Peroxisome proliferator-activated receptor-α staining is associated with worse outcome in colorectal liver metastases

Pang,Tony; Kaufman,Antony; Choi,Julian; Gill,Anthony; Drummond,Martin; Hugh,Thomas; Samra,Jaswinder

doi:10.3892/mco.2014.482

Peroxisome proliferator-activated receptor-α staining is associated with worse outcome in colorectal liver metastases

Authors:
- Tony Pang
- Antony Kaufman
- Julian Choi
- Anthony Gill
- Martin Drummond
- Thomas Hugh
- Jaswinder Samra
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Affiliations: Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, St. Leonards, NSW 2065, Australia, Department of Anatomical Pathology, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia, Northern Clinical School, University of Sydney, St. Leonards, NSW 2065, Australia
Published online on: December 30, 2014 https://doi.org/10.3892/mco.2014.482
Pages: 308-316

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Abstract

Peroxisome proliferator‑activated receptors (PPARs) are a family of nuclear receptors involved in lipid metabolism and liver response to injury. We hypothesised that differences in the expression of PPARs may reflect differences in the cellular microenvironment of the liver and, consequently, in the behaviour of colorectal liver metastases. Of the 145 patients who underwent hepatectomy for colorectal liver metastases between 1998 and 2007, 103 had adequate tissue for PPAR staining and histological re‑evaluation. The histological characteristics evaluated included sinusoidal dilatation, perisinusoidal fibrosis, ballooning and steatosis. PPAR‑α and ‑γ staining was performed and the results were correlated with clinical and survival data. Lobular inflammation and sinusoidal dilatation were the most common histopathological abnormalities. A total of 50% of the patients were PPAR‑α‑negative and 34% were PPAR‑γ‑negative. More patients exhibited lobular inflammation in the PPAR‑α‑positive group (P=0.023) compared to patients with negative PPAR‑α staining, as seen on the multivariate analysis. PPAR‑γ positivity was associated with oxaliplatin use, surgical margins ≥1 mm and a trend towards a lesser degree of fibrosis. The median follow‑up in this cohort of patients was 48 months. Patients with PPAR‑α staining had a worse overall survival (median, 36 vs. 79 months, P=0.037) compared to those with no PPAR‑α staining. There was no correlation between PPAR‑α or ‑γ positivity and disease‑free survival. In conclusion, PPAR‑α staining is associated with lobular inflammation and worse overall survival in patients with colorectal liver metastases. The exact mechanism underlying this finding remains unclear and further research into the diagnostic and therapeutic implications is required.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J and Bouvier AM: Epidemiology and management of liver metastases from colorectal cancer. Ann Surg. 244:254–259. 2006. View Article : Google Scholar : PubMed/NCBI
3	Ramia JM, Lopez-Andujar R, Torras J, et al: Multicentre study of liver metastases from colorectal cancer in pathological livers. HPB (Oxford). 13:320–323. 2011. View Article : Google Scholar : PubMed/NCBI
4	Martinez-Outschoorn UE, Lin Z, Trimmer C, et al: Cancer cells metabolically ‘fertilize’ the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors. Cell Cycle. 10:2504–2520. 2011. View Article : Google Scholar : PubMed/NCBI
5	Hamaya K, Hashimoto H and Maeda Y: Metastatic carcinoma in cirrhotic liver - statistical survey of autopsies in Japan. Acta Pathol Jpn. 25:153–159. 1975.PubMed/NCBI
6	King PD and Perry MC: Hepatotoxicity of chemotherapy. Oncologist. 6:162–176. 2001. View Article : Google Scholar : PubMed/NCBI
7	Rubbia-Brandt L, Audard V, Sartoretti P, et al: Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 15:460–466. 2004. View Article : Google Scholar : PubMed/NCBI
8	Kandutsch S, Klinger M, Hacker S, Wrba F, Gruenberger B and Gruenberger T: Patterns of hepatotoxicity after chemotherapy for colorectal cancer liver metastases. Eur J Surg Oncol. 34:1231–1236. 2008. View Article : Google Scholar : PubMed/NCBI
