NEW YORK (Reuters Health) - The Twist gene, normally active as a master regulator of embryonic morphogenesis, plays a key role in tumor metastasis, according to a report in the June 25th issue of Cell.
“The mechanisms of invasion and metastasis seemed impossibly complex several years ago,” Dr. Robert A. Weinberg from Whitehead Institute for Biomedical Research, Cambridge, Massachusetts told Reuters Health, “but now there is the prospect of understanding much of this in terms of the workings of a small number of genes.”
Dr. Weinberg and colleagues used a mouse mammary tumor model to investigate the possible role of the transcription factor Twist in regulating metastasis.
Twist was differentially expressed in mammary tumor cell lines that metastasize but not in one that does not metastasize, the authors report, and increased expression of Twist correlated with tumor invasion and metastasis.
Blocking Twist with Twist short hairpin-interfering RNA (siRNA) suppressed Twist expression to an undetectable level and markedly reduced the metastatic potential of mammary tumor cells, the report indicates, without reducing the proliferative capacity of the tumor cells.
Suppression of Twist expression also limited the ability of mammary tumor cells to gain access to the blood circulation, the researchers note.
In kidney epithelial cells and in immortalized human mammary epithelial cells, the results indicate, Twist expression induced a loss of cell-cell adhesion and an epithelial-mesenchymal transition (EMT), which is thought to contribute to the dissemination of carcinoma cells from epithelial tumors.
The investigators also report elevated Twist expression in 70% of invasive lobular carcinomas, 32% of invasive ductal carcinomas, and 30% of mixed ductal/lobular carcinomas, based on data from 57 invasive human breast tumor samples.
“Together,” the authors conclude, “the present evidence leads us to propose that activation of Twist and Twist-induced EMT are important components of tumor metastasis.”
“Cancer cells aren’t as clever as they’ve been portrayed to be,” Dr. Weinberg said. “Thus, they do not put together the invasion-metastasis program out of whole cloth. Instead, they simply reactivate a latent embryonic program that provides them with most of the capabilities that they require to execute the invasion-metastasis cascade - the sequence of events that leads a cancer cell from its origins in the primary tumor to its arrival at a distant tissue where it may attempt to undertake the formation of a metastatic colony.”
In ongoing research, Dr. Weinberg said, “We wish to learn two things. First, how do cancer cells acquire the ability to turn on Twist expression in the first place? Second, once Twist expression is on, how does Twist impose its will on the cell by reprogramming the expression of many genes and dramatically changing cell behavior?”
Source: Cell 2004;117:927-939. [ Google search on this article ]
MeSH Headings:Biological Sciences: Biology: Breast Neoplasms: Gene Expression Regulation: Genetics: Genetics, Biochemical: Molecular Biology: Neoplasms: Neoplasms by Site: Biological Sciences: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
