A 'shift' in cancer knowledge

TCGA researchers discover that the tumor cells of clear cell renal cell carcinoma, the most common form of kidney cancer, are capable of metabolic shifts--switching from one metabolic pathway to another

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BETHESDA, Md.—Clear cell renal cell carcinoma (ccRCC), themost common form of kidney cancer, is often associated with a poor prognosisfor patients in the late stages of the disease, and recent research from TheCancer Genome Atlas (TCGA) Research Network has revealed that this may be dueto the tumor cells' metabolism. ccRCC tumor cells appear to be capable ofsomething known as a metabolic shift, in which the cells switch over from usingone metabolic pathway to using another, a change that coincides with tumorstage and severity in some cases.
For this study, the researchers looked at almost 450 ccRCCtumors, comparing each with a normal sample from the same patient, and theirexamination found that low levels of AMPK, a protein essential to cell metabolism,and low levels of acetyl-CoA carboxylase, another protein, were linked to worsepatient outcomes.
Dr. W. Marston Linehan, chief of the National CancerInstitute (NCI) Urologic Oncology Branch and one of the study's leaders, saysthat at present, the cause of the metabolic shift is unknown.
What they do know, Linehan notes, is that "the metabolicshift was seen in patients with high-grade, high-stage clear cell kidney cancerwith decreased survival," or poor prognosis tumors. The study also indicatedchanges in Krebs cycle enzyme levels, which Linehan says "could indicateimpairment of the normal metabolic process that the cell uses to generateenergy," and there may also be an association between alteration in chromatinremodeling genes—mutation of the chromatin remodeling gene BAP1 is also linkedto a poor prognosis—and metabolic shift in ccRCC, which Linehan calls "afascinating possibility."
Additionally, according to Linehan, ccRCC is not the onlytype of cancer known to demonstrate a metabolic shift.
"There are two other types of kidney cancer that arecharacterized by a metabolic shift to aerobic glycolysis. These types of kidneycancer, which are characterized by mutation of Kreb's cycle enzymes, undergo ametabolic shift to an increased dependence on metabolism of glucose for energyproduction. This is referred to as the 'Warburg effect' in cancer and is thesource of great interest in the field," Linehan explains. 
The researchers also discovered that in select cases, thismetabolic shift might be the result of changes in the PI3K cellular pathway,which regulates cell metabolism and is also linked to apoptosis and severaltypes of cancer. Several changes were noted in the genes in the PI3K pathwayand its regulators in tumor cells, including DNA mutations in protein-codingareas and other changes that affect gene expression. Alterations were found ineither the PI3K pathway or AKT and mTOR, its partner pathways, in 29 percent oftumor samples. 
The study also showed a decrease in factors that activatetumor suppressor genes, while at the same time, factors that activate PI3Kpathway inhibitor genes were blocked, two changes that promote activity in thePI3K/AKT/mTOR pathways. 
Linehan notes that all three of these pathways representpossible therapeutic targets, with two agents that target the mTOR pathway as atreatment for advanced kidney cancer having already secured approval andadditional agents under evaluation that target the PI3K pathway and bothpathways simultaneously.
"Earlier findings from the characterization of other typesof cancers have given us important clues as to how to design better therapiesfor these cancers," NCI Director Dr. Harold Varmus, commented in a statement."The new results from the TCGA analysis of clear cell renal cell carcinomasprovide an explanation for how mutations in certain genes can alter chromosomechemistry to produce changes in enzyme levels that affect cell metabolism inways correlated with clinical outcomes. These findings will stimulate some novelideas about therapies for other lethal cancers."
Linehan says this research is moving forward in severaldirections. Researchers at a variety of institutions are engaging in furtherstudy of the metabolic basis of ccRCC, as well as the gene pathways involvedand "the role of chromatin remodeling genes in the initiation and/orprogression of clear cell kidney cancer."
"The molecular analysis of this disease impactsunderstanding of all cancers through furthering insights into the role ofmetabolic perturbation in malignancy," said Dr. Richard A. Gibbs, a leadinvestigator for the project and director of the Human Genome Sequencing Centerat Baylor College of Medicine in Houston.
The data used in this study was generated by TCGA, acollaborative effort funded by the NCI and the National Human Genome ResearchInstitute. The results were published in the June 23 online edition of Nature.

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