9	Cleary JM, Tanabe KT, Lauwers GY and Zhu AX: Hepatic toxicities associated with the use of preoperative systemic therapy in patients with metastatic colorectal adenocarcinoma to the liver. Oncologist. 14:1095–1105. 2009. View Article : Google Scholar : PubMed/NCBI
10	Ryan P, Nanji S, Pollett A, et al: Chemotherapy-induced liver injury in metastatic colorectal cancer: semiquantitative histologic analysis of 334 resected liver specimens shows that vascular injury but not steatohepatitis is associated with preoperative chemotherapy. Am J Surg Pathol. 34:784–791. 2010. View Article : Google Scholar : PubMed/NCBI
11	Tamandl D, Klinger M, Eipeldauer S, et al: Sinusoidal obstruction syndrome impairs long-term outcome of colorectal liver metastases treated with resection after neoadjuvant chemotherapy. Ann Surg Oncol. 18:421–430. 2011. View Article : Google Scholar : PubMed/NCBI
12	Rizzo G and Fiorucci S: PPARs and other nuclear receptors in inflammation. Curr Opin Pharmacol. 6:421–427. 2006. View Article : Google Scholar : PubMed/NCBI
13	Peters JM, Shah YM and Gonzalez FJ: The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rev Cancer. 12:181–195. 2012.PubMed/NCBI
14	Dindo D, Demartines N and Clavien PA: Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 240:205–213. 2004. View Article : Google Scholar : PubMed/NCBI
15	Vauthey JN, Pawlik TM, Ribero D, et al: Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 24:2065–2072. 2006. View Article : Google Scholar : PubMed/NCBI
16	Mehta NN, Ravikumar R, Coldham CA, et al: Effect of preoperative chemotherapy on liver resection for colorectal liver metastases. Eur J Surg Oncol. 34:782–786. 2008. View Article : Google Scholar : PubMed/NCBI
17	Nakano H, Oussoultzoglou E, Rosso E, et al: Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg. 247:118–124. 2008. View Article : Google Scholar : PubMed/NCBI
18	Di Paola R and Cuzzocrea S: Peroxisome proliferator-activated receptors ligands and ischemia-reperfusion injury. Naunyn Schmiedebergs Arch Pharmacol. 375:157–175. 2007.(In Chinese). View Article : Google Scholar : PubMed/NCBI
19	Braissant O, Foufelle F, Scotto C, Dauca M and Wahli W: Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology. 137:354–366. 1996. View Article : Google Scholar : PubMed/NCBI
20	Vidal-Puig AJ, Considine RV, Jimenez-Linan M, et al: Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest. 99:2416–2422. 1997. View Article : Google Scholar : PubMed/NCBI
21	Naishadham D, Lansdorp-Vogelaar I, Siegel R, Cokkinides V and Jemal A: State disparities in colorectal cancer mortality patterns in the United States. Cancer Epidemiol Biomarkers Prev. 20:1296–1302. 2011. View Article : Google Scholar : PubMed/NCBI
22	Kong L, Ren W, Li W, Zhao S, Mi H, Wang R, Zhang Y, Wu W, Nan Y and Yu J: Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol induced steatohepatitis in mice. Lipids Health Dis. 10:2462011. View Article : Google Scholar : PubMed/NCBI
23	Akiyama TE, Nicol CJ, Fievet C, et al: Peroxisome proliferator-activated receptor-alpha regulates lipid homeostasis, but is not associated with obesity: studies with congenic mouse lines. J Biol Chem. 276:39088–39093. 2001. View Article : Google Scholar : PubMed/NCBI
24	Stienstra R, Mandard S, Patsouris D, Maass C, Kersten S and Muller M: Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation. Endocrinology. 148:2753–2763. 2007. View Article : Google Scholar : PubMed/NCBI
25	Okaya T and Lentsch AB: Peroxisome proliferator-activated receptor-alpha regulates postischemic liver injury. Am J Physiol Gastrointest Liver Physiol. 286:G606–G612. 2004. View Article : Google Scholar : PubMed/NCBI
26	Pozzi A, Ibanez MR, Gatica AE, et al: Peroxisomal proliferator-activated receptor-alpha-dependent inhibition of endothelial cell proliferation and tumorigenesis. J Biol Chem. 282:17685–17695. 2007. View Article : Google Scholar : PubMed/NCBI
27	Grau R, Diaz-Munoz MD, Cacheiro-Llaguno C, Fresno M and Iniguez MA: Role of peroxisome proliferator-activated receptor alpha in the control of cyclooxygenase 2 and vascular endothelial growth factor: involvement in tumor growth. PPAR Res. 2008:3524372008. View Article : Google Scholar : PubMed/NCBI
28	Kaipainen A, Kieran MW, Huang S, et al: PPA Ralpha deficiency in inflammatory cells suppresses tumor growth. PLoS One. 2:e2602007. View Article : Google Scholar : PubMed/NCBI