Chromosome 12, frequently deleted in human pancreatic cancer, may encode a tumor-suppressor gene that suppresses angiogenesis

Sumitaka Yamanaka, Makoto Sunamura, Toru Furukawa, Libo Sun, Liviu P. Lefter, Tadayoshi Abe, Toshimasa Yatsuoka, Hiroko Fujimura, Emiko Shibuya, Noriko Kotobuki, Mitsuo Oshimura, Akira Sakurada, Masami Sato, Takashi Kondo, Seiki Matsuno, Akira Horii

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Several lines of evidence have suggested that the long arm of chromosome 12 may carry a tumor-suppressor gene(s) that plays a role in pancreatic ductal carcinogenesis. We have previously found a significant association between loss of heterozygosity of the 12q arm and a poor prognosis in pancreatic cancer patients. In this study, we introduced a normal copy of chromosome 12 into some pancreatic ductal carcinoma cells. Both anchorage-dependent and -independent proliferations as well as invasiveness were similar throughout the hybrid clones when compared with their corresponding parental cells. In sharp contrast, significant suppression of tumorigenesis was observed after inoculation of the hybrid clones into nude mice. Measurements made up to 1 month later showed that there was a significant delay in the growth of tumors into which the introduced normal copy of chromosome 12 had been restored. More significantly, using our dorsal skin chamber and an intravital microscopy system experiment in SCID mice, we demonstrated and visualized directly that implantation of the hybrids failed to promote the angiogenic phenotype encountered in the parental cells. Gene expression profiling using the complementary DNA microarray system identified a set of 24 genes differentially expressed between the hybrids and parental cells. An additional set of 18 genes was also identified that were differentially expressed between the hybrid clone that lost its growth-suppression activity and one that retained such activity. Another set of 25 genes mapped on 12q was detected that showed high expression levels in the hybrid clones retaining growth-suppressive activity. In summary, this study provides the first functional evidence of the existence of an additional tumor-suppressor gene(s) on chromosome 12, whose absence is responsible for the pathogenesis in pancreatic ductal carcinogenesis.

Original languageEnglish
Pages (from-to)1339-1351
Number of pages13
JournalLaboratory Investigation
Volume84
Issue number10
DOIs
Publication statusPublished - 2004 Oct 1

Keywords

  • Angiogenesis
  • Chromosome 12
  • Pancreatic cancer

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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    Yamanaka, S., Sunamura, M., Furukawa, T., Sun, L., Lefter, L. P., Abe, T., Yatsuoka, T., Fujimura, H., Shibuya, E., Kotobuki, N., Oshimura, M., Sakurada, A., Sato, M., Kondo, T., Matsuno, S., & Horii, A. (2004). Chromosome 12, frequently deleted in human pancreatic cancer, may encode a tumor-suppressor gene that suppresses angiogenesis. Laboratory Investigation, 84(10), 1339-1351. https://doi.org/10.1038/labinvest.3700160