World Journal of Surgery

, Volume 19, Issue 4, pp 484–488 | Cite as

Molecular biology of gastric cancer

  • Eiichi Tahara

Abstract

Gastric cancer involves changes in multiple oncogenes and multiple suppressor genes, and it causes genetic instability. Aberrant expression and amplification of the c-met gene, inactivation of the p53 gene, and CD44 abnormal transcripts are common events of both well differentiated and poorly differentiated gastric cancers. Amplification of the cyclin E gene is also observed in gastric cancer regardless of histologic type. Decreased expression of the pic1 (p21) gene occurs independent of the p53 mutations. In addition, K-ras mutations, c-erbB-2 gene amplification, loss of heterozygosity (LOH) and mutations of the APC gene, LOH of the bcl-2 gene, and LOH at the DCC locus are preferentially associated with well differentiated gastric cancer. Moreover, LOH on chromosome 1q is involved in the progression of well differentiated cancer. Precancerous lesions, including hyperplastic polyp, intestinal metaplasia, and adenoma, share genetic changes found in well differentiated cancers. Conversely, genetic instability may be involved in the first step of stomach carcinogenesis of the poorly differentiated type. Reduction or loss of cadherin and catenins, K-sam gene amplification, and c-met gene amplification are necessary for the development and progression of poorly differentiated or scirrhous carcinoma. Interaction between cell-adhesion molecules in the c-met expressed tumor cells and hepatocyte growth factor from stromal cells is implicated in the morphogenesis of two types of gastric cancer. Taken together, different genetic pathways of stomach carcinogenesis may exist for well differentiated and poorly differentiated gastric cancers. Some of the former may develop by a cumulative series of gene alterations similar to those of colorectal cancer. Peritoneal dissemination and metastasis may require LOH on chromosome 7q, reduction in nm23 protein, abnormal transcripts of CD44, changes in cadherin and catenins, and overexpression of a 31-kDa lactoside-binding lectin.

Résumé

Le développement d'un cancer gastrique sous-entend des changements génétiques de multiples oncogènes, des gènes suppresseurs et une instabilité génétique. Parmi ces modifications, une expression aberrante et une amplification du gène c-met, l'inactivation du gène p53 et la transcription anormale du CD44 sont des événements fréquents dans les cancers à la fois bien et mal diflérenciés. L'amplification du gène cycline E peut aussi se voir dans tous les types de cancer gastrique indépendamment de son type histologique. Une expression diminuée et des mutations du gène pic 1 (p21) peut se produire indépendamment de la mutation p53. De plus, des mutations K-ras, l'amplification du gène c-erbB-2, la perte de l'hétérozygoise (LOH) et les mutations du gène APC, la LOH du gène bel-2 ainsi que la LOH au locus DCC sont plus fréquemment associées au cancer bien différencié. Les modifications génétiques qui caractérisent les lésions précancéreuses comprenant les polypes hyperplastiques, la métaplasie du type intestinal et l'adénome sont retrouvées également dans les cancers bien différenciés de l'estomac. L'instabilité génétique pourrait être la première étape de la carcinogen`ese du cancer mal différencié. La réduction ou la perte de la cadhérine et des caténins ainsi que l'amplification du gène sam et du gène c-met sont nécessaires au développement et à l'évolution des cancer mal différenciés et des linites. Une interaction entre les molécules de l'adhésion cellulaire dans les cellules tumorales exprimées par le c-met et le facteur de croissance des hépatocytes à partir des cellules du stroma est impliquée dans la morphogenèse de deux types de cancer gastrique. Dans l'ensemble, des voies génétiques différentes sont impliquées dans la carcinogenèse des cancers gastriques en ce qui concerne les cancers bien et mal différenciés. Pour les premiers, le développement du cancer pourrait se faire suite à une série de modifications similaries à celles observées dans le cancer colorectal. La dissémination péritonéale et le phénomène de métastase pourrait nécessité une LOH du chromosome 7q, une réduction de la protéine nM23, la transcription anormale du CD-44, des modifications de la cadhérine et des caténins, et enfin, une surexpression de la lectine responsable de la liaison du lactoside 31-kDa.

