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© 2003 American Society for Clinical Oncology
c-Kit Proto-Oncogene Product Is Rarely Detected in Colorectal AdenocarcinomaDepartment of Pathology, Baylor College of Medicine and The Methodist Hospital, Houston, TX To the Editor: c-kit (CD117) is a growth factor receptor of the tyrosine kinase subclass III family, normally expressed in a variety of human tissues including hematopoietic stem cells, mast cells, gametocytes, melanocytes, and the interstitial cells of Cajal.1 Binding of the c-kit ligand (stem cell factor) leads to activation of the c-kit tyrosine kinase via receptor homodimerization and auto-phosphorylation of specific tyrosine residues on the intracellular domain of the receptor. c-kit signaling promotes cell survival, proliferation, differentiation, adhesion, and migration.2 Several gain-of-function mutations of the c-kit gene have been identified that produce ligand-independent activation of c-kit and cell proliferation.3 Some of these mutations appear causative in the pathogenesis of adult mastocytosis3 and most gastrointestinal stromal tumors (GISTs).4,5 c-kit mutations have been identified in hematolymphoid malignancies, melanomas, seminomas, neuroblastomas, endometrial carcinoma, and small-cell carcinoma of the lung.6–9 Recent therapeutic breakthroughs in the treatment of GISTs involve STI571 (imatinib mesylate [Gleevec]; Novartis Pharmaceuticals, East Hanover, NJ), a drug that targets mutated c-kit by inhibiting its tyrosine kinase activity.10,11 Several other c-kit tyrosine kinase inhibitors are under investigation.6 These developments have increased interest in identifying other tumors with c-kit activating mutations for potential targeted therapy.11–13 c-kit receptor and its ligand have been demonstrated in human colon cancer cell lines.14–17 On the basis of experiments on colon cancer cell lines, it was suggested that the c-kit tyrosine kinase inhibitor STI571 be considered for clinical trials as chemotherapeutic agent for the prevention and treatment of colon cancer.18 However, a recent study failed to demonstrate c-kit expression in a significant number of colorectal cancers.19 Because of the clinical interest in c-kit expression in colon cancer by our oncologists, and lack of such information in the literature at that time, we previously undertook a study to determine the extent of c-kit expression in human colorectal adenocarcinoma (CRC) tissues. We performed immunoperoxidase staining for c-kit on sections of formalin-fixed and paraffin-embedded tissue from 62 consecutive unselected CRCs using standard methodology, after steam-heat antigen retrieval, and using a polyclonal rabbit antibody at 1/200 dilution (sc-168; Santa Cruz Biotechnology Inc, Santa Cruz, CA). Positive controls were GISTs, and mast cells and/or interstitial cells of Cajal present in all sections of the tumors served as internal positive controls. Negative controls consisted of sections immunostained with nonrelevant rabbit polyclonal antibody or without antibody. The percentage of positive cancer cells was recorded. Only two cases (3%) showed faint cytoplasmic c-kit immunoreactivity in 1% to 10% of the cancer cells. The remaining cases (60 samples, 97%) were completely negative for c-kit. Occasional nonspecific (artifact) staining was noted in luminal debris, apoptotic cancer cells, and intracytoplasmic mucin in cancer cells. Internal positive controls were always positive. Our immunohistochemistry laboratory has been receiving requests from oncologists to perform immunostaining for c-kit on sections of colon cancer patient samples. Of 10 prospective patient samples that we stained on the basis of such requests, nine were completely negative and one had c-kit immunoreactivity in 10% to 25% of the cancer cells. Our combined data (from the study and the prospective patient samples) indicate that c-kit protein is rarely detected in CRC. These results are in agreement with a report by Reed et al.19 A feature of the tyrosine kinase inhibitors currently being developed is their lack of absolute specificity for a subtype of tyrosine kinase. All tyrosine kinase inhibitors that cause c-kit inhibition also inhibit two or more related receptors, including the fusion gene product BCR-ABL (the intended target for which STI571 was developed), platelet-derived growth factor