Loss of expression of transforming growth factor beta in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 90 ·No. 13 ·1993-07-01 ·Pages 6076-80

Glick AB, Kulkarni AB, Tennenbaum T, Hennings H, Flanders KC, O'Reilly M, Sporn MB, Karlsson S, Yuspa SH

Abstract

Mouse skin carcinomas arise from a small subpopulation of benign papillomas with an increased risk of malignant conversion. These papillomas arise with limited stimulation by tumor promoters, appear rapidly, and do not regress, suggesting that they differ in growth properties from the majority of benign tumors. The transforming growth factor beta (TGF-beta) proteins are expressed in the epidermis and are growth inhibitors for mouse keratinocytes in vitro; altered TGF-beta expression could influence the growth properties of high-risk papillomas. Normal epidermis, tumor promoter-treated epidermis, and skin papillomas at low risk for malignant conversion express TGF-beta 1 in the basal cell compartment and TGF-beta 2 in the suprabasal strata. In low-risk tumors, 90% of the proliferating cells are confined to the basal compartment. In contrast, the majority of high-risk papillomas are devoid of both TGF-beta 1 and TGF-beta 2 as soon as they arise; these tumors have up to 40% of the proliferating cells in the suprabasal layers. Squamous cell carcinomas are also devoid of TGF-beta, suggesting that they arise from the TGF-beta-deficient high-risk papillomas. In some high-risk papillomas, TGF-beta 1 loss can occur first and correlates with basal cell hyperproliferation, while TGF-beta 2 loss correlates with suprabasal hyperproliferation. Similarly, TGF-beta 1-null transgenic mice, which express wild-type levels of TGF-beta 2 in epidermis but no TGF-beta 1 in the basal layer, have a hyperproliferative basal cell layer without suprabasal proliferation. In tumors, loss of TGF-beta is controlled at the posttranscriptional level and is associated with expression of keratin 13, a documented marker of malignant progression. These results show that TGF-beta expression and function are compartmentalized in epidermis and epidermal tumors and that loss of TGF-beta is an early, biologically relevant risk factor for malignant progression.

MeSH Terms

Animals Base Sequence Carcinoma, Squamous Cell/chemistry,etiology,pathology Cell Division Cell Transformation, Neoplastic Epidermal Cells Epidermis/chemistry Female Keratins/analysis Mice Mice, Transgenic Molecular Sequence Data Papilloma/chemistry,etiology,pathology Risk Skin Neoplasms/chemistry,etiology,pathology Transforming Growth Factor beta/analysis

Chemicals

Transforming Growth Factor beta Keratins

Authors & Affiliations

9 authors, click to expand affiliations / ORCID

Glick A B

Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Kulkarni A B

Tennenbaum T

Hennings H

Flanders K C

O'Reilly M

Sporn M B

Karlsson S

Yuspa S H

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Article Info

Journal

Proceedings of the National Academy of Sciences of the United States of America

Abbr.

Proc Natl Acad Sci U S A

ISSN

0027-8424

DOI

10.1073/pnas.90.13.6076

Published

1993-07-01

Pages

6076-80

Language

English

Region

United States

NLM ID

7505876

PMCID

PMC46870

Subset

External Links

PubMed source DOI: 10.1073/pnas.90.13.6076 PMC Full Text View journal details

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Loss of expression of transforming growth factor beta in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion.

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