Abstract 5165: Fatty acid diversification in prostate cancer progression

Abstract

Abstract Two clinically significant indices of prostate cancer progression are the dedifferentiation of the gland (as measured by histopathology and graded by Gleason scoring, GS) and extension beyond the prostatic capsule (extracapsular extension, ECE). In order to better understand the underlying biology of prostate cancer progression, we undertook the metabolomic characterization of prostatectomy tissues and correlated our metabolite findings with these post-surgical endpoints. Briefly, frozen tissues from 298 prostatectomy cases were characterized by frozen sections and then disaggregated and the biochemical constituents were extracted into cold methanol as previously reported. These extracts were analyzed in three parallel workflows: gas chromatography-mass spectrometry and ultrahigh performance liquid chromatography and tandem mass spectrometry. The resulting data sets were compared against an in-house chemical reference library of over 2500 authentic standards. Three hundred and fifty-six metabolites were identified across all biochemical classes (amino acids, carbohydrates, lipids, nucleotides, cofactors and xenobiotics (primarily dietary and pharmaceutical compounds)). The steady state abundance profiles of numerous long chain fatty acids increased with Gleason pattern progression. The products of α-oxidation of long chain fatty acids (long chain α-hydroxy fatty acids (2-hydroxypalmitate and 2-hydroxystearate) and odd chain length fatty acids (such as C19:0) increased in tissue samples in conjunction with the amount of Gleason pattern 4 tissue that was present in the tumor. Branched chain fatty acids such as isopalmitate and polyunsaturated C22 species (22:2n6 and 22:3n3) increased in abundance from Gleason 7 to 8. In addition to these changes with Gleason pattern progression, extracapsular extension was found to have biochemical correlates in fatty acid metabolism. Specifically, the monounsaturated fatty acids (14:1n5, 16:1n7, 17:1n7, 18:1n9 and 19:1n9) were all found to increase in abundance in prostate tissue samples where capsular integrity was compromised compared to those tissues where the tumor was confined to the gland. These data demonstrate that during the progression of human prostate cancer, there is tremendous fatty acid diversification. Taken together with other data demonstrating phospholipid turnover and membrane remodeling in prostate cancer, these data suggest that prostate cancer cells can dramatically alter membrane composition. The reliance of many prostate cancers on these fatty acid diversification pathways can be appreciated by the demonstration of chemotherapeutic activities of inhibitors of both fatty acid synthase and stearoyl-coA dehydrogenase. In addition to target validation, metabolomic profiling may also provide insight into therapeutic selection for and monitoring of the prostate cancer patient. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5165. doi:1538-7445.AM2012-5165