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 Citations (Scopus)

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

Fingerprint

Epigenomics
Thyroid Gland
Clone Cells
Epithelium
Neoplasms
Tumor Suppressor Genes
Oncogenes
Thyroid Neoplasms
Cell Division
Epithelial Cells
Mutation
Mortality
Growth
Thyroid Epithelial Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Spontaneous de-differentiation correlates with extended lifespan in transformed thyroid epithelial cells : An epigenetic mechanism of tumour progression? / Bond, Jane A.; Oddweig Ness, Gro; Rowson, Janet; Ivan, Mircea; White, Denise; Wynford-Thomas, David.

In: International Journal of Cancer, Vol. 67, No. 4, 1996, p. 563-572.

Research output: Contribution to journalArticle

Bond, Jane A. ; Oddweig Ness, Gro ; Rowson, Janet ; Ivan, Mircea ; White, Denise ; Wynford-Thomas, David. / Spontaneous de-differentiation correlates with extended lifespan in transformed thyroid epithelial cells : An epigenetic mechanism of tumour progression?. In: International Journal of Cancer. 1996 ; Vol. 67, No. 4. pp. 563-572.
@article{d0f6a2160f024a9bb667ce7980410671,
title = "Spontaneous de-differentiation correlates with extended lifespan in transformed thyroid epithelial cells: An epigenetic mechanism of tumour progression?",
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.",
author = "Bond, {Jane A.} and {Oddweig Ness}, Gro and Janet Rowson and Mircea Ivan and Denise White and David Wynford-Thomas",
year = "1996",
doi = "10.1002/(SICI)1097-0215(19960807)67:4<563::AID-IJC16>3.0.CO;2-8",
language = "English (US)",
volume = "67",
pages = "563--572",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - Spontaneous de-differentiation correlates with extended lifespan in transformed thyroid epithelial cells

T2 - An epigenetic mechanism of tumour progression?

AU - Bond, Jane A.

AU - Oddweig Ness, Gro

AU - Rowson, Janet

AU - Ivan, Mircea

AU - White, Denise

AU - Wynford-Thomas, David

PY - 1996

Y1 - 1996

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=9444263685&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=9444263685&partnerID=8YFLogxK

U2 - 10.1002/(SICI)1097-0215(19960807)67:4<563::AID-IJC16>3.0.CO;2-8

DO - 10.1002/(SICI)1097-0215(19960807)67:4<563::AID-IJC16>3.0.CO;2-8

M3 - Article

C2 - 8759617

AN - SCOPUS:9444263685

VL - 67

SP - 563

EP - 572

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 4

ER -