Expression of the proto-oncogene c-KIT in normal and tumor tissues from colorectal carcinoma patients

Abstract

Background and aims: The proto-oncogene c-KIT encodes a tyrosine kinase receptor essential during embryonic development and postnatal life. Although deregulated expression of c-KIT has been reported, its role in colorectal carcinoma remains controversial: some authors have described a correlation between c-KIT expression and colorectal cancer (CRC), while others have failed to detect the receptor in the majority of neoplasia examined. To address this question, we designed a prospective study to analyze the expression of c-KIT in normal and neoplastic colonic mucosa of the same patient. Patients and methods: We analyzed the tissues of 20 patients undergoing surgical resection for colorectal carcinoma by reverse transcriptase-polymerase chain reaction, Western blot and immunohistochemistry, whose results were correlated with histopathological parameters. Results: Most patients (90%) showed c-KIT expression in normal tissue both at RNA and protein level, while in neoplastic tissue it was observed in 30% of patients at RNA level and in 10% at protein level. By immunohistochemistry the localization of c-KIT protein in the normal colon was restricted to interstitial cells scattered in the stroma, whereas the non-neoplastic epithelium was always negative. The mucinous carcinomas were all c-KIT negative, whereas the only case in which c-KIT was displayed in the neoplastic epithelium was a G3 adenocarcinoma. Conclusion: Most colorectal carcinomas do not express c-KIT. We suggest that c-KIT expression is rarely present in this neoplasia; thus, the use of receptor inhibitors should be conducted in selected sub-groups of colon carcinoma patients, subsequent to the clear demonstration of c-KIT overexpression in the neoplastic cells.

KIT/stem cell factor expression in premalignant and malignant lesions of the colon mucosa in relationship to disease progression and outcomes

“…In another study, faint cytoplasmic KIT positivity was found in 4.8% of CRC cases (8). More recently, Sammarco et al detected KIT-positive staining in the epithelium of the neoplastic colon in 25% of patients examined (10). In a previous preliminary analysis conducted on a small number of patients, we reported KIT immunoreactivity in several malignant mucosa specimens compared to normal counterparts (38).…”

“…The lesson learned from clinical trials of imatinib in GIST is that the mutational status of c-kit is required to achieve a successful response and improve survival (62). The presence of a truncated c-kit form with potentially strong activation capacity has been reported in some colon carcinoma cell lines (54,63) and, at the moment, in a single CRC patient (10). However, since we detected SCF in the majority of KIT-positive CRCs, it is conceivable that, in this tumor, activation of the receptor may be supported by this autocrine circuit.…”

“…Recently, aberrant expression of the proto-oncogene c-kit has been reported in a sub-group of colorectal carcinomas (CRC) (8)(9)(10). c-kit encodes a type III receptor tyrosine kinase, initially identified as the homologue of the Hardy-Zuckerman 4 feline sarcoma virus oncogene (11,12).…”

The prognostic value of c‐Kit, K‐ras codon 12, and p53 codon 72 mutations in Egyptian patients with stage II colorectal cancer

“…Aberrant expression of c-Kit and/ or stem cell factor has been reported in gastrointestinal stromal tumors and colon cancer cell lines [18][19][20] ; however, data regarding c-Kit expression in CRC remain scarce. 21 Cyclooxygenase-2 (COX-2) is an inducible enzyme that regulates prostaglandin synthesis. It is overexpressed at sites of inflammation and in several epithelial cancers, in which it is involved in apoptosis resistance, angiogenesis, and tumor cell invasiveness.…”

“…It is overexpressed at sites of inflammation and in several epithelial cancers, in which it is involved in apoptosis resistance, angiogenesis, and tumor cell invasiveness. 21 Forced COX-2 expression suppresses apoptosis by modulating the level of death receptor 5, an effect that can be reversed by COX-2 inhibitors. 21,22 Several studies have reported COX-2 overexpression in human colon cancers and adenomas, thus making COX-2 a potential target for chemoprevention trials.…”