Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix.

Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis.

Tumor-infiltrating monocytes/macrophages promote tumor invasion and migration by upregulating S100A8 and S100A9 expression in cancer cells.

Myeloid cells promote the development of distant metastases, but little is known about the molecular mechanisms underlying this process. Here we have begun to uncover the effects of myeloid cells on cancer cells in a mouse model of liver metastasis. Monocytes/macrophages, but not granulocytes, isolated from experimental liver metastases stimulated migration and invasion of MC38 colon and Lewis lung carcinoma cells. In response to conditioned media from tumor-infiltrating monocytes/macrophages, cancer cells upregulated S100a8 and S100a9 messenger RNA expression through an extracellular signal-related kinase-dependent mechanism. Suppression of S100A8 and S100A9 in cancer cells using short hairpin RNA significantly diminished migration and invasion in culture. Downregulation of S100A8 and S100A9 had no effect on subcutaneous tumor growth. However, colony size was greatly reduced in liver metastases with decreased invasion into adjacent tissue. In tissue culture and in the liver colonies derived from cancer cells with knockdown of S100A8 and S100A9, MMP2 and MMP9 expression was decreased, consistent with the reduction in migration and invasion. Our findings demonstrate that monocytes/macrophages in the metastatic liver microenvironment induce S100A8 and S100A9 in cancer cells, and that these proteins are essential for tumor cell migration and invasion. S100A8 and S100A9, however, are not responsible for stimulation of proliferation. This study implicates S100A8 and S100A9 as important mediators of tumor cell aggressiveness, and highlights the therapeutic potential of S100A8 and S100A9 for interference of metastasis.

Macrophage migration inhibitory factor: a key cytokine and therapeutic target in colon cancer.

Macrophage migration inhibitory factor (MIF) was one of the first cytokines to be discovered, over 40 years ago. Since that time a burgeoning interest has developed in the role that MIF plays in both the regulation of normal physiology and the response to pathology. MIF is a pleotropic cytokine that functions to promote inflammation, drive cellular proliferation, inhibit apoptosis and regulate the migration and activation state of immune cells. These functions are particularly relevant for the development of cancer and it is notable that various solid tumours over express MIF. This includes tumours of the gastrointestinal tract and MIF appears to play a particularly prominent role in the development and progression of colonic adenocarcinoma. Here we review the role that MIF plays in colonic carcinogenesis through the promotion of colonic inflammation, as well as the progression of primary and metastatic colon cancer. The recent development of various antagonists and antibodies that inhibit MIF activity indicates that we may soon be able to classify MIF as a therapeutic target in colon cancer patients.

Adherence of trials of operative intervention to the CONSORT statement extension for non-pharmacological treatments: a comparative before and after study.

INTRODUCTION: Use of the Consolidated Standards of Reporting Trials (CONSORT) statement has been shown to improve the reporting of randomised controlled trials and it is endorsed by leading surgical journals. The CONSORT statement for non-pharmacological treatment (CONSORT-NPT) provides specific items to aid in the reporting of trials of operative intervention. This study compares the reporting practice of trials of operative intervention published in time periods before and after publication of the CONSORT-NPT statement. METHODS: A 30-point checklist containing the salient CONSORT-NPT items was designed and the adherence of trials meeting the inclusion criteria determined independently by two authors. RESULTS: There was a significant improvement of 3.95 points in the mean CONSORT-NPT score from 2004 to 2010 (95% confidence interval: 3.61-4.29, p<0.001). This related specifically to items present in the original CONSORT statement rather than to CONSORT-NPT items, which remained poorly reported in 2010. The mean CONSORT-NPT score was 17.5 (standard deviation [SD]: 4.5) for trials published in CONSORT endorsing journals compared with 15.6 (SD: 4.0) for those that did not mention endorsement of the CONSORT statement although this was not a significant difference (p=0.064). CONCLUSIONS: Although there has been a significant improvement in the reporting of trials of operative intervention published in the surgical literature since 2004, items specific to the CONSORT-NPT extension remain underreported. Improved awareness of this important addition to the CONSORT statement throughout the surgical community and its endorsement by surgical journals will help to improve the reporting practice of trials of operative intervention.

Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis.

BACKGROUND: Total pancreatectomy and islet autotransplantation (TP/IAT) is a treatment option in a subset of patients with chronic pancreatitis. A systematic review of the literature was performed to evaluate the outcome of this procedure, with an attempt to ascertain when it is indicated. METHODS: MEDLINE (1950 to present), Embase (1980 to present) and the Cochrane Library were searched to identify studies of outcomes in patients undergoing TP/IAT. Cohort studies that reported the outcomes following the procedure were included. The MOOSE guidelines were used as a basis for this review. RESULTS: Five studies met the inclusion criteria. The techniques reported for pancreatectomy and islet cell isolation varied between studies. TP/IAT was successful in reducing pain in patients with chronic pancreatitis. Comparing morphine requirements before and after the procedure, two studies recorded significant reductions. Concurrent IAT reduced the insulin requirement after TP; the rate of insulin independence ranged from 46 per cent of patients at 5 years' mean follow-up to 10 per cent at 8 years. The impact on quality of life was poorly reported. The studies reviewed did not provide evidence for optimal timing of TP/IAT in relation to the evolution of chronic pancreatitis. CONCLUSION: This systematic review showed that TP/IAT had favourable outcomes with regard to pain reduction. Concurrent IAT enabled a significant proportion of patients to remain independent of insulin supplementation.

Systematic review of outcome of downstaging hepatocellular cancer before liver transplantation in patients outside the Milan criteria.

BACKGROUND: The aim of this systematic review was to assess the evidence on tumour downstaging before liver transplantation in patients with hepatocellular carcinoma (HCC) initially staged beyond the Milan criteria. METHODS: MEDLINE (from 1952), Embase (from 1980) and the Cochrane Library were searched. The review included cohort studies that reported the outcomes of patients with HCC outside the Milan criteria who underwent downstaging before transplantation. RESULTS: Eight studies met the inclusion criteria and included a total of 720 patients who underwent transplantation following downstaging after initial presentation with disease outside the Milan criteria. The rate of successful downstaging varied from 24 to 69 per cent of patients. Reported survival rates ranged from 82 to 100 per cent, 79 to 100 per cent and 54·6 to 94 per cent at 1, 3 and 5 years respectively. These were comparable with results for patients presenting within the Milan criteria. CONCLUSION: Successful downstaging of HCC to within the Milan criteria is feasible in a proportion of patients. Absolute and disease-free survival rates in patients transplanted following downstaging are comparable to those in patients within the Milan criteria.

Altered expression of anti-apoptotic proteins in non-involved tissue from cancer-containing breasts.

In a previous investigation reduced apoptosis was identified in normal breast tissue from cancer-containing breasts away from the cancer in comparison to age-matched normal breast from women without cancer. The hypothesis for this study was that defects in expression of apoptotic regulatory and DNA repair proteins would facilitate persistence of genetic alterations and predispose to breast cancer development. Using immunohistochemistry normal breast from 120 age-matched women (58 with breast cancer, 62 without) was analysed for proliferation, apoptosis, bcl2, BAX, caspase 3, Hsp27, Hsp70, BRCA1, ATM and BARD1. All assessments were performed without knowledge as to whether it was a cancer case or control. A significant difference was found for apoptotic index which was higher in controls (P < 0.02). There was no change in apoptotic and proliferation index with age for cancer cases unlike controls. Higher expression of bcl2 (P = 0.001) and Hsp27 (P = 0.001) was found in normal breast from cancer-containing breast in comparison to controls. There were no differences in the other proteins. Apoptosis has been found to be reduced in normal breast in a separate cohort of women with breast cancer, along with increased expression of the anti-apoptotic proteins bcl2 and Hsp27. These alterations in apoptotic regulation would enhance tumour development. Further studies are needed to examine the value of these proteins as risk markers.