Targeted deletion of the TGF-β1 gene causes rapid progression to squamous cell carcinoma

Adam Bleier Glick, Margo M. Lee, Nadine Darwiche, Ashok B. Kulkarni, Stefan Karlsson, Stuart H. Yuspa

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

To study the contribution of autocrine and paracrine TGF-β1 to tumor progression in a well-defined system of multistage carcinogenesis, keratinocytes with a targeted deletion of the TGF-β1 gene were initiated in vitro with the v-ras(Ha) oncogene and their in vivo tumorigenic properties were determined by skin grafting initiated cells onto athymic mice in combination with either wild-type or null dermal fibroblasts. Grafts of v- ras(Ha)-initiated null keratinocytes progressed rapidly to multifocal squamous cell carcinomas within dysplastic papillomas irrespective of the fibroblast genotype, whereas the initiated control genotypes formed well- differentiated papillomas. Malignant progression was not associated with mutations in the c-ras(Ha) gene, alterations in p53 protein, or loss of responsiveness to TGF-β1. The tumor cell labeling index was elevated in grafts of initiated null keratinocytes with wild-type fibroblasts compared to tumors of other genotypes. However, labeling index in all tumors was reduced when TGF-β1 null fibroblasts formed the stroma. The null tumor cells could not accumulate TGF-β1 from the host, but grafts of uninitiated null keratinocytes, which formed a normal epidermis, became TGF-β1 positive even though they did not express TGF-β1 mRNA. These results demonstrate that autocrine TGF-β1 suppresses the frequency and rate of malignant progression, and that autocrine and paracrine TGF-β1 can have opposing effects on tumor cell proliferation. The lack of paracrine inhibition of tumor cell progression appears to result from the inability of tumor cells to localize host-derived TGF-β1 by a mechanism that operates in normal cells.

Original languageEnglish (US)
Pages (from-to)2429-2440
Number of pages12
JournalGenes and Development
Volume8
Issue number20
DOIs
StatePublished - Oct 15 1994

Fingerprint

Squamous Cell Carcinoma
Keratinocytes
Genes
Neoplasms
Fibroblasts
ras Genes
Genotype
Papilloma
Transplants
Null Lymphocytes
Skin Transplantation
Nude Mice
Epidermis
Carcinogenesis
Cell Proliferation
Messenger RNA
Skin
Mutation
Proteins

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Cite this

Glick, Adam Bleier ; Lee, Margo M. ; Darwiche, Nadine ; Kulkarni, Ashok B. ; Karlsson, Stefan ; Yuspa, Stuart H. / Targeted deletion of the TGF-β1 gene causes rapid progression to squamous cell carcinoma. In: Genes and Development. 1994 ; Vol. 8, No. 20. pp. 2429-2440.
@article{731990af54a24b7a9f9e1f4ece0e2f26,
title = "Targeted deletion of the TGF-β1 gene causes rapid progression to squamous cell carcinoma",
abstract = "To study the contribution of autocrine and paracrine TGF-β1 to tumor progression in a well-defined system of multistage carcinogenesis, keratinocytes with a targeted deletion of the TGF-β1 gene were initiated in vitro with the v-ras(Ha) oncogene and their in vivo tumorigenic properties were determined by skin grafting initiated cells onto athymic mice in combination with either wild-type or null dermal fibroblasts. Grafts of v- ras(Ha)-initiated null keratinocytes progressed rapidly to multifocal squamous cell carcinomas within dysplastic papillomas irrespective of the fibroblast genotype, whereas the initiated control genotypes formed well- differentiated papillomas. Malignant progression was not associated with mutations in the c-ras(Ha) gene, alterations in p53 protein, or loss of responsiveness to TGF-β1. The tumor cell labeling index was elevated in grafts of initiated null keratinocytes with wild-type fibroblasts compared to tumors of other genotypes. However, labeling index in all tumors was reduced when TGF-β1 null fibroblasts formed the stroma. The null tumor cells could not accumulate TGF-β1 from the host, but grafts of uninitiated null keratinocytes, which formed a normal epidermis, became TGF-β1 positive even though they did not express TGF-β1 mRNA. These results demonstrate that autocrine TGF-β1 suppresses the frequency and rate of malignant progression, and that autocrine and paracrine TGF-β1 can have opposing effects on tumor cell proliferation. The lack of paracrine inhibition of tumor cell progression appears to result from the inability of tumor cells to localize host-derived TGF-β1 by a mechanism that operates in normal cells.",
author = "Glick, {Adam Bleier} and Lee, {Margo M.} and Nadine Darwiche and Kulkarni, {Ashok B.} and Stefan Karlsson and Yuspa, {Stuart H.}",
year = "1994",
month = "10",
day = "15",
doi = "10.1101/gad.8.20.2429",
language = "English (US)",
volume = "8",
pages = "2429--2440",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "20",

