Cytochrome P450 Profile of Colorectal Cancer: Identification of Markers of Prognosis

Abstract

Purpose: The cytochromes P450 (P450) are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs, carcinogens, and endogenous compounds. The purpose of this study was to define the P450 profile of colorectal cancer and establish the prognostic significance of expression of individual P450s in colorectal cancer. Experimental Design: Immunohistochemistry for a panel of 23 P450s was done on a colorectal cancer tissue microarray consisting of 264 primary colorectal cancers, 91lymph node metastasis, and 10 normal colorectal samples. The intensity of immunoreactivity in each sample was established by light microscopy. Results: The most frequently expressed form of P450 in normal colon was CYP3A4. In primary colorectal cancer, several P450s (CYP1B1, CYP2S1, CYP2U1, CYP3A5, and CYP51) were present at a significantly higher level of intensity compared with normal colon. P450 expression was also detected in lymph node metastasis and the presence of several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP4V2, and CYP39) in the lymph node metastasis strongly correlated with their presence in corresponding primary tumors. The presence of strong CYP51 (log-rank = 12.11, P = 0.0005) or strong CYP2S1 (log-rank = 6.72, P = 0.0095) immunoreactivity were associated with poor prognosis. CYP51 was also an independent marker of prognosis (P = 0.009). Conclusions: The expression of individual P450s has been established in colorectal cancer. Several P450s show increased expression in colorectal cancer. High expression of CYP51or CYP2S1 were associated with poor prognosis and CYP51is an independent marker of prognosis.

Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity

“…Although a variety of endogenous hormones or signaling factors have been suspected to favor metastasis (Aguirre-Ghiso, 2007), little is known in this field on the effects of pollutants. Three independent studies examined cytochrome P450 profile expression in different metastatic tumors and found a significant upregulation of some AhR-target members, including CYP1B1, CYP2S1 and aromatase CYP19 (Downie et al, 2005;Kumarakulasingham et al, 2005;Haas et al, 2006), which is in line with our hypothesis. However, the mechanisms of these upregulations remain elusive particularly because other cytochrome P450 genes are also increased.…”

Characterisation and protein expression profiling of annexins in colorectal cancer

“…Furthermore, a blast search was used to determine that the peptide was unique to annexin A4 (SVLAYRNTA corresponding to amino acids 39 -47 of annexin A4), thus ensuring no crossreactivity with other proteins. The annexin IV peptide conjugated to ovalbumin was used to immunise rabbits subsequently followed with four boosters, with a protocol we have previously used for the development of other antibodies (Kumarakulasingham et al, 2005). Nine weeks after the initial booster, rabbits were bled and serum was tested by ELISA using the peptide as an immunogen.…”

“…Permission for this study was obtained from the Grampian Research Ethics Committee. A colorectal cancer tissue microarray was constructed as described Kumarakulasingham et al, 2005). The tumours within the array were representative of the distribution of anatomical locations and the Dukes stages found in colorectal cancers within this population.…”

“…The lymph node metastases were from the corresponding Dukes C cases (n ¼ 111). Each normal sample (n ¼ 52) was acquired from at least 10 cm distant from the tumour as previously described (Kumarakulasingham et al, 2005). Using a steel Menghini needle, a representative 1.6 mm core of tissue was taken from each donor block and arrayed into the recipient wax block.…”

Somatic mutations in arachidonic acid metabolism pathway genes enhance oral cancer post-treatment disease-free survival

“…Wild-type COX and LOX pathway genes elicit the most potent inflammatory signalling molecules; therefore, blocking these pathways show additive effect in colon cancer cells 65 . We detected mutations in CYPC219 gene, which is known to overexpress in hepatocellular carcinoma in Chinese patients 66 , and also in CYP2U1 gene, which is overexpressed in colorectal and ovarian cancers 67,68 . Combined target inhibition of various combinations of COX, LOX, CYP enzymes as well as inhibition of AA metabolites are effective in human oesophageal, colon, breast and skin cancer 1 .…”