International Journal of Colorectal Disease

, Volume 19, Issue 6, pp 545–553

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

  • Innocenzo Sammarco
  • Gabriele Capurso
  • Luigi Coppola
  • Antonio Paniccià Bonifazi
  • Sara Cassetta
  • Gianfranco Delle Fave
  • Alessandro Carrara
  • Giovanni Battista Grassi
  • Pellegrino Rossi
  • Claudio Sette
  • Raffaele Geremia
Original Article


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.


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.


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.


c-KIT Colorectal cancer Tyrosine kinases 


  1. 1.
    Verdecchia A, Micheli A, Colonna M, Moreno V, Izarzugaza MI, Paci E (2002) EUROPREVAL Working Group. A comparative analysis of cancer prevalence in cancer registry areas of France, Italy and Spain. Ann Oncol 13:1128–1139CrossRefPubMedGoogle Scholar
  2. 2.
    D’Entremont TS, Sun Weijing (2003) Recent advances in colorectal cancer therapy. Cancer Biol Ther 2:6–13PubMedGoogle Scholar
  3. 3.
    Traxler P (2003) Tyrosine kinases as targets in cancer therapy—successes and failures. Expert Opin Ther Targets 7:215–234CrossRefPubMedGoogle Scholar
  4. 4.
    Heinrich MC, Blanke CD, Druker BJ, Corless CL (2002) Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 20:1692–1703CrossRefPubMedGoogle Scholar
  5. 5.
    Besmer P, Manova K, Duttlinger R, et al (1993) The kit-ligand (steel factor) and its receptor c-KIT/W: pleiotropic roles in gametogenesis and melanogenesis. Dev Suppl 125–137Google Scholar
  6. 6.
    Hassan HT, Zander A (1996) Stem cell factor as survival and growth factor in human normal and malignant hematopoiesis. Acta Haematol 95:257–262PubMedGoogle Scholar
  7. 7.
    Ricotti E, Fagioli F, Garelli, E, et al (1998) C-KIT is expressed in soft tissue sarcoma of neuroectodermic origin and its ligand prevents apoptosis of neoplastic cells. Blood 91:2397–2405PubMedGoogle Scholar
  8. 8.
    Huang S, Luca M, Gutman M, et al (1996) Enforced c-KIT expression renders highly metastatic human melanoma cells susceptible to stem cell factor-induced apoptosis and inhibits their tumorigenic and metastatic potential. Oncogene 13:2339–2347PubMedGoogle Scholar
  9. 9.
    He J, deCastro CM, Vandenbark GR, Busciglio J, Gabuzda D (1997) Astrocyte apoptosis induced by HIV-1 transactivation of the c-kit protooncogene. Proc Natl Acad Sci USA 94:3954–3959CrossRefPubMedGoogle Scholar
  10. 10.
    Bellone G, Silvestri S, Artusio E, et al (1997) Growth stimulation of colorectal carcinoma cells via the c-kit receptor is inhibited by TGF-β1. J Cell Physiol 172:1–11CrossRefPubMedGoogle Scholar
  11. 11.
    Natali PG, Nicotra MR, Sures I, Santoro E, Bigotti A, Ullrich A (1992) Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. Cancer Res 52:6139–6143PubMedGoogle Scholar
  12. 12.
    Matsuda R, Takahashi T, Nakamura S, et al (1993) Expression of the c-kit protein in human solid tumours and in corresponding fetal and adult normal tissues. Am J Pathol 142:339–346PubMedGoogle Scholar
  13. 13.
    Reed J, Ouban A, Schickor FK, Muraca P, Yeatman T, Coppola D (2002) Immunohistochemical staining for c-kit (CD117) is a rare event in human colorectal carcinoma. Clin Colorectal Cancer 2:119–122PubMedGoogle Scholar
  14. 14.
    Manley PW, Cowan-Jacob SW, Buchdunger E, et al (2002) Imatinib a selective tyrosine kinase inhibitor. Eur J Cancer 38: S19–S27CrossRefGoogle Scholar
  15. 15.
    Druker BJ, Sawyers CL, Kantarjian H, et al (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042PubMedGoogle Scholar
  16. 16.
    Dagher R, Cohen M, Williams G, et al (2002) Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 8:3034–3038PubMedGoogle Scholar
  17. 17.
    Esposito I, Kleeff J, Bischoff SC, et al (2002) The stem cell factor-c-kit system and mast cells in human pancreatic cancer. Lab Invest 82:1481–1492PubMedGoogle Scholar
  18. 18.
    Fjallskog ML, Lejonklou MH, Oberg KE, Eriksson BK, Janson ET (2003) Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors. Clin Cancer Res 9:1469–1473PubMedGoogle Scholar
