Suppression of the tumorigenic phenotype by chromosome 18 transfer into pancreatic cancer cell lines.
A number of lines of evidence have suggested that the long arm of chromosome 18 apart from SMAD4 may carry a tumor-suppressor gene(s) that plays a role in the early stage of pancreatic ductal carcinogenesis. Thus, adenovirus-mediated introduction of SMAD4 does not suppress in vitro growth in cells with completely inactivated SMAD4, and frequent loss of 18q at the SMAD4 locus is observed in pancreatic cancers but no abnormalities of the normal SMAD4 homolog have been detected. In this study, we introduced a normal copy of chromosome 18 into some pancreatic ductal carcinoma cells with and without a complete inactivation of SMAD4. Both anchorage-dependent and -independent proliferation as well as invasiveness were significantly suppressed in the hybrid clones compared with that of their parental cells. Moreover, significant suppression of tumorigenesis was observed after inoculation in nude mice, irrespective of the SMAD4 status. Our present study provides the first functional evidence of the existence of an additional tumor-suppressor gene(s), other than SMAD4 and DCC, that is responsible for the pathogenesis in the early stage of pancreatic ductal carcinogenesis.
Lefter
Liviu P
LP
Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan.
Furukawa
Toru
T
Sunamura
Makoto
M
Duda
Dan G
DG
Takeda
Kazunori
K
Kotobuki
Noriko
N
Oshimura
Mitsuo
M
Matsuno
Seiki
S
Horii
Akira
A
D000818:Animals; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D002999:Clone Cells; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D006822:Hybrid Cells; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D051901:Smad4 Protein; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators