Investigators in The Cancer Genome Atlas (TCGA) Research Network have uncovered a connection between how tumor cells use energy from metabolic processes and the aggressiveness of the most common form of kidney cancer, clear cell renal cell carcinoma. Their findings demonstrate that normal metabolism is altered in clear cell renal cell carcinoma tumor cells, and involves a metabolic shift that correlates with tumor stage and severity in some cases.
The scientists also found mutations in a pathway that may cause increased aggressiveness in this cancer. Taken together, the findings may offer new insight into underlying disease mechanisms and potential treatments as well as an understanding of how some cancer cells can shift from using normal metabolic pathways to alternative pathways, thereby providing a growth advantage to tumor cells
The scientists used data generated by TCGA, a collaborative effort funded by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI). The results of this study were published online June 23, 2013, in Nature.1
In the study, scientists examined nearly 450 clear cell renal cell carcinoma tumors and matched each with a normal sample from the same patient. When they looked at the amounts of specific proteins expressed in cancer cells, they found that low levels of AMPK, a protein essential to cell metabolism, and high levels of acetyl-CoA carboxylase were associated with worse patient outcomes.
“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,” said NCI Director Harold Varmus, MD. “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.”
Shifts in PI3K Pathway
In addition to the connection between metabolic shift and tumor aggressiveness, TCGA Research Network scientists discovered that, in some cases, the metabolic shift may be caused by changes in the PI3K cellular pathway, which helps regulate cell metabolism. The investigators observed a number of changes in PI3K pathway genes and its regulators in tumor cells, including DNA mutations in protein-coding areas and other changes affecting gene expression. They found such alterations in the PI3K pathway—or its partner pathways, AKT and mTOR—in 29% of tumor samples.
The effects of these changes show the importance of the PI3K/AKT/mTOR pathways. For example, researchers found a decrease in factors that activate tumor-suppressor genes. At the same time, factors activating genes that inhibit the PI3K pathway were blocked. Both of these changes promote activity in the PI3K/AKT/mTOR pathways. The results suggest the pathways’ potential as therapeutic targets with inhibitor drugs.
Potential for Novel Therapies
W. Marston Linehan, MD, Chief of the NCI Urologic Oncology Branch and one of the study’s leaders, sees several implications from the results. “The finding of a metabolic shift in the aggressive tumors could provide the foundation for the development of a number of novel approaches to therapy for patients with advanced kidney cancer,” said Linehan.
New therapies are especially important since advanced kidney cancer is often resistant to chemotherapy. The TCGA data offer insights into various global processes occurring in kidney cancer and can show how different tumor pathways intersect.
“The molecular analysis of this disease impacts understanding of all cancers through furthering insights into the role of metabolic perturbation in malignancy,” said Richard A. Gibbs, PhD, another lead investigator in the project and Director of the Human Genome Sequencing Center at Baylor College of Medicine, Houston. ■
Disclosure: The study authors reported no potential conflicts of interest.
1. The Cancer Genome Atlas Network: Integrative analysis of genomic and molecular alterations in clear cell renal cell carcinoma. Nature. June 23, 2013 (early release online).