Chemoresistance, or the ability of a tumor cell to withstand medications aimed at it, and metastasis, the spread of secondary tumors through the body, often are seen as separate problems of cancer. But "they are probably linked together, as opposed to completely independent mechanisms," Yibin Kang told BioWorld Today.
Kang is an assistant professor of molecular biology at Princeton University and the senior author of a paper in the Jan. 6, 2009, issue of Cancer Cell describing one protein that has a role in both both chemoresistance and metastasis in breast cancer: metadherin.
Kang and his team identified metadherin as a culprit in both processes by first combining the data from several studies on gene signatures of poor-prognosis breast cancers, looking for genes with altered copy numbers through bioinformatic approaches. The approach, Kang explained, "translates differential gene expression into recurrent genomic alterations."
That is, a gene that is overexpressed in cancer patients may be so because the tumor has more copies of it than a regular cell.
Kang and his team first used computational methods to identify 8q22 as a region that is duplicated in more than 30 percent of tumor samples from breast cancer patients, and contributes to a poor prognosis for patients. They then confirmed that high expression levels of metadherin, which contains the 8q22 marker, were indeed due to copy number variations rather than aberrant downstream regulation of the gene.
Kang said that whether protein levels are high due to copy number variations or transcriptional changes "shouldn't matter in most cases." The exception, he added, are when protein levels are high due to changes in regulation of expression, and a drug exists that can target the pathway. Such drugs "may be more effective in targeting genes that are activated transcriptionally, instead of through copy number changes."
When breast cancer cells with knocked-down metadherin were injected into the bloodstream of mice, they formed fewer lung metasases than control cells, showing that metadherin helps cells metastasize.
Cells with more metadherin were able to cling to endothelial cells from several sources better than those who had less of the protein, leading Kang to suspect that the protein is "probably going to play a broader role" in metastasis, rather than one that is limited to the lung.
By a separate mechanism, metadherin also helps cancer cells resist the effects of chemotherapy. When the scientists simultaneously implanted cancer cells with knocked-down or normally expressed metadherin, then treated them with the cancer drugs paclitaxel or doxorubicin, the cells expressing metadherin grew more rapidly than those that did not. In mice that were not treated with chemotherapy, both types of cells grew at an equal rate, indicating that metadherin does not somehow cause cells to divide more rapidly.
Metadherin appears to promote resistance to chemotherapy by up-regulating other proteins. The scientists found that high levels of metadherin led to high levels of aldehyde dehydrogenase 3a and hepatocyte growth factor receptor, both of which are known culprits in chemoresistance.
Kang said that in the short run, metadherin - which he compared to Her2 - could be a useful diagnostic marker. In the longer term, he hopes that the protein can serve as a useful therapeutic target as well. He and his colleagues, who are from Princeton, the Robert Wood Johnson Medical School, the New Jersey Cancer Institute and Ohio State University, are in the process of setting up industry collaborations to further metadherin's practical use.
"Resistance to chemotherapy and metastasis remain major challenges to curative therapy," he said. "These findings establish [metadherin] as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk."