Role of the vanins-myeloperoxidase axis in colorectal carcinogenesis

The presence of chronic inflammation in the colonic mucosa leads to an increased risk of cancer. Among proteins involved in the regulation of mucosal inflammation and that may contribute both to structural damage of the intestinal mucosa and to intestinal carcinogenesis, there are myeloperoxidase (MPO) and vanins. The infiltration of colonic mucosa by neutrophils may promote carcinogenesis through MPO, a key enzyme contained in the lysosomes of neutrophils that regulates local inflammation and the generation of reactive oxygen species (ROS) and mutagenic species. The human vanin gene family consists of three genes: vanin-1, vanin-2 and vanin-3. All vanin molecules are pantetheinases, that hydrolyze pantetheine into pantothenic acid (vitamin B5), and cysteamine, a sulfhydryl compound. Vanin-1 loss confers an increased resistance to stress and acute intestinal inflammation, while vanin-2 regulates adhesion and transmigration of activated neutrophils. The metabolic product of these enzymes has a prominent role in the inflammation processes by affecting glutathione levels, inducing ulcers through a reduction in mucosal blood flow and oxygenation, decreasing local defense mechanisms, and in carcinogenesis by damaging DNA and regulating pathways involved in cell apoptosis, metabolism and growth, as Nrf2 and HIF-1α

Inflammatory pathways in the early steps of colorectal cancer development

Colorectal cancer is a major cause of cancer-related death in many countries. Colorectal carcinogenesis is a stepwise process which, from normal mucosa leads to malignancy. Many factors have been shown to influence this process, however, at present, several points remain obscure. In recent years some hypotheses have been considered on the mechanisms involved in cancer development, expecially in its early stages. Tissue injury resulting from infectious, mechanical, or chemical agents may elicit a chronic immune response resulting in cellular proliferation and regeneration. Chronic inflammation of the large bowel (as in inflammatory bowel diseases), has been associated with the subsequent development of colorectal cancer. In this review we examine the inflammatory pathways involved in the early steps of carcinogenesis, with particular emphasis on colorectal. Firstly, we describe cells and proteins recently suggested as central in the mechanism leading to tumor development. Macrophages and neutrophils are among the cells mostly involved in these processes and proteins, as cyclooxygenases and resolvins, are crucial in these inflammatory pathways. Indeed, the activation of these pathways establishes an oxidative and anaerobic microenvironment with DNA damage to epithelial cells, and shifting from an aerobic to an anaerobic metabolism. Many cellular mechanisms, such as proliferation, apoptosis, and autophagy are altered causing failure to control normal mucosa repair and renewal

Attenuated adenomatous polyposis of the large bowel: Present and future

Attenuated adenomatous polyposis (AAP) is a poorly understood syndrome, that can be defined as the presence of 10-99 synchronous adenomas in the large bowel, and it is considered a phenotypic variant of familial adenomatous polyposis (FAP). This definition has the advantage of simplicity, but it may include sporadic multiple adenomas of the large bowel at an extreme, or FAP cases on the other side. AAP shows a milder phenotype than FAP, with an older age of onset of adenomas and cancer, and less frequent extracolonic manifestations. AAP may be diagnosed as a single case in a family or, less frequently, it may be present in other family members, and it shows distinct pattern of inheritance. In less than 50% of cases, it may be caused by adenomatous polyposis coli (APC) or MUTYH mutations, referred to as APC-associated polyposis, inherited as an autosomal dominant trait, or MUTYH - associated polyposis, which shows an autosomal recessive mechanism of inheritance, respectively. Surveillance should rely on colonoscopy at regular intervals, with removal of adenomas and careful histological examination. When removal of polyps is not possible or advanced lesions are observed, the surgical approach is mandatory, being subtotal colectomy with ileo-rectal anastomosis the treatment of choice. Studies on this syndrome are lacking, and controversies are still present on many issues, thus, other clinical and genetic studies are requested

A West Nile Virus infection expressed as unilateral limb paralysis and complicated by Parsonage–Turner syndrome: a case report

BackgroundWest Nile Virus is a single-stranded Ribonucleic Acid arbovirus of the Flaviviridae family that is transmitted to humans by Culex species mosquitoes. West Nile Virus infection is asymptomatic in the majority of affected people. Of those who develop symptoms, the usual manifestation is a febrile syndrome, while only 1% develop neurological symptoms due to a neuroinvasive form of infection, including encephalitis, meningitis, asymmetrical flaccid paralysis, or a combination of all these features. Parsonage-Turner syndrome is a rare disorder characterized by sudden painful symptoms and subsequent paralysis, involving a shoulder or one of the upper limbs due to post-infective brachial plexopathy. The etiology is unknown, although it can be considered a multifactorial process: a predisposing factor, such as viral infection or strenuous upper-extremity exercise, can trigger an immune-mediated process localized in the brachial plexus.Clinical presentationIn late summer, a 79-year-old male Italian patient was admitted to the emergency department for acute right upper limb weakness and high fever, without any mental status impairment, pain, sensory alterations, or signs of meningeal irritation. Laboratory tests confirmed acute West Nile Virus infection, expressed as a unilateral upper limb flaccid paralysis. After a few days, the patient reported an acute pain in the right upper limb scarcely responsive to nonsteroidal anti-inflammatory drug therapy and a subsequent wider distribution of flaccid paralysis. After multiple examinations, Parsonage-Turner syndrome could be suspected. Patient was treated with steroids and reported an improvement of clinical condition after 2 months, with complete pain remission but partial strength recovery in the affected limb.ConclusionsWest Nile Virus disease has a broad spectrum of neurological manifestations, among which the most common are signs of meningeal irritation or cognitive impairment. We report an unusual presentation of neuroinvasive West Nile Virus infection with arm weakness as expression of unilateral viral neuritis, followed by a post-infective brachial plexopathy consistent with Parsonage-Turner syndrome diagnosis. We diagnosed Parsonage-Turner syndrome after excluding the most common causes of atraumatic acute upper limb pain, through a challenging differential diagnosis in a patient with several comorbidities

Expression of Autophagic and Inflammatory Markers in Normal Mucosa of Individuals with Colorectal Adenomas: A Cross Sectional Study among Italian Outpatients Undergoing Colonoscopy

: Colorectal cancer (CRC) ranks among the three most common cancers in terms of both cancer incidence and cancer-related deaths in Western industrialized countries. Lifetime risk of colorectal cancer may reach 6% of the population living in developed countries. In the current era of personalized medicine, CRC is no longer considered as a single entity. In more recent years many studies have described the distinct differences in epidemiology, pathogenesis, genetic and epigenetic alterations, molecular pathways and outcome depending on the anatomical site. The aim of our study is to assess in a multidimensional model the association between metabolic status and inflammatory and autophagic changes in the normal colorectal mucosa classified as right-sided, left-sided and rectum, and the presence of adenomas. One hundred and sixteen patients undergoing colonoscopy were recruited and underwent a complete serum lipid profile, immunofluorescence analysis of colonic biopsies for MAPLC3 and myeloperoxidase expression, matched with clinical and anthropometric characteristics. Presence of adenomas correlated with cholesterol (total and LDL) levels, IL-6 levels, and MAPLC3 tissue expression, especially in the right colon. In conclusion, serum IL-6 amount and autophagic markers could be good predictors of the presence of colorectal adenomas

Myeloperoxidase expression in human colonic mucosa is related to systemic oxidative balance in healthy subjects

Objectives: To improve understanding of the preclinical stage of colonic inflammation by exploring the existence of a link between early inflammatory changes in the colonic mucosa and the systemic redox balance. Methods: Clinical characteristics, a fasting blood draw, and mucosal biopsies from the right, left, and sigmoid-rectum colonic tracts collected from 28 healthy individuals (14/14 males/females) who underwent colonoscopy. Myeloperoxidase (MPO) positive cells infiltrating colonic mucosa specimens were assessed by immunohistochemistry, and patients divided into high or low MPO expressing cells/optical field groups (MPOhighor MPOlow, respectively).The systemic oxidative balance has been studied through derived-Reactive Oxygen Metabolites (d-ROMs), Biological Antioxidant Potential (BAP), and Lipoperoxide-cholesterol Oxidizing (LP-CHOLOX) tests on serum. Results: MPOhighpatients demonstrated an increased systemic oxidative stress compared to MPOlowindividuals (P = 0.035), especially when MPO is referred to the left-sided colonic mucosa (P = 0.007). MPOlowsubjects in the sigmoid-rectum showed a significant higher antioxidant capacity in the serum (P < 0.02). Sex-specific differences in MPO expression (male and female: 4.6 \ub1 3.2 and 2.6 \ub1 1.5 MPO-positive cells/optical field, respectively, P = 0.044), and a decreasing gradient in MPO expression moving from the cecum to the rectum (ascendant, descendant, and sigmoid-rectum: 3.7 \ub1 2.8, 3.1 \ub1 1.7, and 1.4 \ub1 0.5, respectively, P = 0.012) were also found and discussed. Discussion: The study is the first demonstrating a connection between systemic redox balance and MPO expression in the colonic mucosa, according to the colonic tract and patient gender. Further research evaluating the MPO expression in the human colon and its relationship with pathological conditions could benefit from these results

Proposed roles of the immune response regulator-ThPOK in human colorectal cancer progression

Solid tumours are commonly infiltrated by several immune cells [1-3]. In cancer, immune cells play conflicting roles with both the potentials to eliminate or to promote malignancy. In contrast to infiltration of cells responsible for chronic inflammation, the presence of high numbers of lymphocytes, especially T cells, has been reported to be important as indicator of good prognosis in many types of cancer [4-7]. The thorough knowledge of both manners and pathways with which tumors are able to evade immune-mediated attack, once established, is therefore of crucial importance. The strategies to escape anti-tumor immune responses include the limited priming or differentiation of antitumor T cells and the role of tumor microenvironment in order to prevent infiltration or activation of effector phase functions. We proposed to evaluate the role of Th inducing POZ-Kruppel Factor (ThPOK), a transcriptional regulator of T cell fate, in tumour-induced immune system plasticity during colorectal carcinogenesis. Data were collected on the amounts of CD4+, CD8+ and CD56+ as well as on ThPOK+ cells infiltrated in normal colorectal mucosa (NM), in dysplastic aberrant crypt foci (microadenomas, MA, the earliest detectable lesions in colorectal carcinogenesis) and in colorectal carcinomas (CRC); moreover, the colocalization of ThPOK with the above-mentioned markers of immune cells was evaluated using confocal microscopy. Interestingly, ThPOK showed a prominent increase since MA. A strong colocalization of ThPOK with CD4 both in NM and in MA was observed, weaker in carcinomas. Surprisingly, there was a peak in the colocalization levels of ThPOK with CD8 in MA, which was evident, although to a lesser extent, also in carcinomas. In conclusion, according to the data of the present study, ThPOK may be considered a central regulator of the earliest events in the immune system during colorectal cancer development. The novelty of the present study is the proposed role of ThPOK in influencing the immune response against cancer cells. References [1] Dunn et al. (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21: 137-148. [2] Knaapen et al. (2006) Neutrophils and respiratory tract DNA damage and mutagenesis: a review. Muta-genesis 21: 225-236. [3] Coussens and Werb (2002) Inflammation and cancer. Nature 420: 860-867. [4] Watt and House (1978) Colonic carcinoma: a quantitative assessment of lymphocyte infiltration at the periphery of colonic tumors related to prognosis. Cancer 41: 279-282. [5] Galon et al. (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313: 1960-1964. [6] Pagès et al. (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 27: 5944-5951. [7] Mlecnik et al. (2010) Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal. Gastroenterology 138: 1429-1434

Aberrant crypt foci and microadenoma as markers for colon cancer.

