Duke researchers have identified 10 genes that may protect oxygen-deprived, or hypoxic, cancer cells--allowing them to thrive even when exposed to radiation and chemotherapy.
The results, published in the Journal of the National Cancer Institute, suggest that researchers could exploit the genes to treat patients with cancer.
"What we have provided is a more complete and quantitative picture of the transcriptional response to hypoxia," said lead investigator Dr. Greg Riggins, assistant professor of pathology and genetics. But he cautioned, "This work is in a very early stage. We are a gene discovery laboratory, and the potential applications of such work are many years down the road."
The scientists examined 24,504 genes expressed in oxygen-deprived brain cancer cells and identified 10 of them that were strongly activated, presumably those that could protect cell growth in oxygen-deficient conditions. Previously, researchers believed blood vessel generation, or angiogenesis, was regulated by a small group of genes, but the new findings suggest that there may be multiple ones at work.
"We observed a mixture of known and unknown genes, in particular three genes where only a complete or partial sequence was known, but no known function," Riggins said. "We also observed several genes that were known for their role in cancer or other diseases, but had not been known to be induced by hypoxia."
In order to grow, tumors depend on receiving oxygen from the blood supply. When this blood supply is cut off, tumors are starved of oxygen and consequently shrink or do not grow beyond a small size. Most solid tumors develop hypoxic regions in inaccessible areas, but other tumors continue to thrive in this situation by altering gene expression to induce angiogenesis. Radiation and chemotherapy are ineffective in treating these hypoxic sites.
Riggins and Anita Lal, a postdoctoral fellow in pathology, will continue to investigate the roles of these newly identified genes, which may clarify their mechanism for protecting tumors.
For example, one of the observed genes is a member of a family of proteins known to trigger blood vessel growth, which the researchers suspect may be secreted to stabilize the blood supply in response to hypoxia. Another gene called carbonic anhydrase may be involved in regulating the pH of tumors.
Furthermore, there are still questions about how these genes originated. Some believe genes may be mutations of normal-functioning genes. "Tumor cells may have mutations in some of the hypoxia-responsive genes so that those genes are either turned on all of the time, or they may not respond to a hypoxia stimulus," said research collaborator Mark Dewhirst, a professor of radiation oncology, pathology and biomedical engineering.
However, researchers express skepticism about the finding's immediate use in treating patients. "It is not likely that these discoveries will change treatment of patients with cancer in the near future. "We will have to learn a lot more about what they do," Dewhirst said.
"Once that is found, then these genes could become targets for tumor-specific therapy in the future, but that is speculation, at best."
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