TIMP-1 Alters-Susceptibility to Carcinogenesis

Jin Sae Rhee, Robert Diaz, Lidiya Korets, J. Graeme Hodgson, Lisa Coussens

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Tissue inhibitors of metalloproteinases (TIMPs) are a family of multifunctional proteins known to possess a broad range of biological activities, including inhibition of metalloproteinase activity, regulation of proliferation and apoptosis of a variety of cell types, and, depending on the context, differential regulation of angiogenic and inflammatory responses. Elevated mRNA expression of TIMP family members correlates with malignancy and clinical outcome in many human cancer types; however, a protective role for TIMPs also has been observed in various mouse models of human cancer. In the current study, we found distinct spatial-temporal expression patterns for the mRNA of TIMP family members in a mouse model of epithelial carcinogenesis [i.e., keratin 14-human papillomavirus 16 (K14-HPV16) transgenic mice]. To test the hypothesis that elevated expression of TIMP-1 functionally regulates epithelial carcinogenesis, we introduced a human TIMP-1 transgene into K14-HPV16 transgenic mice and assessed neoplastic progression. Results from these studies suggest that TIMP-1 enhances tumorgenicity by potentiating keratinocyte hyperproliferation and appearance of chromosomal aberrations in premalignant cells, thereby increasing their risk to undergo malignant conversion. In addition, TIMP-1 inhibits tissue gelatinolytic activity in tumor stroma, affects stabilization of collagen fibrils, but does not inhibit malignant conversion of dysplasias into carcinomas or development of metastases. The combined implications of these studies suggest that TIMP-1 is an important contributor to epithelial neoplastic progression and supports the concept that TIMP-1 exerts differential regulation on tissues in a stage-dependent manner.

Original languageEnglish (US)
Pages (from-to)952-961
Number of pages10
JournalCancer Research
Volume64
Issue number3
DOIs
StatePublished - Feb 1 2004
Externally publishedYes

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Tissue Inhibitor of Metalloproteinase-1
Tissue Inhibitor of Metalloproteinases
Carcinogenesis
Keratin-14
Human papillomavirus 16
Transgenic Mice
Neoplasms
Messenger RNA
Metalloproteases
Transgenes
Keratinocytes
Chromosome Aberrations
Collagen
Apoptosis
Neoplasm Metastasis
Carcinoma
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

TIMP-1 Alters-Susceptibility to Carcinogenesis. / Rhee, Jin Sae; Diaz, Robert; Korets, Lidiya; Hodgson, J. Graeme; Coussens, Lisa.

In: Cancer Research, Vol. 64, No. 3, 01.02.2004, p. 952-961.

Research output: Contribution to journalArticle

Rhee, JS, Diaz, R, Korets, L, Hodgson, JG & Coussens, L 2004, 'TIMP-1 Alters-Susceptibility to Carcinogenesis', Cancer Research, vol. 64, no. 3, pp. 952-961. https://doi.org/10.1158/0008-5472.CAN-03-2445
Rhee, Jin Sae ; Diaz, Robert ; Korets, Lidiya ; Hodgson, J. Graeme ; Coussens, Lisa. / TIMP-1 Alters-Susceptibility to Carcinogenesis. In: Cancer Research. 2004 ; Vol. 64, No. 3. pp. 952-961.
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