Cell kinetics and gene expression changes in colorectal cancer patients given resistant starch: a randomised controlled trial
- 1 Department of Surgery, North Tyneside General Hospital, North Shields, UK
- 2 Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle Upon Tyne, UK
- 3 Institute of Human Genetics, Centre for Life, Newcastle University, Newcastle Upon Tyne, UK
- Mr S S Dronamraju, Department of General Surgery, North Tyneside General Hospital, Rake Lane, North Shields NE29 8NH, UK;
- Revised 12 September 2008
- Accepted 14 October 2008
- Published Online First 31 October 2008
Objective: This study investigated the effects of oral supplementation of resistant starch (RS) on tumour cell and colonic mucosal cell kinetics and on gene expression in patients with colorectal cancer (CRC), and its potential role in colon cancer prevention.
Methods: 65 patients with CRC were randomised to treatment with RS or ordinary starch (OS) and were given starch treatment for up to 4 weeks. Pretreatment and post-treatment biopsies were obtained from the tumour and colonic mucosa, and the effects of the starch treatment on cell proliferation and expression of the cell cycle regulatory genes CDK4 (cyclin-dependent kinase 4) and GADD45A (growth arrest and DNA damage-inducible, alpha) were investigated.
Results: The proportion of mitotic cells in the top half of the colonic crypt was significantly lower following RS treatment (3.1 (1.5), mean (SEM)) as compared with OS treatment (13.7 (3.2)) (p = 0.028). However, there was no effect of RS treatment on crypt dimensions and tumour cell proliferation index. There was significant upregulation in expression of CDK4 (p<0.01) and downregulation in expression of GADD45A (p<0.001) in the tumour tissue when compared with macroscopically normal mucosa. Following RS treatment, CDK4 expression in tumours (0.88 (0.15)) was twofold higher than that in the OS group (0.37 (0.16)) (p = 0.02). The expression of GADD45A, which was downregulated in the presence of cancer, was significantly upregulated (p = 0.048) following RS treatment (1.41 (0.26)) as compared with OS treatment (0.56 (0.3)). However, there were no significant differences in the expression of these genes in the normal mucosa following starch treatment.
Conclusions: Cell proliferation in the upper part of colonic crypts is a premalignant marker and its reduction by RS supplementation is consistent with an antineoplastic action of this food component. Differential expression of the key cell cycle regulatory genes may contribute to the molecular mechanisms underlying these antineoplastic effects of RS.
Trial registration number: ISRCTN93586244.
See Commentary, p 327
Funding: This project was funded by the Biotechnology and Biological Sciences Research Council (BBRSC), UK (grant no. 13D/20173).
Competing interests: None.
Ethics approval: The study protocol and the subsequent amendments were approved by the local regional ethics committees and the research and development department of the local NHS Trust.
Patient consent: All patients enrolled in the study gave a written informed consent for their participation in the study and for the biopsies to be used exclusively for this study. No individual patient-identifiable information was used and all the patient data collected for this study were anonymised.