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. 2005 Aug 19;94(4):315–320. doi: 10.1111/j.1349-7006.2003.tb01439.x

Gastrointestinal stromal tumors (GIST): A model for molecule‐based diagnosis and treatment of solid tumors

Yukihiko Kitamura 1,✉, Seiichi Hirota 1, Toshirou Nishida 2
PMCID: PMC11160165  PMID: 12824897

Abstract

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal (GI) tract. The c‐kit receptor tyrosine kinase (KIT) is expressed by practically all GISTs, and gain‐of‐function mutations of KIT are present in most GISTs. Interstitial cells of Cajal (ICC) are the pacemaker of the peristaltic movement of the GI tract. Since signals through KIT are essential for development of ICC and since multiple GISTs develop from the hyperplastic lesion of ICCs in familial GIST patients with germ‐line mutations of KIT, GISTs are considered to originate from ICC. Imatinib mesylate, which was developed for treatment of chronic myeloid leukemia (CML), was found to be useful for treatment of GISTs. Imatinib mesylate inhibits BCR‐ABL fused tyrosine kinase that causes CML. Imatinib mesylate also inhibits the mutated KIT observed in most GISTs, and this explains the effectiveness of Imatinib mesylate on GISTs. GISTs appear to serve as a model for molecule‐based diagnosis and treatment of solid tumors. (Cancer Sci 2003; 94: 315–320)