Resumen

El cáncer gástrico implica cambios genéticos en oncogenes, múltiples genes supresores e inestabilidad genética. Entre tales cambios, la expresión aberrante y la amplificación del gen c-met, la inactivación del gen p53 y las transcripciones CD44 anormales son eventos comunes tanto en los cánceres gástricos bien differenciados como en los pobremente diferenciados. También se observa la amplificación del gen ciclin E, no importa cual sea el tipo histológico. Una expresión disminuida del gen pic1 (p21) ocurre en forma independiente de las mutaciones p53. Además, las mutaciones K-ras, amplificación del gen c-erbB-2, pérdida de heterozigocidad (LOH) y mutaciones del gen APC, del gen bcl-2 y LOH en el locus DCC se ven preferencialmente asociados con el cáncer gástrico bien diferenciado. Por lo demás, el LOH en el cromosoma 1q está involucrado en la progresión del cáncer bien diferenciado. Las lesiones preneoplásicas, incluyendo pólipos hiperplásicos, metaplasia intestinal y adenoma, también comparten los cambios genéticos que se encuentran en los cánceres bien diferenciados. Por el contrario, la inestabilidad genética puede estar involucrada en el primer paso del proceso de carcinogenesis de los tumores gástricos pobremente diferenciados. La reducción o la pérdida de cadherina y cateninas, la amplificación del gen K-sam y la amplificación del gen c-met son necesarios para el desarrollo y la progresión de los carcinomas pobremente diferenciados o esquirrosos. La interacción entre las moléculas de adherencia celular en las células tumorales de expresión c-met y el factor de crecimiento del hepatocito de las células estromales está implicada en la morfogénesis de dos tipos de cáncer gástrico. Consideradas en conjunto, diversas vías de carcinogenesis gástrica pueden existir tanto para los carcinomas bien diferenciados como para los pobremente diferenciados. Alguna de las primeras pueden desarrollarse a través de una serie de alteraciones acumulativas similares a las del cáncer colorrectal. La diseminación peritoneal y las metástasis pueden requerir LOH sobre el cromosoma 7q, reducción de la proteína nm23, transcripción anormal de CD44, cambios en cadherina y cateninas y sobreexpresión de la lectina ligadora de 31-hDa lactósido.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Tahara, E.: Molecular mechanism of stomach carcinogenesis. J. Cancer Res. Clin. Oncol. 119:265–272, 1993Google Scholar
  2. 2.
    Kunivasu, H., Yasui, W., Kitadai, Y., Yokozaki, H., Ito, H., Tahara, E.: Frequent amplification of the c-met gene in scirrhous type stomach cancer. Biochem. Biophys. Res. Commun. 189:227–232, 1992Google Scholar
  3. 3.
    Kuniyasu, H., Yasui, W., Yokozaki, H., Kitadai, Y., Tahara, E.: Aberrant expression of c-met mRNA in human gastric carcinomas. Int. J. Cancer 55:72–75, 1993Google Scholar
  4. 4.
    Katoh, M., Terada, M.: Oncogenes and tumor suppressor genes. In Gastric Cancer, M. Nishi, H. Ichikawa, T. Nakajima, K. Maruyama, E. Tahara, editors, Tokyo, Springer-Verlag, 1993, pp 196–208Google Scholar
  5. 5.
    Kameda, T., Yasui, W., Yoshida, K., Tsujino, T., Nakayama, H., Ito, M., Ito, H., Tahara, E., Expression of ERBB2 in human gastric carcinomas: relationship between p185ERBB2 expression and the gene amplification. Cancer Res. 50:8002–8009, 1990Google Scholar
  6. 6.
    Tahara, E.: Growth factors and oncogenes in human gastrointestinal carcinomas. J. Cancer Res. Clin. Oncol. 116:121–131, 1990Google Scholar
  7. 7.
    Tahara, E., Yokozaki, H., Yasui, W.: Growth factors in gastric cancer. In Gastric Cancer (ed. Nishi, M., Ichikawa, H., Nakajima, T., Maruyama, K., Tahara, E.): Springer-Verlag, Tokyo, pp. 209–217, 1993Google Scholar
