heterogeneously in adenomas and in colon cancer. The expression of RON was significantly related to the degree of differentiation of colon cancer. The RT-PCR analysis of RNA isolated from malignant and non-malignant colonic tissue revealed the presence of two RON mRNA isoforms. Direct sequencing of two major products was revealed to be identical to that of human wild-type RON and a splicing variant of RON transcript which has been reported in human gastric cancer cell line, KATO-III. It is indicated that both wild type RON and its valiant isoform play an important role in regulating the normal function of colonic mucosa such as differentiation and motile activity, and the expression of both wild-type RON and its valiant isoform could be considered to be reduced during malignancy of human colonic mucosa. [Copyright &y& Elsevier]

Nonsteroidal anti-inflammatory drugs (NSAIDs) have a preventive effect against colorectal cancer. Although inhibition of cyclooxygenase-2 plays a crucial role in the suppression of tumors, precise mechanisms of their action remain to be disclosed. To identify genes involved in the growth-suppressive effect of NSAIDs, we utilized cDNA microarray containing 23,040 genes and analyzed time-dependent alteration of gene expression in response to sulindac or aspirin in NSAIDs-sensitive SW480 and SW948 colon-cancer cells as well as in relatively resistant SNU-C4 cells. Consequently we identified 112 genes with commonly altered expression by sulindac and 176 with commonly altered expression by aspirin in the three lines. Addition of sulindac and that of aspirin altered expression levels of 130 and 140 genes, respectively, in SW480 and SW948 cells but not in SNU-C4 cells. These data may lead to a better understanding of growth-suppressive effects on colonic epithelium, and may provide clues for identifying novel therapeutic and/or preventive molecular targets of colon cancer. [Copyright &y& Elsevier]