Foci of aberrant crypts similar to those seen in experimental animals exposed to colon carcinogens have been identified and quantified on the mucosal surface of fixed resections of human colon after methylene blue staining. Many of the foci in humans showed dysplasia on histologic examination and were considered to be microadenoma (MA). These lesions may be precursors for adenomatous polyps and colorectal cancer. Rats and mice initiated with azoxymethane, then fed diets containing sucrose or casein heated at 180 degrees C to stimulate normal cooking conditions, had three to five times more large MA after 100 days than controls. Thus, cooked sugar and protein contain promoters of the growth of colonic MA. 5-Hydroxymethylfuraldehyde was identified as a promoter in cooked sugar

Matrix metalloproteinases 15 and 19 are stromal regulators of colorectal cancer development from the early stages

Matrix metalloproteinases (MMPs) have been well characterized for their ability to degrade extracellular matrix proteins and, thus, they have been studied to elucidate their involvement in both tumor development and progression. In the present study, attention was focused on MMP-15 and MMP-19, two less known members of the MMP family. The expression profile of MMP-15 and -19 was assayed in samples of normal colorectal mucosa, microadenomas and cancer using confocal analysis, western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Both qRT-PCR and western blotting showed that MMP-15 and MMP-19 appeared to be upregulated during colorectal tumorigenesis, with different expression patterns: MMP-15 expression level increases from normal mucosa to microadenomas, with a reduced level in cancer with respect to microadenomas; the semiquantitative immunofluorescence analysis showed a stromal localization of this protein in the early phases of neoplastic transformation. Increasing amount of MMP-19 mRNA and protein levels were observed in the progression of colonic lesions; MMP-19 staining increased in the normal mucosa-microadenoma-carcinoma sequence. Such different expression patterns, are probably due to the different roles played in colorectal tumorigenesis by these two molecules. Conflicting data on the role of these proteins in tumor progression have been reported, thus, an improved understandingof the biological roles of MMPs, in particular the lesser known members such as MMP-15 and 19, in colorectal cancer may lead to a re-evaluation of the use of MMP inhibitors and suggests the need of integrated translational studies on MMP expression patterns

Attenuated polyposis of the large bowel: a morphologic and molecular approach

Attenuated polyposis could be defined as a variant of familial adenomatous polyposis (FAP) in which synchronous polyps of the large bowel range between 10 and 99. We analysed all cases of attenuated polyposis observed over the last 30 years with the objectives: (A) to classify the disease according to different type and proportion of polyps; (B) To ascertain the contribution of APC and MutYH genes; (C) to discover features which could arise the suspicion of mutations; (D) To obtain indications for management and follow-up. 84 individuals in 82 families were studied. Polyps were classified into four groups as adenoma, hyperplastic, other serrated lesions or others; APC and MutYH mutations were assessed. Mean age at diagnosis was 54 ± 14 years in men and 48 ± 13 in women (P = 0.005). Polyps were more numerous in women (37 ± 26 vs 29 ± 22). Sixty % of patients underwent bowel resection, mainly for cancer; the remaining were managed through endoscopy. A total of 2586 polyps were detected at diagnostic endoscopy: 2026 (80 %) were removed and analysed. Adenomas were diagnosed in 1445 (70 %), hyperplastic polyps in 541 (26 %), other serrated lesions in 61 (2.9 %). Adenomas and hyperplastic lesions were detected in the majority of patients. In 68 patients (81 %) in whom studies were executed, APC mutations were found in 8 and MutYH mutations in 10. Genetic variants were more frequent in women (12 vs 6, P = 0.039). Taking into consideration the prevalent (&gt;50 %) histology and presence of mutations, patients could be subdivided into four groups: (1) APC mutated polyposis (AFAP), when adenomas were &gt;50 % and APC mutations detected (no. 8, 10 %); (2) MutYH mutated polyposis (MAP), adenomas &gt;50 % and biallelic MutYH mutations (no. 10, 12 %); (1) attenuated polyposis without detectable mutations, prevalence of adenomas, 48 cases (57 %); (1) hyperplastic-serrated polyposis, with prevalence (&gt;50 %) of hyperplastic/other serrated lesions and no constitutional mutation (no. 18, 21 %). Aggregation of tumors, cancer in probands, distribution of polyps and other clinical characteristics showed no difference among the four groups. In conclusions, AFAP and MAP, the polyposis labeled by constitutional mutations, represented about 25 % of all attenuated polyposis. Mutation-associated cases showed an earlier age of onset of polyps and were more frequent in the female sex