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

Abstract

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.

Obesity and colorectal cancer: molecular features of adipose tissue

“…4-hydroxy-2-nonenal increase PPAR gene expression and accelerate adiponectin protein degradation in adipocytes [ 65 ]. Peroxisome-proliferator-activated receptors has been also reported to arrest colorectal cancer proliferation [ 66 , 67 ], however it has also been linked to poor outcome in metastatic colorectal cancer (mCRC) [ 68 ]. 4-hydroxy-2-nonenal also upregulates prostaglandin E2 [ 69 ] and cyclooxygenase-2 (COX-2) [ 70 ], two factors associated with high proliferative colorectal cancer [ 71 ].…”

PPARG expression in colorectal cancer and its association with staging and clinical evolution

“…PPARA (alpha) immunohistochemical expression in colorectal hepatic metastasis has been associated with worse overall survival as compared to cases that do not express this gene. This association has not been confirmed for PPARG 21 . PPARD (delta) promotes tumorigenesis and is probably clinically relevant: elevated PPARD and COX-2 expression in tumor tissues has been correlated with worse prognosis in patients with CRC 22 , 23 .…”

The Anticancer Potential of Peroxisome Proliferator‐Activated Receptor Antagonists

“…Excessive PPARα expression has been found to lead to progression of tumor growth in several cancers, including renal cancer, hepatocellular carcinoma, breast cancer, and glioblastoma . Notably, PPARα staining has been associated with worse overall survival in patients with liver metastases from colorectal cancer . Thus, PPARα activation plays a critical role in tumor biology, and its inhibition by PPARα antagonists may be beneficial in tumors overexpressing this receptor.…”

“…[66][67][68][69][70] Notably,P PARa staining has been associatedw ith worse overall survival in patients with liver metastases from colorectal cancer. [71] Thus, PPARa activation plays ac ritical role in tumor biology,a nd its inhibition by PPARa antagonists may be beneficial in tumors overexpressing this receptor.…”