Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: The role of extracellular matrix and its degrading enzymes

M. J. Bissell, P. A. Kenny, D. C. Radisky

Research output: Contribution to journalArticle

195 Citations (Scopus)

Abstract

It is now widely accepted that elements of the cellular and tissue microenvironment are crucial regulators of cell behavior in culture and homeostasis in vivo, and that many of the same factors influence the course of tumor progression. Less well established is the extent to which extracellular factors actually cause cancer, and the circumstances under which this may occur. Using physiologically relevant three-dimensional culture assays and transgenic animals, we have explored how the environmental and architectural context of cells, tissues, and organs controls mammary-specific gene expression, growth regulation, apoptosis, and drug resistance and have found that loss of tissue structure is a prerequisite for cancer progression. Here we summarize this evidence and highlight two of our recent studies. Using mouse mammary epithelial cells, we show that exposure to matrix metalloproteinase-3 (MMP-3) stimulates production of reactive oxygen species (ROS) that destabilize the genome and induce epithelial-mesenchymal transition, causing malignant transformation. Using a human breast cancer progression series, we find that ADAM-dependent growth factor shedding plays a crucial role in acquisition of the malignant phenotype. These findings illustrate how normal tissue structure controls the response to extracellular signals so as to preserve tissue specificity and growth status.

Original languageEnglish (US)
Pages (from-to)343-356
Number of pages14
JournalCold Spring Harbor Symposia on Quantitative Biology
Volume70
DOIs
StatePublished - 2005
Externally publishedYes

Fingerprint

extracellular matrix
Extracellular Matrix
Tumors
Tissue
neoplasms
Enzymes
enzymes
Neoplasms
Breast
breasts
Cellular Microenvironment
Matrix Metalloproteinase 3
Organ Specificity
Genetically Modified Animals
Epithelial-Mesenchymal Transition
stromelysin 1
Gene Expression Regulation
Growth
transgenic animals
Drug Resistance

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

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