  19. 19.
    Hibi K, Takahashi T, Sekido Y, et al (1991) Coexpression of the stem cell factor and the c-kit genes in small cell lung cancer. Oncogene 6:2291–2296PubMedGoogle Scholar
  20. 20.
    Timeus F, Crescenzio N, Valle P, et al (1997) Stem cell factor suppress apoptosis in neuroblastoma cell lines. Exp Hematol 25:1253–1260PubMedGoogle Scholar
  21. 21.
    Natali PG, Nicotra MR, Sures I, Mottolese M, Botti C, Ullrich A (1992) Breast cancer is associated with loss of the c-kit oncogene product. Int J Cancer 52:713–717PubMedGoogle Scholar
  22. 22.
    Natali PG, Berlingieri MT, Nicotra MR, et al (1995) Transformation of thyroid epithelium is associated with loss of c-kit receptor. Cancer Res 55:1787–1791PubMedGoogle Scholar
  23. 23.
    Tonary AM, McDonald EA, Faugh W, Senterman MK, Vanderhyden BC (2000) Lack of expression of c-kit in ovarian cancers is associated with poor prognosis. Int J Cancer 89:242–250CrossRefPubMedGoogle Scholar
  24. 24.
    Burger H, den Bakker MA, Stoter G, Verweij J, Nooter K (2003) Lack of c-kit exon 11 activating mutations in c-KIT/CD117-positive SCLC tumour specimens. Eur J Cancer 39:793–799CrossRefPubMedGoogle Scholar
  25. 25.
    Lyford GL, He C-L, Soffer E, et al, (2002) Pan-colonic decrease in interstitial cells of Cajal in patients with slow transit constipation. Gut 51:496–501CrossRefPubMedGoogle Scholar
  26. 26.
    Hornick JL, Fletcher CD, (2003) Validating immunohistochemical staining for KIT (CD117). Am J Clin Pathol 119:325–327PubMedGoogle Scholar
  27. 27.
    Toyota M, Hinoda Y, Itoh F, Takaoka A, Imai K, Yachi A (1994) Complementary DNA cloning of truncated form of c-kit in human colon carcinoma cells. Cancer Res 54: 272–275PubMedGoogle Scholar
  28. 28.
    Takaoka A, Toyota M, Hinoda Y, Itoh F, Mita H, Kakiuchi H, Adachi M, Imai K (1997) Expression and identification of aberrant c-kit transcripts in human cancer cells. Cancer Lett 115:257–261CrossRefPubMedGoogle Scholar
  29. 29.
    Rossi P, Marziali G, Albanesi C, Charlesworth A, Geremia R, Sorrentino V (1992) A novel c-kit transcript, potentially encoding a truncated receptor, originates within a kit gene intron in mouse spermatids. Dev Biol 152:203–207PubMedGoogle Scholar
  30. 30.
    Sette C, Paronetto MP, Barchi M, Bevilacqua A, Geremia R, Rossi P (2002) Tr-kit-induced resumption of the cell cycle in mouse eggs requires activation of a Src-like kinase. EMBO J 21:5386–5395CrossRefPubMedGoogle Scholar
  31. 31.
    Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W, Karl R, Fujita DJ, Jove R, Yeatman TJ (1999) Activating SRC mutation in a subset of advanced human colon cancers. Nat Genet 21:187–190CrossRefPubMedGoogle Scholar
  32. 32.
    Windham TC, Parikh NU, Siwak DR, Summy JM, McConkey DJ, Kraker AJ, Gallick GE (2002) Src activation regulates anoikis in human colon tumor cell lines. Oncogene 21:7797–7807CrossRefPubMedGoogle Scholar
  33. 33.
    Shawer L, Slamon D, Ullrich A (2002) Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell 1:117–123CrossRefPubMedGoogle Scholar
  34. 34.
    Attoub S, Rivat C, Rodrigues S, et al (2002) The c-kit tyrosine kinase inhibitor STI571 for colorectal cancer therapy. Cancer Res 62:4879–4883PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Innocenzo Sammarco
    • 1
  • Gabriele Capurso
    • 2
  • Luigi Coppola
    • 3
  • Antonio Paniccià Bonifazi
    • 3
  • Sara Cassetta
    • 2
  • Gianfranco Delle Fave
    • 2
  • Alessandro Carrara
    • 4
  • Giovanni Battista Grassi
    • 4
  • Pellegrino Rossi
    • 1
  • Claudio Sette
    • 1
  • Raffaele Geremia
    • 1
  1. 1.Department of Public Health and Cell BiologyUniversity of Rome “Tor Vergata”RomeItaly
  2. 2.Digestive and Liver Disease UnitII Medical SchoolRomeItaly
  3. 3.Department of Laboratory MedicineU.O.C. of Pathology AnatomyRomeItaly
  4. 4.Department of Surgical OncologyS. Filippo Neri HospitalRomeItaly

Personalised recommendations