In two separate studies, Boston researchers (primarily) have discovered and begun to characterize the intriguing and likely important finding that protein metabolites found in human serum are elevated typically years before the diagnosis of pancreatic cancer (ductal adenocarcinoma of the pancreas) is established. The implications of this discovery have cast a new light on the early development of pancreatic cancer.
The central finding is that amino acids in the proteinogenic class known as branched-chain amino acids appear to be elevated in serum most often years prior to the diagnosis of pancreatic cancer. Specifically, these metabolic factors are the three amino acids isoleucine, leucine, and valine.
The research team for the initial study was led by scientists from the Dana-Farber Cancer Institute (and other Harvard institutions) and MIT. Also included among these scientists were those from other American universities and Canada. The results from this primary paper were published in the October 2014 issue of NATURE Medicine journal. The researchers gained access to blood samples that had been earlier collected (at least two years) from about 1,500 people in other medical tracking studies. They analyzed these samples for more than 100 metabolites and discovered 15 that were present in those people who eventually were diagnosed with pancreatic cancer as compared with matched controls (p ≤ 0.05). On further inspection, the remarkable probabilities of the noted three branched-chain amino acid elevations were determined as significant at p ≤ 0.0006 in those later diagnosed with pancreatic cancer.
The branched-chain amino acid elevations were most strongly noted during the period between two to five years before the diagnosis of pancreatic cancer, and the range was 2 to 25 years prior. The median duration between the branched-chain amino acid elevations and the diagnosis of pancreatic cancer was 8.7 years.
The causation of amino acid elevations is not fully clear. Circulation serum branched-chain amino acid elevations are seen in obese individuals and in those with insulin resistance. Subsequent tests by the researchers using mice did not appear to find a relationship between the elevated branched-chain amino acid levels and diabetes mellitus or with pancreatitis. There did again appear to be a relationship between the elevated amino acid levels and early pancreatic cancer, though this was essentially only seen in mice with Kras associated pancreatic cancer tumors. The authors note that unlike other amino acids, branched-chain amino acids are not regulated by the liver. That the levels are typically determined by dietary intake, tissue metabolism, and the breakdown of muscle and other bodily proteins. Further mice studies appeared to indicate that the early elevated branched-chain amino acid load associated with later pancreatic cancer may be related to muscle catabolism.
The second related study included some of the same aforementioned researchers, comprised primarily of Boston located scientists mainly from Harvard and MIT institutions. This work, published in the September 2016 issue of the journal Science (American Association for the Advancement of Science), built on an aspect of the earlier study to further explicate the tissue context related to tumor development by determining and comparing metabolic use patterns of branched-chain amino acids in pancreatic cancer as compared to non-small lung cancer. The authors note that both pancreatic cancer and non-small cell lung cancer often include mutations of Kras and p53, but that each of these tumors use branched-chain amino acids differently. NSCLC utilizes these amino acids as a nitrogen source (thus, increased uptake), whereas pancreatic cancer demonstrates diminished uptake of branched-chain amino acids. The differences in the levels of branched-chain amino acids between these tumors were shown to be at least in part metabolically based though enzyme variation. The different amino acid levels in these two tumor types appear to hold in mice as well as humans. The authors conclude that tissue origin appears to determine how tumors fulfil their metabolic needs.
The finding and explication related to elevations of branched-chain amino acids in serum years prior to the diagnosis of pancreatic cancer has to be judged as highly significant. It is not clear at this point the direction that this line of inquiry will assume, but one hopes that it continues and that the final destination will lead to the earlier diagnosis of pancreatic cancer.
Dale O’Brien, MD