<i>c-Kit</i> Proto-Oncogene Product Is Rarely Detected in Colorectal Adenocarcinoma

Yorke, Rebecca; Chirala, Minnie; Younes, Mamoun

doi:10.1200/jco.2003.99.213

Cited by 14 publications

(16 citation statements)

References 16 publications

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“…One previous report also showed worse prognostic correlation with KIT expression in colon cancers (37), but several studies found no prognostic correlations (38,39). These findings might result from the variable and low incidence of KIT expression in colon cancers, marked intratumoral heterogeneity of KIT expression in colon cancers, requirement of continuous SCF stimulation to the KIT expressing tumors, and varying concomitant activations of endogenous KIT and PKC-d in human colorectal cancers.…”

Section: Discussionmentioning

confidence: 63%

Protein Kinase C-δ–Mediated Recycling of Active KIT in Colon Cancer

Park

Kim

Song

et al. 2013

Clinical Cancer Research

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Purpose: Abnormal signaling through receptor tyrosine kinase (RTK) moieties is important in tumorigenesis and drug targeting of colorectal cancers. Wild-type KIT (WT-KIT), a RTK that is activated upon binding with stem cell factor (SCF), is highly expressed in some colon cancers; however, little is known about the functional role of SCF-dependent KIT activation in colon cancer pathogenesis. We aimed to elucidate the conditions and roles of WT-KIT activation in colon cancer tumorigenesis.Experimental Design: Colorectal cancers with KIT expression were characterized by immunoblotting and immunohistochemistry. The biologic alterations after KIT-SCF binding were analyzed with or without protein kinase C (PKC) activation.Results: We found that WT-KIT was expressed in a subset of colon cancer cell lines and was activated by SCF, leading to activation of downstream AKT and extracellular signal-regulated kinase (ERK) signaling pathways. We also showed that KIT expression gradually decreased, after prolonged SCF stimulation, due to lysosomal degradation. Degradation of WT-KIT after SCF binding was significantly rescued when PKC was activated. We also showed the involvement of activated PKC-d in the recycling of WT-KIT. We further showed that a subset of colorectal cancers exhibit expressions of both WT-KIT and activated PKC-d and that expression of KIT is correlated with poor patient survival (P ¼ 0.004).Conclusions: Continuous downstream signal activation after KIT-SCF binding is accomplished through PKC-d-mediated recycling of KIT. This sustained KIT activation may contribute to tumor progression in a subset of colon cancers with KIT expression and might provide the rationale for a therapeutic approach targeting KIT.

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Section: Discussionmentioning

confidence: 63%

Protein Kinase C-δ–Mediated Recycling of Active KIT in Colon Cancer

Park

Kim

Song

et al. 2013

Clinical Cancer Research

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“…Reed et al, using stage-oriented human cancer tissue microarrays, reported that in situ KIT expression is sparse in colorectal carcinomas with only 1.6% of positive tumors, being poorly-differentiated carcinomas arising at the anorectal junction (9). 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).…”

Section: Discussionmentioning

confidence: 92%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Bellone¹,

Smirne²,

Carbone³

et al. 2006

Int J Oncol

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Abstract. Autocrine/paracrine stimulation of KIT has been observed in colorectal carcinoma (CRC) cell lines. We investigated the expression of KIT and stem cell factor (SCF) in CRC in comparison with premalignant colon lesions and normal colonic mucosa to assess the prognostic and therapeutic relevance of this receptor/ligand system in CRC. Transcript levels of c-kit and the two SCF splicing variants were determined quantitatively by real-time RT-PCR using cDNA obtained from normal, premalignant and malignant snap frozen colon tissue specimens. Immunohistochemistry with specific anti-KIT and anti-SCF antibodies was performed on paraffin-embedded tissue sections in order to localize the relative protein expression in epithelial compartments. Approximately 10% of patients expressed KIT in their adenoma or primary tumor. The majority of KIT-positive carcinomas co-expressed SCF. Real-time RT-PCR showed expression of c-kit and SCF transcripts in all cDNA specimens examined. A significant association between the co-expression of KIT/SCF and a worse clinical outcome was found. In conclusion, KIT expression was observed in a proportion of premalignant and malignant colonic lesions, while it was virtually absent in normal colon mucosa. Moreover, the majority of KIT-positive carcinomas co-expressed SCF, suggesting the possibility of aberrant signaling by an autocrine loop, as confirmed by the negative prognostic value of this association. Therefore, in the subset of CRC patients with concomitant KIT/SCF expression, the activity of Imatinib mesylate, a selective inhibitor of specific tyrosine kinases including KIT, may be exploited in combination with standard therapy.

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“…A novel and interesting finding in the current study is the high frequency of c-Kit overexpression in stage II CRC patients (59.3%) compared with what was reported in other studies. 20,33,34 Sammarco et al 21 reported c-Kit RNA overexpression in 30% of patients with CRC; however, only 10% of their patients had protein overexpression. Reported differences in the frequency of c-Kit overexpression may be attributed to differences in the studied populations, disease stages, sampling techniques, detection methods (including sensitivity and specificity of the antibodies used), or PCR protocols.…”

Section: Discussionmentioning

confidence: 99%

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

El-Serafi

Bahnassy

Ali

et al. 2010

Cancer

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BACKGROUND:The prognosis for patients with colorectal cancer (CRC) depends mainly on standard clinicopathologic factors. However, patients with similar disease characteristics exhibit various outcomes, especially in stage II. Therefore, the identification of molecular prognostic markers is needed to predict patient outcomes. METHODS: The authors assessed the prognostic value of c-Kit (also called cluster of differentiation 117 [CD117] or KIT), cyclooxygenase-2 (COX-2), tumor protein 53 (p53), and Kirsten rat sarcoma viral oncogene homolog (K-ras) aberrations in 90 patients with stage II CRC using immunohistochemistry and molecular techniques. The results were correlated with standard clinicopathologic prognostic factors, overall survival (OS), and disease-free survival (DFS). RESULTS: COX2 and c-Kit overexpression was detected in 54.6% and 59.3% of patients, respectively. Overexpression of p53 was detected in 47 patients, including 29 who had mutations, and a unique mutation pattern was detected with 3 hotspots at codons 72, 245, and 273. Overexpression of ras was detected in 44 patients, including 37 who had mutations. On multivariate analysis, c-Kit overexpression, p53 codon 72 mutations, perforation, and performance status were independent prognostic factors for DFS (P ¼ .054, P ¼ .015, P < .0001, and P ¼ .043, respectively); whereas codon 12 K-ras mutation, performance status, and perforation were independent prognostic factors for OS (P ¼ .033, P ¼ .006, and P < .0001, respectively). CONCLUSIONS: The current results provide evidence for the prognostic value of c-Kit overexpression in patients with stage II CRC. The high p53 mutation rate and the unique hotspot in codon 72 have not been reported previously in CRC. This may be related to environmental or racial features that are unique to the studied population. Cancer 2010;116:4954-64.

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c-Kit Proto-Oncogene Product Is Rarely Detected in Colorectal Adenocarcinoma

Cited by 14 publications

References 16 publications

Protein Kinase C-δ–Mediated Recycling of Active KIT in Colon Cancer

Protein Kinase C-δ–Mediated Recycling of Active KIT in Colon Cancer

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

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

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