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Robert Weinberg: Research Can Begin to Rationalize Complex Process of the Development of Metastases

"The process of tumor metastasis has until recently been one of bewildering complexity. However, one can now begin to rationalize this complex process in terms of a relatively small number of master control genes which normally operate during normal development and which are appropriated and exploited by cancer cells", Dr. Robert Weinberg, a pioneer in cancer research from the Whitehead Institute for Biomedical Research, Cambridge, USA, said in Berlin.

The reason for this is the discovery of transcription factors in the last few years. "Transcription factors are proteins that turn genes on and off and can act to program many of the traits of highly malignant cells", as described by Dr. Weinberg, who is also a Professor at the Massachusetts Institute of Technology (MIT).

He delivered the key note lecture at the opening of the International Conference on "Invasion and Metastasis" of the Max Delbrück Center for Molecular Medicine (MDC) in Berlin, Germany on Wednesday evening (March 26). He is most widely known for his discoveries of the first human oncogene - a gene that causes normal cells to form tumors - and the first tumor suppressor gene.

In 2007, almost 560,000 Americans and more than 1,8 million Europeans died of cancer, according to the American Cancer Society.

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"The vast majority (90 percent) of these patients were struck down by metastases, cancer cells that have disseminated and colonized in organs far from the primary tumor", Dr. Weinberg pointed out. "Only ten percent of cancer patients die of their primary tumors".

The majority of life-threatening cancers about 80 per cent, occur in epithelial tissue. Epithelial cells cover the outside of the body, skin cells, and line the inner organs such as breast glands, the colon, the prostrate, and blood and lymph vessels. But what exactly enables cancer cells to leave the primary tumor and "travel by the body's highways - the blood and the lymphatic vessels -", as Dr. Weinberg put it, to seek new sites where they may found new colonies?

Drastic change of the cell's traits

Recent research suggests that a drastic alteration of the primary cancer cells (called epithelial- mesenchymal transition or EMT) plays a crucial role in this complex biological process. "The EMT involves a profound change in the biological phenotype of cells in which they shed their epithelial traits together with their gene expression pattern and acquire mesenchymal ones instead", Dr. Weinberg explained.

Special epithelial markers, like E-cadherin and beta-Catenin, are depressed. These markers normally keep the epithelial cells tightly together. The mesenchymal state frees these cells to move about and to invade other tissues, and also makes them resistant to apoptosis, programmed cell death. "This pathological process is strikingly similar to the EMT normally occurring during embryogenesis and wound healing", said Weinberg.

EMT is an important program which enables carcinoma cells to become mobile and invasive. "Nonetheless, it is still unclear whether EMT underlies the malignant behavior of all carcinoma cells or whether alternative programs are activated to enable metastatic dissemination," Dr. Weinberg pointed out.

Many other questions still remain: Why do breast cancers typically metastasize in the brain, liver, bones, and lungs, prostrate cancers in the bones, and colon carcinomas in the liver? Why, after many years, do some micrometastases develop into macrometastases, which eventually lead to patient death? And, finally, why do some cancers not develop any metastases at all?

Altogether, about 160 scientists from Europe, Israel, Japan, the USA, Singapore, and Turkey participate in the conference which runs from March 26th through March 29th . The conference organizers are Prof. Walter Birchmeier and Dr. Ulrike Ziebold (both Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch) and Prof. Jürgen Behrens (University of Erlangen). Both Prof. Birchmeier and Prof. Behrens have published significant results about the formation of metastases during the past years. The conference is funded by the Deutsche Krebshilfe (German Cancer Research Foundation) and the Deutsche Forschungsgemeinschaft (DFG).

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

Barbara Bachtler | idw
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