MicroRNA manipulation in colorectal cancer cells: from laboratory to clinical application.

The development of Colorectal Cancer (CRC) follows a sequential progression from adenoma to the carcinoma. Therefore, opportunities exist to interfere with the natural course of disease development and progression. Dysregulation of microRNAs (miRNAs) in cancer cells indirectly results in higher levels of messenger RNA (mRNA) specific to tumour promoter genes or tumour suppressor genes. This narrative review aims to provide a comprehensive review of the literature about the manipulation of oncogenic or tumour suppressor miRNAs in colorectal cancer cells for the purpose of development of anticancer therapies. A literature search identified studies describing manipulation of miRNAs in colorectal cancer cells in vivo and in vitro. Studies were also included to provide an update on the role of miRNAs in CRC development, progression and diagnosis. Strategy based on restoration of silenced miRNAs or inhibition of over expressed miRNAs has opened a new area of research in cancer therapy. In this review article different techniques for miRNA manipulation are reviewed and their utility for colorectal cancer therapy has been discussed in detail. Restoration of normal equilibrium for cancer related miRNAs can result in inhibition of tumour growth, apoptosis, blocking of invasion, angiogenesis and metastasis. Furthermore, drug resistant cancer cells can be turned into drug sensitive cells on alteration of specific miRNAs in cancer cells. MiRNA modulation in cancer cells holds great potential to replace current anticancer therapies. However, further work is needed on tissue specific delivery systems and strategies to avoid side effects.

The "two-week wait" referral pathway is not associated with improved survival for patients with colorectal cancer.

AIM: To improve survival rates in patients diagnosed with cancer in the UK, a two-week wait (2ww) referral to first appointment target and a 62 day referral to treatment target were introduced in 2004. This study analyses survival rates for patients diagnosed with colorectal cancer (CRC) by mode of referral and referral to treatment time. METHOD: A prospectively maintained database of CRC outcomes at the University Hospitals of Leicester NHS Trust was analysed. Data for patients diagnosed with CRC was analysed for survival. Comparisons were made by mode of referral (2ww, urgent, routine, emergency, national bowel cancer screening programme (NBCSP) and other screening pathways). In addition, this study assessed referral to initial treatment times for patients undergoing cancer resection (<62days group vs. >62days group). Inter-group comparisons were made using the Mann-Whitney-U-test. Kaplan-Meier survival probability estimates were calculated for overall survival and the log-rank test was used to compare the survival distributions in different groups. RESULTS: Overall survival (median time) was significantly lower for patients referred by the '2ww' pathway (3.5 years, 95% CI: 2.7-4.30), in comparison to the 'routine' (5.4 years, 95% CI: 4.5-6.6) pathway (p < 0.001). Patients referred on the '2ww' pathway were 1.34 times more likely to have stage IV disease at presentation in comparison to patients referred by the 'routine' pathway. Comparison of referral to initial treatment times showed there was no significant difference in survival between the <62days group and the >62days group (7.1 vs. 6.54, p = 0.620). CONCLUSION: Patients diagnosed with CRC by the 2ww pathway had shorter survival times than those referred by a routine pathway.

MicroRNAs associated with initiation and progression of colonic polyp: a feasibility study.

INTRODUCTION: Colorectal cancer is the third most common neoplasm worldwide. The sequential progression of colorectal cancer from adenoma to carcinoma highlights that opportunities exist to alter the natural course of disease progression. The aim of this study was to characterize the expression levels of microRNAs linked to development and progression of colorectal neoplasia. Patient, Design, Patients & Methods: MicroRNA expression signature was developed for RNA extracted from freshly frozen tumour and adjacent normal tissue (n = 5). Based on differential expression and literature search, hsa-miR-135b was selected for further characterisation in different types of colonic polyps and cancer tissue. Formalin Fixed Paraffin Embedded tissue were studied for miRNA expression, KRAS, BRAF, PIK3CA mutations, and immuno-histochemistry for APC and p53 proteins for normal colon (n=11), hyperplastic polyps (n=11), high grade adenomas (n=10), low grade adenomas (n=34) and adenocarcinoma (n=13). RESULTS: CRC tissue had significantly higher expression levels of hsa-miR-135b (p=0.0017) than their adjacent paired normal tissues (mean increase=8.90 fold, 95% CI=2.98-26.50). Linear trend analysis showed a progressive increase in expression level of hsa-miR-135b across normal epithelium, low grade adenomas, high grade adenomas and carcinomas (p=0.0007, R squared 0.16, slope -0.35). KRAS mutant colonic polyps and cancer tissue had significantly higher (3.04 fold, 95% CI=1.23-7.46) expression levels of hsa-miR-135b compared to polyps and cancers with non mutant KRAS gene (p=0.001). Whereas, hsa-miR-135b expression levels were significantly lower in colonic polyp and cancer tissue stained positively for APC proteins (p<0.001). CONCLUSION: There is a progressive increase in expression levels of hsa-miR-135b correlating with the sequential progression of normal epithelium to adenoma and carcinoma. Expression levels of hsa-miR-135b correlate with expression of APC proteins in colorectal tissue suggesting its role in tumour initiation. HIGHLIGHTS: This study highlights the role of tissue microRNAs for their role in the development of colorectal carcinoma. Identification of tissue specific microRNAs will help is designing microRNAs based gene therapies to control the development and progression of colonic neoplasia.

Ten years experience of managing the primary tumours in patients with stage IV colorectal cancers.

INTRODUCTION: Approximately 20% of patients with colorectal cancer have metastases at the time of presentation. Such patients are often offered systemic chemotherapy but debate continues as to whether these patients benefit from resection of the primary tumour. We describe our ten years experience of managing the primary tumours in patients with stage IV colorectal cancer. The aim of this study was to describe the overall survival of patients undergoing surgery in these circumstances and to determine whether any prognostic indicators could be identified. PATIENTS & METHODS: 920 consecutive patients presenting with stage IV colorectal cancer disease were identified from the Leicester Colorectal Cancer database. Patients undergoing resection of the primary tumour (Resection Group) with the residual metastatic disease were compared to those patients who had not their primary tumour excised (Non-Resection Group). Various different variables in two groups were compared by using Mann-Whitney U test. Kaplan-Meier survival analysis and log-rank test were used to compare the overall survivals. Univariate analysis was performed for each group to elicit the significant prognostic factors whereas Cox regression model was used to identify the independent predictors of overall survival. RESULTS: The Kaplan-Meier survival analysis of two groups showed prolonged survival for Resection Group compared to the Non-Resection Group (median; 14.5 Vs 5.83 months, p = <0.005). The multivariate analysis of different survival predicting variables, revealed the resection of the primary tumour as an independent predictor of overall survival (p < 0.001). The univariate analysis of resection group identified age at presentation, tumour site, tumour stage (pT), lymph nodal stage (pN), complete histological resection, tumour fixity, ASA grade, mode of surgery, post-operative chemotherapy and sites of metastasis as significant factors (p < 0.05) for survival prediction. When these factors were used in Cox-Regression model, only the age at presentation (p = 0.001), tumour fixity (p = 0.012) and lymph nodal involvement (p = 0.042) were independent predictors for overall survival. Treatment with post-operative chemotherapy and a smaller volume of liver metastases were associated with prolonged survival (p < 0.05). CONCLUSIONS: Surgical resection of primary tumour for stage IV colorectal cancers is associated with prolonged survival for selected patients. Age at presentation, extent of liver involvement, tumour fixity and ASA grade can help to decide the patients who will benefit from surgery.

Synchronous ileal carcinoid and primary colonic neoplasms: a case report.

Primary colonic tumours with synchronous ileal carcinoid tumours are rare in occurrence and are mainly found incidentally on autopsies or pathological examination of resected surgical specimens. This article describes a case of adenomatous colonic polyps, adenocarcinoma of sigmoid colon and concurrent malignant carcinoid tumour of ileocaecal junction, detected on colonoscopic examination. The radiological staging investigations revealed no distant spread of disease. The patient was effectively treated with subtotal colectomy, resection of terminal ileum, excision of locoregional lymph nodes and the bowel continuity was restored with stapled ileo-rectal anastomosis. This article is as an example of concomitant presence of two types of malignant tumours, effectively managed surgically.