Membrane protein as a tumor marker

New findings for tailor-made treatment of human tumors

Staining of a tissue section of a patient with rhabdomyosarcoma. The binding of an Eag1-specific antibody attached to the alkaline phosphatase causes a color reaction and appears in the picture as a dark blue discoloration. The discoloration marks only tumor cells, whereas the adjacent healthy tissue is not labeled. The Eag1 antibody thus clearly marks the tumor. © Max Planck Institute for Experimental Medicine
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A specific cell membrane protein, the so-called Eag1 channel, frequently occurs in tumor cells and appears to play an important role in the development of cancer. This has now been discovered by an international team of scientists. However, the researchers have not only found a new approach to detecting and diagnosing cancer. Since Eag1 inhibition leads to a reduction in tumor growth, the channel protein could also be a promising approach for the tailor-made treatment of human tumors.

Ion channels often play a role in the development of various diseases. They are well-suited as therapeutic targets because they are easily accessible, cell-surface-expressed molecules that are relatively easy to attack with drugs. A number of ion channels are already known to be associated with tumors. Eag1 is now the first ion channel directly related to tumor progression.

No unwanted side effects?

Using reverse transcription real-time (PCR) methods and specially designed and modified anti-Eag1 monoclonal antibodies, scientists have demonstrated that the expression of the human Eag1 potassium channel, also known as KCNH1 or Kv10.1, is normally targeted to specific brain regions and regions isolated certain cell populations in the body is limited. Because of this exceptional distribution of Eag1-expressing cells, the undesirable side effects of therapies could be avoided.

To evaluate the relevance of Eag1 as a possible approach to cancer therapy, the researchers studied the distribution and frequency of expression of the Eag1 channel in normal tissue and in a large number of tumor tissue samples using molecular biological and immunohistochemical techniques. Of a total of 756 patients, 77 percent of cases showed strong overexpression of the canal. This exceptional frequency is probably due to the fact that the Eag1-expressing cells have a higher survival rate and therefore have a selection advantage. This is supported by the fact that those cells, which were taken only months after the first malignant changes, have a significantly higher proportion of Eag1-expressing cells.

In the second publication, scientists used the same specific monoclonal antibodies to determine expression levels of Eag1 in soft tissue sarcomas. Soft tissue sarcomas are rare tumors (less than one percent of all cancers) with poor prognoses - over 40 percent mortality in the first year after diagnosis. The relatively small number of cases and the great variety of their appearance, anatomical position and biological behavior make a comprehensive understanding of this disease extremely difficult. Physicians and patients still have limited therapeutic options that offer little improvement in survival. display

Correlation between Eag1 expression and low life expectancy

Eag1 was expressed in 71 percent of the 210 sarcomas examined. The incidence of Eag1 ereberexpression in soft tissue tumors ranges from 56 percent (liposarcoma) to 82 percent (rhabdomyosarcoma). The differences in expression levels can only be linked to the histological type, but not to the sex or age of the patients, the degree of malignancy or the size of the tumor. For some histological types, researchers found a correlation between Eag1 expression and low life expectancy. As in the first study, the cell types that cause sarcoma do not show Eag1 expression.

As examples of relevant histological types (fibrosarcoma and rhabdomyosarcoma), the researchers have finally tested four cell lines with reverse transcription real-time PCR as positive for Eag1 expression. In addition, suppression of Eag1 expression by RNA interference in these cells resulted in a decrease in cell proliferation.

Eag1 channels directly involved in cell growth

Taken together, these results show that the Eag1 channels are directly involved in cell growth. The findings suggest that Eag1 plays an important role in the conversion of normal cells into tumor cells. Outside the brain, Eag1 channels only occur in very few cell types. In contrast, tumor cells of very different kinds express Eag1 channels at a higher frequency than the usual tumor markers. As a result, Eag1 offers a new approach to detecting and diagnosing cancer. Moreover, it is a transmembrane protein and therefore accessible from outside the tumor cells.

Normal cells expressing Eag1 are either protected by the blood-brain barrier or represent the final stage of normal development. These facts, as well as the knowledge that Eag1 inhibition leads to a reduction in tumor growth, mean that this channel protein represents a promising approach for tailor-made treatment of human tumors. Moreover, therapies based on this should only cause a minor side effect.

(idw - MPG, 18.10.2006 - DLO)