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Biomedical subjects

S Shirasawa

Publications and source records attributed to S Shirasawa.

25 records · Page 2Linked to original sources
PubMed1995

Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis.

The growth of solid tumors in vivo beyond 1-2 mm in diameter requires induction and maintenance of an angiogenic response. This can occur through the release of various angiogenic growth factors from tumor cells. One such factor is vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), a secreted and specific mitogen for vascular endothelial cells. We show that one of the most commonly encountered genetic changes detected in human cancer, i.e., expression of mutant ras oncogenes, is associated with marked up-regulation of VEGF/VPF in transformed epithelial cells. Thus, elevation of the levels of both VEGF/VPF mRNA and secreted functional protein were detected in human and rodent tumor cell lines expressing mutant K-ras or H-ras oncogenes, respectively. Genetic disruption of the mutant K-ras allele in human colon carcinoma cells was associated with a reduction in VEGF/VPF activity. Furthermore, pharmacological disruption of mutant RAS protein function in H-ras transformed rat intestinal epithelial cells by treatment with L-739,749 (a protein farnesyltransferase inhibitor) caused a significant suppression of VEGF/VPF. The results suggest that dominantly acting ras oncogenes may contribute to the growth of solid tumors in vivo not only by a direct effect on tumor cell proliferation but also indirectly, i.e., by facilitating tumor angiogenesis. Hence, pharmacologically targeting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-induced angiogenesis.

Alkyl and Aryl Transferases↗
PubMed1993

Altered growth of human colon cancer cell lines disrupted at activated Ki-ras.

Point mutations that activate the Ki-ras proto-oncogene are presented in about 50 percent of human colorectal tumors. To study the functional significance of these mutations, the activated Ki-ras genes in two human colon carcinoma cell lines, DLD-1 and HCT 116, were disrupted by homologous recombination. Compared with parental cells, cells disrupted at the activated Ki-ras gene were morphologically altered, lost the capacity for anchorage-independent growth, grew more slowly both in vitro and in nude mice, and showed reduced expression of c-myc. Thus, the activated Ki-ras gene plays a key role in colorectal tumorigenesis through altered cell differentiation and cell growth.

Animals↗
PubMed1993

[Analysis of molecular mechanism in colorectal tumorigenesis].

Genetic alterations of Ki-ras gene, p53 gene, and DCC gene were analyzed in human colon cancer cell lines (HCCLs). On the basis of these analyses, a HCCL (HCT116)-human chromosome 18 hybrids, and targeted cell lines that were disrupted at the activated Ki-ras gene in HCCLs (HCT116 and DLD-1), were established. Tumorigenicity and expression of c-myc gene were investigated in these cell lines, respectively. 1. Point mutations of Ki-ras gene, p53 gene, and insertion mutations of DCC gene were detected in 10 out of 18 HCCLs, 8 out of 15 HCCLs, and 3 out of 16 HCCLs, respectively. 2. HCT116-chromosome 18 hybrids were morphologically similar to the parental line, and were not suppressed for tumorigenicity in vitro, but they produced slowly growing tumors in nude mice compared with the growth of the parental line. 3. The targeted cell lines that were disrupted at the activated Ki-ras gene were morphologically altered and lost neoplastic phenotypes, including tumorigenicity in nude mice and anchorage-independent growth. Furthermore, expression of c-myc gene in these clones was much reduced compared with findings in the parental line, regardless of their growth rates.

Animals↗
PubMed1991

p53 gene mutations in colorectal tumors from patients with familial polyposis coli.

The p53 gene has been elucidated as a tumor suppressor gene, and inactivation of this gene caused by deletion or point mutations may play a crucial role in the development of human malignancies. In colorectal carcinomas with an allelic deletion of the p53 gene, the remaining p53 gene was mutated with considerable frequency. It is most difficult to detect point mutations or small deletions of the gene because the mutations occur in diverse regions, although four hot spots have been observed [J.M. Nigro et al., Nature (Lond.), 342: 705-708, 1989]. The polymerase chain reaction and denaturing gradient gel electrophoresis facilitate detection of mutations in the hot spots of the p53 gene. Using these methods, we detected mutations in three adenomatous polyps and one carcinoma from familial polyposis coli patients and three carcinomas of sporadic cases. The DNA sequence analysis confirmed mutations of the p53 gene in 2 adenomas (13 base-pair deletions in one and a point mutation in the other) and 1 carcinoma (point mutation) from familial polyposis coli patients. These results suggest that the p53 gene mutations may be involved in the formation not only of carcinomas but also of adenomas which occur in familial polyposis coli patients.

Adenomatous Polyposis Coli↗
PubMed1991

[Diagnosis of colorectal cancer from DNA level].

The inherited cancer-inducing disease familial polyposis coli (FPC) provides an excellent model not only for studying tumor progression in colorectal cancer but also for elucidating molecular mechanisms in general oncogenesis. This paper reviewed recent remarkable progresses of molecular mechanisms in colorectal tumorigenesis. This is concerned with the various kinds of genetic alterations that accumulate in the development from normal mucosa to adenoma, and then to adenocarcinoma in comparison with FPC and sporadic cases. This review included also information on the localization of FPC major gene. These observations indicate that in cases of colorectal tumorigenesis several genetic alterations may be involved, including activation of K-ras gene, deregulated expression of c-myc gene or c-fos gene and inactivation of tumor suppressor genes such as p53 and DCC genes, as well as the loss of heterozygosity. The observation suggest that adenomas will have undergone several gene or chromosome mutations before reaching to the fully malignant state. Therefore, DNA diagnosis for colorectal tumors in the clinical level may contribute to more accurate prognosis and better results for further therapy.

Adenoma↗