References

  • 1. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Tunio GM, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y. Gain‐of‐function mutations of c‐kit in human gastrointestinal stromal tumors. Science 1998; 279: 577–80. [DOI] [PubMed] [Google Scholar]
  • 2. O'Leary T, Berman JJ. Gastrointestinal stromal tumors: answers and questions. Hum. Pathol 2002; 33: 456–8. [DOI] [PubMed] [Google Scholar]
  • 3. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum. Pathol 2002; 33: 484–95. [DOI] [PubMed] [Google Scholar]
  • 4. Kindblom LG, Remotti HE, Aldenborg F, Meis‐Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 1998; 152: 1259–69. [PMC free article] [PubMed] [Google Scholar]
  • 5. Thomsen L, Robinson TL, Lee JC, Farraway LA, Hughes MJ, Andrews DW, Huizinga JD. Interstitial cells of Cajal generate a rhythmic pacemaker current. Nat Med 1998; 4: 848–51. [DOI] [PubMed] [Google Scholar]
  • 6. Dematteo RP, Heinrich MC, E1‐Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI‐571. Hum. Pathol 2002; 33: 466–77. [DOI] [PubMed] [Google Scholar]
  • 7. Joensuu H, Roberts PJ, Sarlomo‐Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman S, Capdeville R, Dimitrijevic S, Druker B, Demetri GD. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Merf 2001; 344: 1052–6. [DOI] [PubMed] [Google Scholar]
  • 8. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr‐Abl positive cells. Nat Med 1996; 2: 561–6. [DOI] [PubMed] [Google Scholar]
  • 9. Buchdunger E, Cioffi CL, Law N, Stover D, Ohno‐Jones S, Druker BJ, Lydon NB. Abl protein‐tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c‐kit and platelet‐derived growth factor receptors. J Pharmacol Exp Ther 2000; 295: 139–45. [PubMed] [Google Scholar]
  • 10. Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CD, Fletcher JA, Demetri GD. STI571 inactivation of the gastrointestinal stromal tumor c‐KIT oncoprotein: biological and clinical implications. Oncogene 2001; 20: 5054–8. [DOI] [PubMed] [Google Scholar]
  • 11. Kitamura Y, Go S, Hatanaka K. Decrease of mast cells in W/WV mice and their increase by bone marrow transplantation. Blood 1978; 52: 447–52. [PubMed] [Google Scholar]
  • 12. Kitamura Y, Go S. Decreased production of mast cells in S1/S1d anemic mice. Blood 1979; 53: 492–7. [PubMed] [Google Scholar]
  • 13. Tsujimura T, Koshimizu U, Katoh H, Isozaki K, Kanakura Y, Tono T, Adachi S, Kasugai T, Tei H, Nishimune Y, Nomura S, Kitamura Y. Mast cell number in the skin of heterozygotes reflects molecular nature of c‐kit mutation. Blood 1993; 81: 2530–8. [PubMed] [Google Scholar]
  • 14. Isozaki K, Hirota S, Nakama A, Miyagawa J‐I, Shinomura Y, Xu Z, Nomura S, Kitamura Y. Disturbed intestinal movement, bile reflux to the stomach, and deficiency of c‐kit‐expressing cells in Ws/Ws mutant rats. Gastroenterology 1995; 109: 456–64. [DOI] [PubMed] [Google Scholar]
  • 15. Yarden Y, Kuang WJ, Yang‐Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A. Human proto‐oncogene c‐kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 1987; 6: 3341–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Chabot B, Stephenson DA, Chapman VM, Besmer P, Bernstein A. The proto‐oncogene c‐kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature 1988; 335: 88–9. [DOI] [PubMed] [Google Scholar]
  • 17. Geissler EN, Ryan MA, Housman DE. The dominant‐white spotting (W) locus of the mouse encodes the c‐kit proto‐oncogene. Cell 1988; 55: 185–92. [DOI] [PubMed] [Google Scholar]
  • 18. Nocka K, Tan JC, Chiu E, Chu TY, Ray P, Traktman P, Besmer P. Molecular bases of dominant negative and loss of function mutation at the murine c‐kit/ white spotting locus: W37, Wv, W41 and W. EMBO J 1990; 9: 1805–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Hayashi S, Kunisada T, Ogawa M, Yamaguchi K, Nishikawa S. Exon skipping by mutation of an authentic splice site of c‐kit gene in W/W mouse. Nucleic Acids Res 1991; 19: 1267–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Maeda H, Yamagata A, Nishikawa S, Yoshinaga K, Kobayashi S, Nishi K, Nishikawa S‐I. Requirement of c‐kit for development of intestinal pacemaker system. Development 1992; 116: 369–75. [DOI] [PubMed] [Google Scholar]
  • 21. Witte ON. Steel locus defines new multipotent growth factor. Cell 1990; 63: 5–6. [DOI] [PubMed] [Google Scholar]
  • 22. Kitamura Y, Yokoyama M, Matsuda H, Shimada M. Coincidental development of forestomach papilloma and prepyloric ulcer in nontreated mutant mice of W/WV and S1/S1d genotypes. Cancer Res 1980; 40: 3392–7. [PubMed] [Google Scholar]
  • 23. Shimada M, Kitamura Y, Yokoyama M, Miyano Y, Maeyama K, Yamatodani A, Takahashi Y, Tatsuta M. Spontaneous stomach ulcer in genetically mast cell depleted W/WV mice. Nature 1980; 293: 662–4. [DOI] [PubMed] [Google Scholar]