  8. 8.
    Ito, H., Tahara, E.: Endocrine cell tumor of the stomach. In Gastric Cancer, M. Nishi, H. Ichikawa, T. Nakajima, K. Maruyama, E. Tahara, editors, Tokyo, Springer-Verlag, 1993, pp. 151–167Google Scholar
  9. 9.
    Kitadai, Y., Yasui, W., Yokozaki, H., Kuniyasu, H., Haruma, K., Kajiyama, G., Tahara, E.: The level of a transcription factor Sp1 is correlated with the expression of EGF receptor in human gastric carcinomas. Biochem. Biophys. Res. Commun. 189:1342–1348, 1992Google Scholar
  10. 10.
    Kitadai, Y., Yamazaki, H., Yasui, W., Kyo, E., Yokozaki, H., Kajiyama, G., Johnson, A.C., Pastan, I., Tahara, E.: GC factor represses transcription of several growth factor/receptor genes and causes growth inhibition of human gastric carcinoma cell lines. Cell Growth and Differentiation 4:291–296, 1993Google Scholar
  11. 11.
    Tahara, E., Kuniyasu, H., Yasui, W., Yokozaki, H.: Abnormal expression of growth factors and their receptors in stomach cancer. Gann Monograph on Cancer Res. 42:163–173, 1994Google Scholar
  12. 12.
    Ito, R., Kitadai, Y., Kyo, E., Yokozaki, H., Yasui, W., Yamashita, U., Nikai, H., Tahara, E.: Interleukin 1α acts as an autocrine growth stimulator for human gastric carcinoma cells. Cancer Res. 53:4102–4106, 1993Google Scholar
  13. 13.
    Kuniyasu, H., Yoshida, K., Yokozaki, H., Yasui, W., Ito, H., Toge, T., Ciardiello, F., Persico, M.G., Sacki, T., Salomon, D.S., Tahara, E.: Expression of cripto, a novel gene of the epidermal growth factor family, in human gastrointestinal carcinomas. Jpn. J. Cancer Res. 82:969–973, 1991Google Scholar
  14. 14.
    Kuniyasu, H., Yasui, W., Akama, Y., Akagi, M., Tohdo, H., Ji, Z.O., Kitadai, Y., Yokozaki, H., Tahara, E.: Expression of cripto in human gastric carcinomas: an association with tumor stage and prognosis. J. Exp. Clin. Cancer Res. 13:151–157, 1994Google Scholar
  15. 15.
    Ito, M., Yasui, W., Kyo, E., Yokozaki, H., Nakayama, H., Ito, H., Tahara, E.: Growth inhibition of transforming growth factor β on human gastric carcinoma cells: receptor and postreceptor signaling. Cancer Res. 52:295–300, 1992Google Scholar
  16. 16.
    Ito, M., Yasui, W., Nakayama, H., Yokozaki, H., Ito, H., Tahara, E.: Reduced levels of transforming growth factor-beta type I receptor in human gastric carcinomas. Jpn. J. Cancer Res. 83:86–92, 1992Google Scholar
  17. 17.
    Yokozaki, H., Ito, M., Yasui, W., Kyo, E., Kuniyasu, H., Kitadai, Y., Tsubouchi, H., Daikuhara, Y., Tahara, E.: Biologic effect of human hepatocyte growth factor on human gastric carcinoma cell lines. Int. J. Oncology 3:89–93, 1993Google Scholar
  18. 18.
    Noda, A., Ning, Y., Venable, S.F., Pereira-Smith, O.M., Smith, J.R.: Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp. Cell. Res. 211:90–98, 1994Google Scholar
  19. 19.
    El-Deiry, W.S., Tokino, T., Velculescu, V.E., Levy, D.B., Parsons, R., Trent, J.M., Lin, D., Mercer, W.E., Kinzler, K.W., Vogelstein, B.: WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825, 1993Google Scholar
  20. 20.
    Harper, J.W., Adami, G.R., Wei, N., Keyomarsi, K., Elledge, S.J.: The p21 cdk-interacting protein cip1 is a potent inhibitor of G1 cyclindependent kinases. Cell 75:805–816, 1993Google Scholar
  21. 21.
    Xiong, Y., Hannon, G.J., Zhang, H., Casso, D., Kobayashi, R., Beach, D.: p21 is a universal inhibitor of cyclin kinases. Nature 366:701–704, 1993Google Scholar
  22. 22.
    Michieli, P., Chedid, M., Lin, D., Pierce, J.H., Mercer, W.E., Givol, D.: Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res. 54:3391–3395, 1994Google Scholar
