A 'shift' in cancer knowledge
BETHESDA, Md.—Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is often associated with a poor prognosis for patients in the late stages of the disease, and recent research from The Cancer Genome Atlas (TCGA) Research Network has revealed that this may be due to the tumor cells' metabolism. ccRCC tumor cells appear to be capable of something known as a metabolic shift, in which the cells switch over from using one metabolic pathway to using another, a change that coincides with tumor stage and severity in some cases.
For this study, the researchers looked at almost 450 ccRCC tumors, comparing each with a normal sample from the same patient, and their examination found that low levels of AMPK, a protein essential to cell metabolism, and low levels of acetyl-CoA carboxylase, another protein, were linked to worse patient outcomes.
Dr. W. Marston Linehan, chief of the National Cancer Institute (NCI) Urologic Oncology Branch and one of the study's leaders, says that at present, the cause of the metabolic shift is unknown.
What they do know, Linehan notes, is that "the metabolic shift was seen in patients with high- grade, high-stage clear cell kidney cancer with decreased survival," or poor prognosis tumors. The study also indicated changes in Krebs cycle enzyme levels, which Linehan says "could indicate impairment of the normal metabolic process that the cell uses to generate energy," and there may also be an association between alteration in chromatin remodeling genes—mutation of the chromatin remodeling gene BAP1 is also linked to a poor prognosis—and metabolic shift in ccRCC, which Linehan calls "a fascinating possibility."
Additionally, according to Linehan, ccRCC is not the only type of cancer known to demonstrate a metabolic shift.
"There are two other types of kidney cancer that are characterized by a metabolic shift to aerobic glycolysis. These types of kidney cancer, which are characterized by mutation of Kreb's cycle enzymes, undergo a metabolic shift to an increased dependence on metabolism of glucose for energy production. This is referred to as the 'Warburg effect' in cancer and is the source of great interest in the field," Linehan explains.
The researchers also discovered that in select cases, this metabolic shift might be the result of changes in the PI3K cellular pathway, which regulates cell metabolism and is also linked to apoptosis and several types of cancer. Several changes were noted in the genes in the PI3K pathway and its regulators in tumor cells, including DNA mutations in protein-coding areas and other changes that affect gene expression. Alterations were found in either the PI3K pathway or AKT and mTOR, its partner pathways, in 29 percent of tumor samples.
The study also showed a decrease in factors that activate tumor suppressor genes, while at the same time, factors that activate PI3K pathway inhibitor genes were blocked, two changes that promote activity in the PI3K/AKT/mTOR pathways.
Linehan notes that all three of these pathways represent possible therapeutic targets, with two agents that target the mTOR pathway as a treatment for advanced kidney cancer having already secured approval and additional agents under evaluation that target the PI3K pathway and both pathways simultaneously.
"Earlier findings from the characterization of other types of cancers have given us important clues as to how to design better therapies for these cancers," NCI Director Dr. Harold Varmus, commented in a statement. "The new results from the TCGA analysis of clear cell renal cell carcinomas provide an explanation for how mutations in certain genes can alter chromosome chemistry to produce changes in enzyme levels that affect cell metabolism in ways correlated with clinical outcomes. These findings will stimulate some novel ideas about therapies for other lethal cancers."
Linehan says this research is moving forward in several directions. Researchers at a variety of institutions are engaging in further study of the metabolic basis of ccRCC, as well as the gene pathways involved and "the role of chromatin remodeling genes in the initiation and/or progression of clear cell kidney cancer."
"The molecular analysis of this disease impacts understanding of all cancers through furthering insights into the role of metabolic perturbation in malignancy," said Dr. Richard A. Gibbs, a lead investigator for the project and director of the Human Genome Sequencing Center at Baylor College of Medicine in Houston.