}

Glick, AB, Lee, MM, Darwiche, N, Kulkarni, AB, Karlsson, S & Yuspa, SH 1994, 'Targeted deletion of the TGF-β1 gene causes rapid progression to squamous cell carcinoma', Genes and Development, vol. 8, no. 20, pp. 2429-2440. https://doi.org/10.1101/gad.8.20.2429

Targeted deletion of the TGF-β1 gene causes rapid progression to squamous cell carcinoma. / Glick, Adam Bleier; Lee, Margo M.; Darwiche, Nadine; Kulkarni, Ashok B.; Karlsson, Stefan; Yuspa, Stuart H.

In: Genes and Development, Vol. 8, No. 20, 15.10.1994, p. 2429-2440.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeted deletion of the TGF-β1 gene causes rapid progression to squamous cell carcinoma

AU - Glick, Adam Bleier

AU - Lee, Margo M.

AU - Darwiche, Nadine

AU - Kulkarni, Ashok B.

AU - Karlsson, Stefan

AU - Yuspa, Stuart H.

PY - 1994/10/15

Y1 - 1994/10/15

N2 - To study the contribution of autocrine and paracrine TGF-β1 to tumor progression in a well-defined system of multistage carcinogenesis, keratinocytes with a targeted deletion of the TGF-β1 gene were initiated in vitro with the v-ras(Ha) oncogene and their in vivo tumorigenic properties were determined by skin grafting initiated cells onto athymic mice in combination with either wild-type or null dermal fibroblasts. Grafts of v- ras(Ha)-initiated null keratinocytes progressed rapidly to multifocal squamous cell carcinomas within dysplastic papillomas irrespective of the fibroblast genotype, whereas the initiated control genotypes formed well- differentiated papillomas. Malignant progression was not associated with mutations in the c-ras(Ha) gene, alterations in p53 protein, or loss of responsiveness to TGF-β1. The tumor cell labeling index was elevated in grafts of initiated null keratinocytes with wild-type fibroblasts compared to tumors of other genotypes. However, labeling index in all tumors was reduced when TGF-β1 null fibroblasts formed the stroma. The null tumor cells could not accumulate TGF-β1 from the host, but grafts of uninitiated null keratinocytes, which formed a normal epidermis, became TGF-β1 positive even though they did not express TGF-β1 mRNA. These results demonstrate that autocrine TGF-β1 suppresses the frequency and rate of malignant progression, and that autocrine and paracrine TGF-β1 can have opposing effects on tumor cell proliferation. The lack of paracrine inhibition of tumor cell progression appears to result from the inability of tumor cells to localize host-derived TGF-β1 by a mechanism that operates in normal cells.

AB - To study the contribution of autocrine and paracrine TGF-β1 to tumor progression in a well-defined system of multistage carcinogenesis, keratinocytes with a targeted deletion of the TGF-β1 gene were initiated in vitro with the v-ras(Ha) oncogene and their in vivo tumorigenic properties were determined by skin grafting initiated cells onto athymic mice in combination with either wild-type or null dermal fibroblasts. Grafts of v- ras(Ha)-initiated null keratinocytes progressed rapidly to multifocal squamous cell carcinomas within dysplastic papillomas irrespective of the fibroblast genotype, whereas the initiated control genotypes formed well- differentiated papillomas. Malignant progression was not associated with mutations in the c-ras(Ha) gene, alterations in p53 protein, or loss of responsiveness to TGF-β1. The tumor cell labeling index was elevated in grafts of initiated null keratinocytes with wild-type fibroblasts compared to tumors of other genotypes. However, labeling index in all tumors was reduced when TGF-β1 null fibroblasts formed the stroma. The null tumor cells could not accumulate TGF-β1 from the host, but grafts of uninitiated null keratinocytes, which formed a normal epidermis, became TGF-β1 positive even though they did not express TGF-β1 mRNA. These results demonstrate that autocrine TGF-β1 suppresses the frequency and rate of malignant progression, and that autocrine and paracrine TGF-β1 can have opposing effects on tumor cell proliferation. The lack of paracrine inhibition of tumor cell progression appears to result from the inability of tumor cells to localize host-derived TGF-β1 by a mechanism that operates in normal cells.

UR - http://www.scopus.com/inward/record.url?scp=0028171401&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028171401&partnerID=8YFLogxK

U2 - 10.1101/gad.8.20.2429

DO - 10.1101/gad.8.20.2429

M3 - Article

VL - 8

SP - 2429

EP - 2440

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 20

ER -