Recent Publications

Bissell MJ, Radisky D. Putting tumours in context.
Nat Rev Cancer. 2001 Oct;1(1):46-54.

Radisky D, Muschler J, Bissell MJ. Order and disorder: the role of extracellular matrix in epithelial cancer. Cancer Invest. 2002;20(1):139-53

Sternlicht MD, Bissell MJ, Werb Z. The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter. Oncogene. 2000 Feb 21;19(8):1102-13.

Lochter A, Werb Z, Bissell MJ. Transcriptional regulation of stromelysin-1 gene expression is altered during progression of mouse mammary epithelial cells from functionally normal to malignant. Matrix Biol. 1999 Oct;18(5):455-67.

Sternlicht MD, Lochter A, Sympson CJ, Huey B, Rougier JP, Gray JW, Pinkel D, Bissell MJ, Werb Z.
The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell. 1999 Jul 23;98(2):137-46.

While normal stroma can delay or prevent tumorigenesis, abnormal stromal components can promote tumor growth. Acquired or inherited mutations that alter stromal cell function can release the context-suppressed malignant cells. Literature spanning more than a century has shown that inflammation associated with tissue wounding can produce tumours.

Matrix metalloproteinases (MMPs) can degrade ECM and are involved in promoting the inflammatory response, normal tissue remodelling, wound healing and angiogenesis. These enzymes also play an important role in malignancy, however. The sustained presence of these proteases in the tumor environment, produced both by the activated cells and by the cancer cells themselves, leads to destruction of normal ECM. Degradation of ECM stimulates both proliferative and apoptotic mechanisms, which can lead to the selection of apoptosis-resistant carcinoma cells and enhanced invasive potential. In the tumor context, direct association of MMPs with specific ECM receptors provides spatial control of MMP activity and directional signals to the invading tumor cells44.
Stromelysin-1 (SL-1, also known as MMP-3), is an MMP that is involved in both mammary gland development and breast cancer. In transgenic mice that express SL-1 in mammary luminal epithelial cells (WAP-SL-1), the mammary glands show morphogenesis defects and contain pre-neoplastic lesions that eventually lead to full malignancies (Figure a). Here, the causative mechanism appears to be that SL-1 — expressed ectopically at low levels in the epithelial cells — is subsequently produced at much higher levels by the stromal fibroblasts, showing that a moderate disruption contributes to a self-sustaining tumorigenic state. Similar reciprocal feedback mechanisms have been observed in transgenic mice with altered expression of MMP-7, MMP-11, and MT1-MMP. CGH analysis of tumors from different WAP-SL-1 transgenic mice revealed common patterns of genomic rearrangements (Figure b), showing that extracellular SL-1 could directly act to induce gennomic instability. Experiments using cultured cells have shown that cellular context determines the response of mammary epithelial cells to SL-1 treatment: when grown in basement membrane gels, mammary epithelial cells undergo growth arrest and become functionally differentiated; subsequent treatment of these cells with SL-1 causes apoptosis47. However, when cultured on two-dimensional matrices and allowed to continuously proliferate, mammary epithelial cells react to treatment with SL-1 by undergoing an epithelial–mesenchymal transition (Figure c) and becoming tumorigenic. Current experiments suggest that SL-1-mediated conversion to the mesenchymal phenotypic is accompanied by acquisition of genomic instability, and the underlying mechanism is a current topic of investigation.