Sequential loss of suppressor genes for three specific functions during in vivo carcinogenesis

J. R. Moroco, D. B. Solt, P. J. Polverini*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

As normal cells undergo neoplastic transformation, multiple suppressor gene functions are lost or inactivated. However, the relative contribution that individual suppressor gene defects play in the sequential evolution of solid tumors has not yet been evaluated in a readily analyzable experimental model of carcinogenesis. The present study was undertaken to: (a) document the loss of suppressor genes implicated in the control of angiogenic activity, anchorage and serum growth requirements, and proliferative life span, in populations of hamster buccal pouch (HBP) keratinocytes (Kr) initiated in vivo with the chemical carcinogen 7,12 dimethylbenz(a) anthracene and (b), to determine what combination of defective suppressor genes are necessary for tumorigenesis. Kr were isolated from HBPs at various times after treating the mucosal surfaces in vivo with 7,12 dimethylbenz(a)anthracene. Cells or their conditioned culture media were evaluated for: (a) angiogenic activity in vivo and in vitro, (b) anchorage independent growth, (c) growth in low serum, (d) immortality, and (e) tumorigenicity. Angiogenic activity and immortality were the first two phenotypes detected with anchorage independence and tumorigenesis emerging late in the carcinogenic process. Hybrids generated between Kr which were angiogenic, but otherwise negative for all other phenotypic traits, and a transformed and tumorigenic HBP carcinoma cell line, E1-1, were suppressed for all phenotypes except angiogenic activity and none of the hybrids were tumorigenic. In contrast, Kr positive for angiogenic activity, anchorage independence, immortality, and tumorigenicity and hybrids generated between these cells and E1-1 carcinoma, were tumorigenic. However, hybrids between a nontumorigenic, anchorage independent, immortal but nonangiogenic Kr, and the E1-1 line were not tumorigenic. These results suggest that (a) angiogenic activity is an early phenotypic trait that emerges as a result of the loss of a suppressor gene function and (b) loss of this function is essential but not sufficient for the development of HBP tumors.

Original languageEnglish (US)
Pages (from-to)298-306
Number of pages9
JournalLaboratory Investigation
Volume63
Issue number3
StatePublished - 1990

Keywords

  • 7,12-dimethylbenz(a)anthracene
  • Angiogenesis
  • DMBA
  • Hamster buccal pouch HBP
  • Keratinocytes
  • Kr
  • Transformed phenotypes
  • Tumorigenesis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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