  • 24. Yokoyama M, Tatsuta M, Baba M, Kitamura Y. Bile reflux: a possible cause of stomach ulcer in nontreated mutant mice of W/WV genotype. Gastroenterology 1982; 82: 857–63. [PubMed] [Google Scholar]
  • 25. Huizinga JD, Thuneberg L, Kluppel M, Malysz J, Mikkelsen HB, Bernstein A. W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 1995; 373: 347–9. [DOI] [PubMed] [Google Scholar]
  • 26. Ward SM, Burns AJ, Torihashi S, Harney SC, Sanders KM. Impaired development of interstitial cells and intestinal electrical rhythmicity in steel mutants. Am. J Physiol 1995; 269: 1577–85. [DOI] [PubMed] [Google Scholar]
  • 27. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990; 61: 203–12. [DOI] [PubMed] [Google Scholar]
  • 28. Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U, Sugahara H, Butterfield JH, Ashman LK, Kanayama Y, Matsuzawa Y, Kitamura Y, Kanakura Y. Identification of mutations in the coding sequence of the proto‐oncogene c‐kit in a human mast cell leukemia cell line causing ligand‐independent activation of c‐kit product. J Clin Invest 1993; 92: 1736–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Tsujimura T, Furitsu T, Morimoto M, Isozaki K, Nomura S, Matsuzawa Y, Kitamura Y, Kanakura Y. Ligand‐independent activation of c‐kit receptor tyrosine kinase in a murine mastocytoma cell line P‐815 generated by a point mutation. Blood 1994; 83: 2619–26. [PubMed] [Google Scholar]
  • 30. Tsujimura T, Furitsu T, Morimoto M, Kanayama Y, Nomura S, Matsuzawa Y, Kitamura Y, Kanakura Y. Substitution of an aspartic acid results in constitutive activation of c‐kit receptor tyrosine kinase in a rat tumor mast cell line RBL‐2H3. Int Arch Allergy Immunol 1995; 106: 377–85. [DOI] [PubMed] [Google Scholar]
  • 31. Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, Metcalfe DD. Identification of a point mutation in the catalytic domain of the protooncogene c‐kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci USA 1995; 92: 10560–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Longley BJ, Tyrrell L, Lu S‐Z, Ma Y‐S, Langley K, Ding T‐G, Duffy T, Jacobs P, Tang LH, Modlin I. Somatic c‐kit activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet 1996; 12: 312–4. [DOI] [PubMed] [Google Scholar]
  • 33. London CA, Galli SJ, Yuuki T, Hu ZQ, Helfand SC, Geissler EN. Spontaneous canine mast cell tumors express tandem duplications in the proto‐onco‐gene c‐kit. Exp Hematol 1999; 27: 689–97. [DOI] [PubMed] [Google Scholar]
  • 34. Tian Q, Frierson HF Jr, Krystal GW, Moskaluk CA. Activating c‐kit gene mutations in human germ cell tumors. Am J Pathol 1999; 154: 1643–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Hashimoto K, Tsujimura T, Moriyama Y, Yamatodani A, Kimura M, Tohya K, Morimoto M, Kitayama H, Kanakura Y, Kitamura Y. Transforming and differentiation‐inducing potentials of constitutively activated c‐kit mutant genes in the IC‐2 murine interleukin‐3‐dependent mast cell line. Am J Pathol 1996; 148: 189–200. [PMC free article] [PubMed] [Google Scholar]
  • 36. Koyasu S, Nakauchi H, Kitamura K, Yonehara S, Okumura K, Tada T, Yahara I. Production of interleukin 3 and gamma‐interferon by an antigenspecific mouse suppressor T cell clone. J Immunol 1985; 134: 3130–6. [PubMed] [Google Scholar]
  • 37. Kitayama H, Kanakura Y, Furitsu T, Tsujimura T, Oritani K, Ikeda H, Sugahara H, Mitsui H, Kanayama Y, Kitamura Y, Matsuzawa Y. Constitutively activating mutations of c‐kit receptor tyrosine kinase confer factor‐independent growth and tumorigenicity of factor‐dependent hematopoietic cell lines. Blood 1995; 85: 790–8. [PubMed] [Google Scholar]
  • 38. Tsujimura T, Morimoto M, Hashimoto K, Moriyama Y, Kitayama H, Matsuzawa Y, Kitamura Y, Kanakura Y. Constitutive activation of c‐kit in FMA3 murine mastocytoma cells caused by deletion of seven amino acids at the juxtamembrane domain. Blood 1996; 87: 273–83. [PubMed] [Google Scholar]
  • 39. Miettinen M, El‐Rifai W, Sobin H L L, Lasota J. Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol 2002; 33: 478–83. [DOI] [PubMed] [Google Scholar]
  • 40. Lux ML, Rubin BP, Biase TL, Chen C‐J, Maclure T, Demetri G, Xiao S, Singer S, Fletcher CDM, Fletcher JA. KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am. J Pathol 2000; 156: 791–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Lasota J, Wozniak A, Sarlomo‐Rikala M, Rys J, Kordek R, Nassar A, Sobin LH, Miettinen M. Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors. Am. J Pathol 2000; 157: 1091–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Hirota S, Nishida T, Isozaki K, Taniguchi M, Nakamura J, Okazaki T, Kitamura Y. Gain‐of‐function mutation at the extracellular domain of KIT in gastrointestinal stromal tumours. J Pathol 2001; 193: 505–10. [DOI] [PubMed] [Google Scholar]
  • 43. Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R, Hibbard MK, Chen CJ, Xiao S, Tuveson DA, Demetri GD, Fletcher CD, Fletcher JA. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 2001; 61: 8118–21. [PubMed] [Google Scholar]
  • 44. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003; 299: 708–10. [DOI] [PubMed] [Google Scholar]
  • 45. Allander SV, Nupponen NN, Ringner M, Hostetter G, Maher GW, Goldberger N, Chen Y, Carpten J, Elkahloun AG, Mellzer PS. Gastroinlesli‐nal stromal lumors with KIT mulalions exhibil a remarkably homogenous gene expression profile. Cancer Res 2001; 61: 8624–8. [PubMed] [Google Scholar]
  • 46. Corless CL, McGreevey L, Haley A, Town A, Heinrich MC. KIT mulalions are common in incidental gastroinlestinal stromal tumors one centimeler or less in size. Am. J Pathol 2002; 160: 1567–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Taniguchi M, Nishida T, Hirola S, Isozaki K, Ito T, Nomura T, Malsuda H, Kilmura Y. Effect of c‐kit mutation on prognosis of gaslroinleslinal stromal tumors. Cancer Res 1999; 59: 4297–300. [PubMed] [Google Scholar]
  • 48. Flelcher CD, Berman JJ, Corless C, Gorslein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remolli H, Rubin BP, Shmookler B, Sobin LH, Weiss SW Diagnosis of gastroinlestinal stromal tumors: a consensus approach. Hum. Pathol 2002; 33: 459–65. [DOI] [PubMed] [Google Scholar]
  • 49. Nishida T, Hirola S, Taniguchi M, Hashimoto K, Isozaki K, Nakamura H, Kanakura Y, Tanaka T, Takabayashi A, Malsuda H, Kilamura Y. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet 1998; 19: 323–4. [DOI] [PubMed] [Google Scholar]
  • 50. Hirota S, Okazaki T, Kitamura Y, O'Brien P, Kapusta L, Dardick I. Cause of familial and multiple gaslroinleslinal aulonomic nerve lumors wilh hyperplasia of inlerslilial cells of Cajal is germline mulalion of the c‐kit gene. Am. J Surg Pathol 2000; 24: 326–7. [DOI] [PubMed] [Google Scholar]
  • 51. Hirola S, Nishida T, Isozaki K, Taniguchi M, Nishikawa K, Ohashi A, Takabayashi A, Obayashi T, Okuno T, Kinoshila K, Chen H, Shinomura Y, Kitamura Y. Famitial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene. Gastroenterology 2002; 122: 1493–9. [DOI] [PubMed] [Google Scholar]
  • 52. O'Brien P, Kapusta L, Dardick I, Axler J, Gnidec A. Multiple familial gastrointestinal autonomic nerve tumors and small intestinal neuronal dysplasia. Am. J Surg Pathol 1999; 23: 198–204. [DOI] [PubMed] [Google Scholar]
  • 53. Isozaki K, Terris B, Belghili J, Schiffmann S, Hirola S, Vanderwinden J‐M. Germline‐aclivaling mulation in Ihe kinase domain of KIT gene in familial gastrointestinal slromal lumors. Am. J Pathol 2000; 157: 1581–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Maeyama H, Hidaka E, Ola H, Minami S, Kajiyama M, Kuraishi A, Mori H, Malsuda Y, Wada S, Sodeyama H, Nakala S, Kawamura N, Hata S, Walanabe M, Iijima Y, Katsuyama T. Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c‐kit gene. Gastroenterology 2001; 120: 210–5. [DOI] [PubMed] [Google Scholar]
  • 55. Beghini A, Tibiletti MG, Roversi G, Chiaravalli AM, Serio G, Capella C, Larizza L. Germline mulation in Ihe juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer 2001; 92: 657–62. [DOI] [PubMed] [Google Scholar]
  • 56. Chen H, Hirota S, Isozaki K, Sun H, Ohashi A, Kinoshita K, O'Brien P, Kapusta L, Dardick I, Obayashi T, Okazaki T, Shinomura Y, Malsuzawa Y, Kitamura Y. Polyclonal nature of diffuse proliferation of interstitial cells of Cajal in palients with familial and multiple gastrointestinal stromal tumours. Gut 2002; 51: 793–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Mauro MJ, Druker BJ. STI571: targeling BCR‐ABL as therapy for CML. Oncologist 2001; 6: 233–8. [DOI] [PubMed] [Google Scholar]
  • 58. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno‐Jones S, Sawyers CL. Efficacy and safely of a specific inhibitor of the BCR‐ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–7. [DOI] [PubMed] [Google Scholar]
  • 59. Chen H, Isozaki K, Kinoshila K, Ohashi A, Shinomura Y, Malsuzawa Y, Kitamura Y, Hirota S. Imatinib inhibits various types of activating mutant KIT found in gastrointestinal stromal tumors. Int J Cancer in press. [DOI] [PubMed]
  • 60. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H. Efficacy and safety of imalinib mesylate in advanced gaslrointestinal stromal tumors. N Engl J Med 2002; 347: 472–80. [DOI] [PubMed] [Google Scholar]
  • 61. Ma Y, Zeng S, Melcalfe DD, Akin C, Dimitrijevic S, Butterfield JH, McMahon G, Longley BJ. The c‐KIT mulalion causing human maslocylosis is resislanl to STI571 and olher KIT kinase inhibitors; kinases wilh enzymatic site mutations show different inhibitor sensilivily profiles than wild‐type kinases and those wilh regulatory‐type mutations. Blood 2002; 99: 1741–4. [DOI] [PubMed] [Google Scholar]
  • 62. Fuller CE, Williams GT. Gaslroinlestinal manifestations of lype 1 neurifibro malosis (von Recklinghausen's disease). Histopathology 1991; 19: 1–11. [DOI] [PubMed] [Google Scholar]

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