Abstract 1876: Oxidative metabolism by human peritoneal cancer cells stimulated with death ligands.
Authors: Braun Donald P. , Johnson Derek M. , Rosales Adriana , Brown C. Komen 
Published: August 2014

Anatomic environments harboring cancer are known to influence tumor sensitivity to most forms of therapy. In general, the effects are negative with respect to clinical response. Thus, manipulation of tumor environments to favor treatment outcome is justified. The human peritoneal cavity harbors multiple types of primary and metastatic cancer whose presence elicits a substantial inflammatory response with consequent diverse and conflicting effects on tumor growth and treatment response. The present study used peritoneal tumors (PT) from patients to investigate expression of oxidative metabolism (OM) genes relevant to inflammation within the peritoneal cavity. Briefly, PT were used to establish cell lines which were stimulated with pathophysiologic concentrations of the inflammatory death ligands, rTNF and rTRAIL followed by gene expression analysis with real time pcr. Lines from a metastatic lesion on the stomach of a colorectal cancer patient (CR) as well as tissue from a patient with extensive peritoneal carcinomatosis (PC) were used. Stimulation (expressed as fold increase above media controls) of the PC line with rTNF elicited significantly increased expression of multiple OM gene families and multiple isoforms within each family including the gluathione peroxidase (isoforms 1-4, range = 2.1-4.8 fold); peroxiredoxin (isoforms 1-6, range = 2.6-5.1 fold); superoxide dismutase (isoforms 1-3, range = 2.4-2.6 fold); and, arachidonate metabolism (Cox1, Cox2 and 12-Lipox, range =2.1-16 fold) families. Significant increases were also seen for ApoE (3.8 fold); gluathione synthetase, transferase, and reductase (3.1, 2.6, and 7.1 fold respectively); and scavenger receptor A (4.1 fold). The results with rTRAIL also showed significant increases in expression of selected isoforms of the same OM families, but were of lesser magnitude and involved only 1 or 2 of the isoforms from each family. OM gene expression in the CR line was not significantly increased in most gene families by inflammatory death ligands, with statistically significant increases of &lt;3 fold observed for glutathione peroxidases 5, 6 and 7; lactoperoxidase; myeloperoxidase; and Cox1. Incubation of the CR and PC line with rTNF and rTRAIL produced only modest inhibition of proliferation in an MTS assay. These results demonstrate that innflammatory death ligands shown to be increased in the peritoneal cavity of cancer patients can elicit increased expression of OM genes in primary PT cell lines. The types of genes stimulated suggest that PT cells can create a highly anti-oxidant local microenvironment within an inflammed peritoneal cavity. This effect may substantially inhibit the tumoricidal effects of chemotherapy, radiation, and antitumor immunity while promoting tumor angiogenesis and progression. Tumor-targeted inhibition of OM may improve clinical treatment outcomes in peritoneal cancers.

Citation Format: Donald P. Braun, Derek M. Johnson, Adriana Rosales, C. Komen Brown. Oxidative metabolism by human peritoneal cancer cells stimulated with death ligands. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1876. doi:10.1158/1538-7445.AM2013-1876