Spontaneous de-differentiation correlates with extended lifespan in transformed thyroid epithelial cells: An epigenetic mechanism of tumour progression?

Jane A. Bond, Gro Oddweig Ness, Janet Rowson, Mircea Ivan, Denise White, David Wynford-Thomas

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Normal thyroid follicular cells, like many highly differentiated epithelia, have limited proliferative capacity. We previously showed that this could be extended by expression of the SV40 large T oncogene, but that immortal lines always lost thyroid-specific differentiation. Detailed analysis now shows that clones expressing T undergo 2 mutually exclusive fates. They either (i) remain well-differentiated, in which case they undergo irreversible growth arrest after 5 to 15 p.d., or (ii) spontaneously develop poorly differentiated sub-clones that exhibit greatly extended proliferative life spans (up to 75 p.d.). The frequency of this event (>3 per 104 cell divisions) greatly exceeds that expected from somatic mutation, suggesting an epigenetic basis. This is supported by our finding of rare de-differentiated epithelial cells in normal thyroid that all generate clones with extended life spans, indistinguishable from the above, following introduction of SV40 T. Escape from early mortality in differentiated thyroid epithelium therefore requires not only loss of tumour suppressor gene function (induced here by SV40 T), but also a switch in differentiation programme, with the latter effectively converting the follicular cell into a cell type with increased intrinsic proliferative potential. The analogy between this in vitro model and the progression of thyroid cancer from the well-differentiated to the highly aggressive, anaplastic form suggests that de-differentiation may play a causal rather than a passive role in this critical switch in tumour behaviour.

Original languageEnglish (US)
Pages (from-to)563-572
Number of pages10
JournalInternational Journal of Cancer
Volume67
Issue number4
DOIs
StatePublished - 1996
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Spontaneous de-differentiation correlates with extended lifespan in transformed thyroid epithelial cells: An epigenetic mechanism of tumour progression?'. Together they form a unique fingerprint.

  • Cite this