  23. 23.
    Waga, S., Hannon, G.J., Beach, D., Stillman, B.: The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature 369:574–578, 1994Google Scholar
  24. 24.
    Kamb, A., Gruis, N.A., Weaver-Feldhaus, J., Liu, Q., Harshman, K., Tavtigian, S.V., Stockert, E., Day III, R.S., Johnson, B.E., Skolnick, M.H.: A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440, 1994Google Scholar
  25. 25.
    Mori, T., Miura, K., Aoki, T., Nishihira, T., Mori, S., Nakamura, Y.: Frequent somatic mutation of the MTS1/CDK41 (multiple tumor suppressor/cyclin-dependent kinase 4 inhibitor) gene in esophageal squamous cell carcinoma. Cancer Res. 54:3396–3397, 1994Google Scholar
  26. 26.
    Nakatsuru, S., Yanagisawa, A., Ichii, S., Tahara, E., Kato, Y., Nakamura, Y., Horii, A.: Somatic mutation of the APC gene in gastric cancer: frequent mutations in very well differentiated adenocarcinoma and signet-ring cell carcinoma. Human Molecular Genetics 1:559–563, 1992Google Scholar
  27. 27.
    Peifer, M.: Cancer, catenins, and cuticle pattern: a complex connection. Science 262:1667–1668, 1993Google Scholar
  28. 28.
    Ayhan, A., Yasui, W., Yokozaki, H., Seto, M., Ueda, R., Tahara, E.: Loss of heterozygosity at the bcl-2 gene locus and expression of bcl-2 in human gastric and colorectal carcinomas. Jpn. J. Cancer Res. 85:584–591, 1994Google Scholar
  29. 29.
    Han, H.-J., Yanagisawa, A., Kato, Y., Park, J.-G., Nakamura, Y.: Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res 53:5087–5089, 1993Google Scholar
  30. 30.
    Horii, A., Han, H.-J., Shimada, M., Yanagisawa, A., Kato, Y., Ohta, H., Yasui, W., Tahara, E.: Flequent replication errors at microsatellite loci in tumors of patients with multiple primary cancer. Cancer Res. 54:3373–3375, 1994Google Scholar
  31. 31.
    Hastie, N.D., Dempster, M., Dunlop, M.G., Thompson, A.M., Green, D.K., Allshire, R.C.: Telomere reduction in human colorectal carcinoma and with ageing. Nature 346:866–868, 1990Google Scholar
  32. 32.
    Matsumura, Y., Tarin, D.: Significance of CD44 gene products for cancer diagnosis and disease evaluation. The Lancet 340:1053–1058, 1992Google Scholar
  33. 33.
    Yokozaki, H., Ito, R., Nakayama, H., Kuniyasu, H., Taniyama, K., Tahara, E.: Expression of CD44 abnormal transcripts in human gastric carcinomas. Cancer Letters 83:229–234, 1994Google Scholar
  34. 34.
    Nakayama, H., Yasui, W., Yokozaki, H., Tahara, E.: Reduced expression of nm23 is associated with metastasis of human gastric carcinomas. Jpn. J. Cancer Res. 84:184–190, 1993Google Scholar
  35. 35.
    Ayhan, A., Yasui, W., Yokozaki, H., Kitadai, Y., Tahara, E.: Reduced expression of nm23 protein is associated with advanced tumor stage and distant metastases in human colorectal carcinomas. Virchow Archiv B 63:213–218, 1993Google Scholar
  36. 36.
    Lotan, R., Ito, H., Yasui, W., Yokozaki, H., Lotan, D., Tahara, E.: Expression of a 31-kDa lactoside-binding lectin in normal human gastric mucosa and in primary and metastatic gastric carcinomas. Int. J. Cancer 56:474–480, 1994Google Scholar
  37. 37.
    Kuniyasu, H., Yasui, W., Yokozaki, H., Akagi, M., Akama, Y., Kitahara, K., Fujii, K., Tahara, E.: Frequent loss of heterozygosity of the long arm of chromosome 7 is closely associated with progression of human gastric carcinomas. Int. J. Cancer 59:597–600, 1994Google Scholar

Copyright information

© Société Internationale de Chirurgie 1995

Authors and Affiliations

  • Eiichi Tahara
    • 1
  1. 1.Department of PathologyHiroshima University School of MedicineHiroshimaJapan

Personalised recommendations