receptor, kinase insert domain receptor, insulin receptor, fibroblast growth factor receptor, and macrophage colony-stimulating factor receptor.6 Although our findings suggest that c-kit kinase activation is not a prominent pathogenetic feature of CRC, some of the tyrosine kinase inhibitors may nonetheless be beneficial in treatment of CRC as a result of inhibition of related tyrosine kinases.6,20 Therefore, negative c-kit immunostaining in CRC should not be interpreted as evidence that the patient will not respond to treatment with tyrosine kinase inhibitors. On the other hand, our findings strongly suggest that c-kit immunostaining is not a cost-effective, and perhaps not a sensitive, method of identifying patients with CRC who may benefit from treatment with tyrosine kinase inhibitors AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES 1. Ashman LK: The biology of stem cell factor and its receptor C-kit. Int J Biochem Cell Biol 31:1037–1051, 1999[CrossRef][Medline] 2. Vliagoftis H, Worobec AS, Metcalfe DD: The protooncogene c-kit and c-kit ligand in human disease. J Allergy Clin Immunol 100:435–440, 1997[CrossRef][Medline] 3. Longley BJ, Reguera MJ, Yongsheng MA: Classes of c-KIT activating mutations: Proposed mechanisms of action and implications for disease classification and therapy. Leuk Res 25:571–576, 2001[CrossRef][Medline]
4. Hirota S, Isozaki K, Moriyama Y, et al: Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580, 1998
5. Lux ML, Rubin BP, Biase TL, et al: KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol 156:791–795, 2000
6. Heinrich MC, Blanke CD, Druker BJ, et al: Inhibition of KIT tyrosine kinase activity: A novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 20:1692–1703, 2002
7. Natali PG, Nicortra MR, Sures I, et al: Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. Cancer Res 52:6139–6143, 1992 8. Tsuura Y, Hiraki H, Watanabe K, et al: Preferential localization of c-kit product in tissue mast cells, basal cells of skin, epithelial cells of breast, small cell lung carcinoma and seminoma/dysgerminoma in human: Immunohistochemical study on formalin-fixed, paraffin-embedded tissues. Virchows Arch 424:135–141, 1994[Medline] 9. Elmore LW, Domson K, Moore JR, et al: Expression of c-kit (CD117) in benign and malignant human endometrial epithelium. Arch Pathol Lab Med 125:146–151, 2001[Medline]
10. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al: Effect of the tyrosine kinase inhibitor ST1571 in a patient with metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056, 2001 11. Demetri GD: Targeting c-kit mutations in solid tumors: Scientific rationale and novel therapeutic options. Semin Oncol 28:19–29, 2001 (5 suppl 17)[Medline] 12. Longley BJ, Ma Y, Carter E, et al: New approaches to therapy for mastocytosis: A case for treatment with kit kinase inhibitors. Hematol Oncol Clin North Am 14:689–695, 2000[CrossRef][Medline] 13. Longley BJ, Metcalfe DD: A proposed classification for mastocytosis incorporating molecular genetics. Hematol Oncol Clin North Am 14:697–701, 2000[CrossRef][Medline] 14. Toyota M, Hinoda Y, Takaoka A, et al: Expression of c-kit and kit ligand in human colon carcinoma cells. Tumour Biol 14:295–302, 1993[Medline] 15. Lahm H, Amstad P, Yilmaz A, et al: Interleukin 4 down-regulates expression of c-kit and autocrine stem cell factor in human colorectal carcinoma cells. Cell Growth Differ 6:1111–1118, 1995[Abstract] 16. Bellone G, Silvestri S, Artusio E, et al: Growth stimulation of colorectal carcinoma cells via the c-kit receptor is inhibited by TGF-beta-1. J Cell Physiol 172:1–11, 1997[CrossRef][Medline]
17. Bellone G, Carbone A, Sibona N, et al: Aberrant activation of c-kit protects colon carcinoma cells against apoptosis and enhances their invasive potential. Cancer Res 61:2200–2206, 2001
18. Attoub S, Rivat C, Rodrigues S, et al: The c-kit tyrosine kinase inhibitor STI571 for colorectal cancer therapy. Cancer Res 62:4879–4883, 2002 19. Reed J, Ouban A, Schickor FK, et al: Immunohistochemical staining for c-kit (CD117) is a rare event in human colorectal carcinoma. Clin Colorectal Cancer 2:119–122, 2002[Medline]
20. Shaheen RM, Tseng WW, Davis DW, et al: Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. Cancer Res 61:1464–1468, 2001 Related Article
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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