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Split molecule on an evil mission

How an important tumor factor speeds up cancer growth

Munich, 01/13/2009

Cancer cells originate from perfectly normal body cells, which is what makes them so difficult for the immune system or drugs to combat. However, they do bear certain differences – and these differences can be exploited as targets for drugs. We see with particularly high frequency, for example, that tumor cells abundantly express the transmembrane protein EpCAM, short for “epithelial cell adhesion molecule”. Its excessive presence is a tragic omen for cancer patients. Yet, it has so far been unclear exactly what molecular functions EpCAM performs in tumor cells.  An international group led by Dr. Olivier Gires, a researcher at Helmholtz Zentrum München (Translational Research Group for Molecular Oncology) and LMU, has now shown, in cooperation with Micromet, a Munich-based biotechnology company, how this molecule speeds up cell division – and with it cancerous growth. “This function of EpCAM could explain why the protein is so frequently produced in such abundance by tumor cells,” says Gires. “The protein is already a target for therapeutic antibodies being investigated as drug candidates. But the new findings into EpCAM’s function ought to significantly improve any ongoing work on therapeutic agents, and make it easier to prevent undesirable side-effects.”

Stem and precursor cells are undifferentiated cells that can develop into any type of cell in the body. They carry high quantities of the protein EpCAM in their membrane. As soon as stem cells become differentiated tissue cells, they largely stop expressing EpCAM. “The protein’s production is under strict control,” says Gires. “It probably only appears temporarily while the cell is in a proliferation phase – that is, when it is growing and dividing.” It appears, however, that some cells can evade this strict regulation. Very frequently, it turns out, cancer cells and their precursors produce EpCAM in great abundance. Among others, this holds true for carcinomas, which account for about 80 percent of all malignant tumors.

It has long been known that excessive production of EpCAM is typical to many types of cancer, such as colonic or breast tumors. What has not been known, however, is what this protein’s actual molecular function is in cancer cells. Because EpCAM in healthy tissue is important for cell adhesion, holding cells together, the prevailing assumption has been that it must have a similar function in tumors –  this assumption, however, neither explained the high-frequency and high-level expression of EpCAM seen in cancer, nor does this knowledge improve the prognosis for patients with EpCAM-harboring cancer cells.

The previous work of a research group headed by Gires already showed that EpCAM plays an important role in carcinogenesis. Among other things, the protein activates the gene c-myc, which then leads to cell proliferation. In the present work, the researchers managed to explain in detail the molecular basis for effects mediated by EpCAM. It turns out, for example, that this transmembrane protein is split into two parts by two enzymes. The EpEX part outside the cell comes loose. The EpICD part released inside the cell migrates – aided through several steps by factors of the so-called Wnt signal path – into the nucleus, where it regulates the transcription of c-myc and other genes.

“This effect does not occur in healthy colon cells, for example,” Gires reports. “One possible explanation is that they lack certain factors that allow EpICD to penetrate into the nucleus. It has been demonstrated in colonic carcinoma patients, for instance, that EpICD only migrates into the nucleus in tumor cells, but not in healthy cells.” Just how important this transmembrane protein is to the onset of cancer becomes fully appreciable when we consider the fact that both EpCAM and the fragment EpICD can trigger tumors when injected into immunodeficient mice.

“So far, the predominant view has been that EpCAM is a relatively inert molecule that is only important for cell adhesion,” Gires says. “This perception is now certain to change radically. Our results demonstrate why EpCAM is produced so frequently and in such abundance in carcinomas. Our findings on the exact function of the protein could also significantly improve the development of therapeutic agents – and also make it easier to prevent undesirable side-effects of these agents.”

The fact that cancer stem cells severely over-express EpCAM in combination with other markers can only serve to arouse further interest in this signaling protein. Evidence has namely been mounting over several years that these mutant stem cells are essential in the formation of all malignant tumors, and for their reappearance after therapy. Cancer stem cells are accordingly highly promising new targets for therapeutic approaches. “EpCAM is entering a new era”, Gires declares.

“Nuclear signalling by tumour-associated antigen EpCAM”,
Dorothea Maetzel, Sabine Denzel, Brigitte Mack, Martin Canis, Philip Went, Michael Benk, Cuong Kieu, Peer Papior, Patrick A. Baeuerle, Markus Munz and Olivier Gires,
Nature Cell Biology online, 11 January 2009

PD Dr. Olivier Gires
Helmholtz Zentrum München, Translational Research Group for Molecular Oncology
LMU Department of Otorhinolaryngology, Head and Neck Surgery
Tel.: ++49 (0) 89 / 7095-3895
Fax: ++49 (0) 89 / 7095-6896

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