Abstract
Colorectal cancer is one of the most common types of cancer with over fifty percent of patients presenting at an advanced stage. Retinoic acid is a metabolite of vitamin A and is essential for normal cell growth and aberrant retinoic acid metabolism is implicated in tumourigenesis. This study has profiled the expression of retinoic acid metabolising enzymes using a well characterised colorectal cancer tissue microarray containing 650 primary colorectal cancers, 285 lymph node metastasis and 50 normal colonic mucosal samples. Immunohistochemistry was performed on the tissue microarray using monoclonal antibodies which we have developed to the retinoic acid metabolising enzymes CYP26A1, CYP26B1, CYP26C1 and lecithin retinol acyl transferase (LRAT) using a semi-quantitative scoring scheme to assess expression. Moderate or strong expression of CYP26A1was observed in 32.5% of cancers compared to 10% of normal colonic epithelium samples (p<0.001). CYP26B1 was moderately or strongly expressed in 25.2% of tumours and was significantly less expressed in normal colonic epithelium (p<0.001). CYP26C1 was not expressed in any sample. LRAT also showed significantly increased expression in primary colorectal cancers compared with normal colonic epithelium (p<0.001). Strong CYP26B1 expression was significantly associated with poor prognosis (HR = 1.239, 95%CI = 1.104–1.390, χ2 = 15.063, p = 0.002). Strong LRAT was also associated with poorer outcome (HR = 1.321, 95%CI = 1.034–1.688, χ2 = 5.039, p = 0.025). In mismatch repair proficient tumours strong CYP26B1 (HR = 1.330, 95%CI = 1.173–1.509, χ2 = 21.493, p<0.001) and strong LRAT (HR = 1.464, 95%CI = 1.110–1.930, χ2 = 7.425, p = 0.006) were also associated with poorer prognosis. This study has shown that the retinoic acid metabolising enzymes CYP26A1, CYP26B1 and LRAT are significantly overexpressed in colorectal cancer and that CYP26B1 and LRAT are significantly associated with prognosis both in the total cohort and in those tumours which are mismatch repair proficient. CYP26B1 was independently prognostic in a multivariate model both in the whole patient cohort (HR = 1.177, 95%CI = 1.020–1.216, p = 0.026) and in mismatch repair proficient tumours (HR = 1.255, 95%CI = 1.073–1.467, p = 0.004).
Highlights
Colorectal cancer is one of the commonest types of malignancy whose 5 year survival remains at approximately fifty percent despite the introduction of bowel cancer screening programmes [1]
Retinoic acid (RA) is a metabolite of vitamin A, which performs essential functions in normal cell growth and differentiation and dysregulated retinoic acid metabolism has been implicated in tumourigenesis [16,17]
Monoclonal antibodies Monoclonal antibodies to CYP26A1, CYP26B1, CYP26C1 and lecithin retinol acyl transferase (LRAT) were developed in collaboration with Vertebrate Antibodies Ltd (Aberdeen, UK) using synthetic peptides
Summary
Colorectal cancer is one of the commonest types of malignancy whose 5 year survival remains at approximately fifty percent despite the introduction of bowel cancer screening programmes [1]. Retinoic acid (RA) is a metabolite of vitamin A (retinol), which performs essential functions in normal cell growth and differentiation and dysregulated retinoic acid metabolism has been implicated in tumourigenesis [16,17]. A term used to describe natural or synthetic compounds showing a structural or functional resemblance to retinol, have prominent roles to play in cell growth, differentiation and apoptosis [16]. The most active form of RA, all-trans retinoic acid (atRA), has a gene regulatory function and plays a crucial role in development of the multiple organs. 4-oxo-9-cis-retinoic acid (9-cis-RA) and 4-oxo-13-cisretinoic acid (13-cis-RA) are stereo-isomers of atRA and play an important role in RA signalling. Some retinoids possess anticancer properties that have already been exploited for the treatment of several types of cancer including cervical cancer and promyelocytic leukaemia
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