Topical retinoic acid reduces skin papilloma formation but resistant papillomas are at high risk for malignant conversion

Tamar Tennenbaum, David Lowry, Nadine Darwiche, David L. Morgan, Marina Gartsbein, Laura A. Hansen, Luigi M. De Luca, Henry Hennings, Stuart H. Yuspa

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Retinoic acid (RA) was topically applied to the skin of Sencar mice during the promotion phase of specific tumor induction protocols that produce papillomas at low (12-O-tetradecanoylphorbol-13-acetate promoted, TPA) or high (mezerein-promoted) risk for premalignant progression and malignant conversion. RA consistently reduced the yield of papillomas and carcinomas in both protocols, but the frequency of malignant conversion in papillomas that emerged during RA treatment was not reduced. When TPA was reapplied after cessation of RA treatment, the number of papillomas increased 2-fold, suggesting that RA had not eliminated initiated cells. In vitro, RA prevented the emergence of transformed keratinocytes in an assay that mimics malignant conversion, suggesting that RA can suppress conversion if applied during the stage of premalignant progression. Examination of tumor markers at weeks 14 and 22 of the tumor-induction experiments in vivo indicated that papillomas evolving during RA treatment exhibited a phenotype of high progression risk, even in the TPA-promoted groups. In the majority of these tumors, the α6β4 integrin and retinoid X receptor a transcripts were detected suprabasally, indicating an advanced state of premalignant progression. RA-treated tumors also expressed higher levels of transcripts for transforming growth factor (TGF)-β1 and localized TGF-β1 peptide in the basal portions of the tumor fronds. Because up-regulated expression of TGF-β1 suppresses papilloma formation, these studies suggest a mechanism whereby RA can prevent papilloma eruption via a TGF-β intermediate, but papillomas resistant to RA may have altered TGF-β signaling and progress to carcinomas at an increased frequency.

Original languageEnglish
Pages (from-to)1435-1443
Number of pages9
JournalCancer Research
Volume58
Issue number7
StatePublished - Apr 1 1998
Externally publishedYes

Fingerprint

Papilloma
Tretinoin
Skin
Transforming Growth Factors
Neoplasms
Carcinoma
Retinoid X Receptors
Tetradecanoylphorbol Acetate
Tumor Biomarkers
Keratinocytes
Integrins
Phenotype
Peptides

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Tennenbaum, T., Lowry, D., Darwiche, N., Morgan, D. L., Gartsbein, M., Hansen, L. A., ... Yuspa, S. H. (1998). Topical retinoic acid reduces skin papilloma formation but resistant papillomas are at high risk for malignant conversion. Cancer Research, 58(7), 1435-1443.

Topical retinoic acid reduces skin papilloma formation but resistant papillomas are at high risk for malignant conversion. / Tennenbaum, Tamar; Lowry, David; Darwiche, Nadine; Morgan, David L.; Gartsbein, Marina; Hansen, Laura A.; De Luca, Luigi M.; Hennings, Henry; Yuspa, Stuart H.

In: Cancer Research, Vol. 58, No. 7, 01.04.1998, p. 1435-1443.

Research output: Contribution to journalArticle

Tennenbaum, T, Lowry, D, Darwiche, N, Morgan, DL, Gartsbein, M, Hansen, LA, De Luca, LM, Hennings, H & Yuspa, SH 1998, 'Topical retinoic acid reduces skin papilloma formation but resistant papillomas are at high risk for malignant conversion', Cancer Research, vol. 58, no. 7, pp. 1435-1443.
Tennenbaum, Tamar ; Lowry, David ; Darwiche, Nadine ; Morgan, David L. ; Gartsbein, Marina ; Hansen, Laura A. ; De Luca, Luigi M. ; Hennings, Henry ; Yuspa, Stuart H. / Topical retinoic acid reduces skin papilloma formation but resistant papillomas are at high risk for malignant conversion. In: Cancer Research. 1998 ; Vol. 58, No. 7. pp. 1435-1443.
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