From Hydra to Humans

They are fairly ubiquitous as they occur from hydra (polyps) to humans. However, they also play a crucial role in the development of cancer and in metastasis. These enzymes are called matrix metalloproteases (MMPs). The name refers to one of their many abilities: they are able to degrade proteins of the extracellular matrix (ECM), a foundation in which cells are embedded. And their catalytic activity depends on metal ions. Hopes have been high of preventing these enzymes from promoting tumours by administering specific inhibitors. “However, results achieved in animal and clincial trials have been disappointing”, Professor Zena Werb from the University of California in San Francisco, USA, said at an international conference on “Cell Migration in Development and Disease” of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch on Friday, November 30, 2001. “But far more mechanisms remain unidentified or unproven, thus leaving the field ripe for important new insights and further progress,” the researcher is convinced.

“The ability of enzymes such as MMPs to degrade extracelluar proteins of the ECM thus recognizing and eliminating defective, unassembled or misfolded proteins is essential for any individual cell to interact properly with its immediate surroundings and for multicellular organisms to develop and function normally”, Prof. Werb explained. MMPs influence embryo and tissue development and wound repair, for example. “However, if this socalled proteolytic mechanism is inapproppriate it can cause or exacerbate a number of diseases such as inflammatory conditions or cancer.

“Cancer is a rare occurence in an average lifetime”

 “MMPs are generally present in greater amounts and activated more often in and around tumours than in normal tissues”, Prof. Werb pointed out. This is due to the fact, that “most, if not all cancers, acquire the same set of functions during their development”, she said. The steps needed for a tumour cell to survive and grow are: enhancement of growth signalling during excessive formation of cells (hyperplasia) and abnormal development (dysplasia), tissue invasion, enriched growth of blood vessels (angiogenesis) which ensures the tumour`s nourishment, and also metastasis. According to Prof. Werb “each of these steps represent an evasion of normal regulation in cells and tissues”. “Breaching in all steps is unlikely to happen by accident, and thus, this multi-layered protection is virtually fail-safe and might explain why cancer is a rare occurence in an average lifetime”.

MMPs clearly play a role in metastatic processes

Researchers have been able to elucidate many processes that promote the onset of cancer. They have shown that fibrotic and inflammatory processes and also some familial cancer syndromes increase the risk for cancer. “They are the result of gene defects that produce changes in stromal cells - they support and nourish endothelial cells - before changes in epithelial cells ever occur”, Prof. Werb pointed out. “In epithelial cancers MMPs are expressed by the supporting stromal cells rather than by the tumour cells themselves”. “So it happens, that MMPs from adjacent stromal cells are often induced and commandeered by the malignant epithelial cells.” Therefore, researchers assume that the rise in MMP activity in stromal cells may contribute to cancer susceptiblity. But MMPs clearly play a role in metastatic processes. Their ability to break down the physical barriers of the extracellular matrix enables tumour cells to leave their site of origin and invade tissue or organs at distant sites.

Obesity is now recognized as an important risk factor for a variety of medical problems including cardiovascular diseases, such as hypertension and diabetes. "It is the most important risk factor for the development of type-2 diabetes", Prof. Seidell said. Given the increase in obesity, WHO currently predicts that the worldwide prevalence of diabetes will increase from 140 million in 1997 to about 300 million in 2025.

Considerable progress has been made in elucidating the processes involved in  the degradation of the ECM and the role and function of MMPs in normal development and disease.  “The challenge now is to determine exactly which of the many potential mechanisms and reactions regulate the physiologic and pathologic processes”, Prof Werb stressed.

Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC)
Berlin-Buch
Robert-Rössle-Straße 10; 13125 Berlin; Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax:  +49 (0) 30
94 06 - 38 33
e-mail: presse@mdc-berlin.de
http://www.mdc-berlin.de/englisch/about_the_mdc/public_relations/e_index.htm