It has become evident that the tissue surrounding a tumour can have as important a role in its development as the genetic changes that occur in the cancer cells themselves. How does the microenvironment mediate these carcinogenic effects? Derek Radisky et al. report in Nature that, in mammary tissue, overproduction of matrix metalloproteinase-3 (MMP3) causes surrounding cells to increase production of reactive oxygen species (ROS), leading to DNA damage and genomic instability, and eventually to malignant transformation.

MMPs are extracellular-matrix-degrading enzymes that are produced by the tumour stroma and have well-known roles in late-stage tumour progression, promoting cell recruitment and invasion, and metastasis. Radisky et al. have been trying to determine how some MMPs, such as MMP3, can also directly transform mammary epithelial cells.

Changes in the morphology of MMP3-transformed mammary epithelial cells indicated that alterations in a cytoskeletal regulatory protein might be involved. In examining expression levels of a number of cytoskeletal regulators, the authors found that an alternatively spliced form of the GTPase RAC1 (RAC1b) was overproduced in MMP3-transformed cells. Interestingly, this isoform had been previously reported to be upregulated in human breast- and colorectal-tumours, and to have transforming capabilities in cultured cells.

How could RAC1b mediate transformation? In addition to its roles in regulating formation of cytoskeletal structures, RAC1 can also stimulate production and release of mitochondrial superoxide into the cytoplasm. The authors showed that treatment of cells with MMP3 produced RAC1-dependent increases in cellular levels of ROS, which led to various cellular changes that are associated with tumorigenesis: altered expression of transcription factors, induction of the epithelial to mesenchymal transition, along with increased cell motility and invasiveness. All these changes were prevented with the ROS-quenching agent N-acetyl cysteine (NAC). Most importantly, MMP3-induced ROS production also led to DNA damage, as well as genomic amplifications and deletions in cells — hallmarks of tumorigenesis.

It is still not clear how increased extracellular levels of MMP3 upregulate this alternative splice product of RAC1, although it could be through the ability of MMP3 to cleave the extracellular receptor protein E-cadherin ( CDH1 ), which initiates an intracellular signalling cascade. The search is now on for other microenvironmental factors that can also stimulate phenotypic and genotypic transformation of normal cells.