Metformin induces apoptosis and alters cellular responses to oxidative stress in Ht29 colon cancer cells: Preliminary findings

Accumulating evidence suggests that metformin, used as an antidiabetic drug, possesses anti-cancer properties. Metformin reduced the incidence and growth of experimental tumors in vivo. In a randomized clinical trial among nondiabetic patients, metformin treatment significantly decreased the number of aberrant crypt foci compared to the untreated group with a follow-up of 1 month. In our study, HT29 cells were treated with graded concentrations of metformin, 10 mM/25 mM/50 mM for 24/48 h. We performed immunofluorescence experiments by means of confocal microscopy and western blot analysis to evaluate a panel of factors involved in apoptotic/autophagic processes and oxidative stress response. Moreover, HT29 cells treated with metformin were analyzed by a flow cytometry assay to detect the cell apoptotic rate. The results demonstrate that metformin exerts growth inhibitory effects on cultured HT29 cells by increasing both apoptosis and autophagy; moreover, it affects the survival of cultured cells inhibiting the transcriptional activation of Nuclear factor E2-related factor 2 (NRF-2) and nuclear factor-kappa B (NF-\u3baB). The effects of metformin on HT29 cells were dose- and time-dependent. These results are very intriguing since metformin is emerging as a multi-faceted drug: It has a good safety profile and is associated with low cost and might be a promising candidate for the prevention or the treatment of colorectal cancer

Th Inducing POZ-Kruppel Factor (ThPOK) Is a Key Regulator of the Immune Response since the Early Steps of Colorectal Carcinogenesis

We purposed to evaluate the role of Th inducing POZ-Kruppel Factor (ThPOK), a transcriptional regulator of T cell fate, in tumour-induced immune system plasticity in colorectal carcinogenesis. The amounts of CD4+, CD8+ and CD56+ and ThPOK+ cells infiltrate in normal colorectal mucosa (NM), in dysplastic aberrant crypt foci (microadenomas, MA), the earliest detectable lesions in colorectal carcinogenesis, and in colorectal carcinomas (CRC), were measured, and 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, in carcinomas, too. 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, decreasing the immune response against cancer cells

Colon cancer in a 12-year-old girl with hypertriglyceridemia

Colorectal cancer is usually considered a disease of the elderly; however, in a small fraction of patients (2%-3% of all affected individuals), colorectal malignancies may develop earlier. The reasons whereby some individuals develop colorectal cancer at a young age are poorly understood. In a 12-year-old girl, a malignancy was diagnosed in the ascending colon. There was no familial history of Lynch syndrome or familial adenomatous polyposis. The metabolic profile of the patient revealed hypertriglyceridemia and low high-density lipoprotein cholesterol levels at nine years, then diagnosed as familial hypertriglyceridemia due to a constitutional mutation in the APOA5 gene (c.427delC). Moreover, variants possibly increasing the risk of cancer were detected in MSH6 (c.3438+11_3438+14delCTTA, intron 5) and APC (I1307K). The patient showed a rather unusual dietary pattern, since her basic alimentation from weaning consisted almost exclusively of meat homogenates and, subsequently, roasted meat or cutlets. Other foods, including fish, vegetables, sweets, and pasta, were refused. In this case, genetic and environmental factors could have acted in a particularly accelerated manner. Indeed, the genetic background of the patient (familial hypertriglyceridemia and polymorphisms predisposing to colorectal cancer) may have favored a dietary-driven colorectal carcinogenesis, resulting in an extremely early onset development of malignancy

Aberrant crypt foci in patients with colorectal cancer.

Aberrant crypt foci (ACF) are clusters of abnormally large colonic crypts identified on the mucosal surface of the human colon. They are thought to be preneoplastic lesions. The aim of the present study was to compare density (number of ACF per square cm of mucosal surface), crypt multiplicity (number of crypts per ACF) and histology of ACF in colonic resections of colorectal cancer patients resident in two Italian provinces with a twofold difference in colorectal cancer incidence rates. Thirty-two and 26 colonic resections were collected after operation in Ragusa (Southern Italy) and Modena (Northern Italy), respectively, and fixed in 10% formalin. Mucosal layers were observed under a light microscope at 25x after staining with methylene blue. Density of ACF was significantly higher in Modena (median 0.101 ACF cm(-2)) than in Ragusa (0.049, P = 0.001), whereas there was no difference in crypt multiplicity. ACF were classified into three groups according to histological features: ACF with mild alterations (hypertrophic ACF, 73%), ACF with hyperplasia (hyperplastic ACF, 17%) and ACF with dysplasia (microadenomas, 10%). The proportions of ACF in the three groups were similar in the two provinces. Density of ACF was higher and crypt multiplicity lower proceeding from proximal to distal large bowel. Microadenomas were observed only in the colon, whereas hyperplastic ACF were more frequent in the rectum. In conclusion, density of ACF correlates with colorectal cancer rates in two Italian provinces, and shows a positive gradient from proximal to distal large bowel. Histology of ACF suggests that they may be precursors of both hyperplastic and adenomatous polyps. These data provide further evidence of the role of ACF in human colorectal carcinogenesis

The effect of family size on estimates of the frequency of hereditary non-polyposis colorectal cancer.

Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is currently based on phenotypical analysis of an expanded pedigree. Diagnostic guidelines ('Amsterdam criteria') proposed by the International Collaborative Group on HNPCC are often too stringent for use with small families. There is also the possibility of false-positive diagnosis in large pedigrees that may contain chance clusters of tumours. This study was conducted to determine the effect of family size on the probability of diagnosing HNPCC according to the Amsterdam criteria. A total of 1052 patients with colorectal cancer were classified as HNPCC or non-HNPCC according to the Amsterdam criteria. Associations between this diagnosis and the size of the first-degree pedigree were evaluated in logistic regression and linear discriminant analyses. Logistic regression showed a significant association for family size with the Amsterdam-criteria-based HNPCC diagnosis. Linear discriminant analysis showed that HNPCC diagnosis was most likely to occur when first-degree pedigrees contained more than seven relatives. Failure to consider family size in phenotypic diagnosis of HNPCC can lead to both under- and overestimation of the frequency of this disease. Small pedigrees must be expanded to reliably exclude HNPCC. Positive diagnoses based on assessment of eight or more first-degree relatives should be supported by other clinical features

ITALIAN CANCER FIGURES - REPORT 2015: The burden of rare cancers in Italy = I TUMORI IN ITALIA - RAPPORTO 2015: I tumori rari in Italia

OBJECTIVES: This collaborative study, based on data collected by the network of Italian Cancer Registries (AIRTUM), describes the burden of rare cancers in Italy. Estimated number of new rare cancer cases yearly diagnosed (incidence), proportion of patients alive after diagnosis (survival), and estimated number of people still alive after a new cancer diagnosis (prevalence) are provided for about 200 different cancer entities. MATERIALS AND METHODS: Data herein presented were provided by AIRTUM population- based cancer registries (CRs), covering nowadays 52% of the Italian population. This monograph uses the AIRTUM database (January 2015), which includes all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to the International Classification of Diseases for Oncology (ICD-O-3). Data underwent standard quality checks (described in the AIRTUM data management protocol) and were checked against rare-cancer specific quality indicators proposed and published by RARECARE and HAEMACARE (www.rarecarenet.eu; www.haemacare.eu). The definition and list of rare cancers proposed by the RARECAREnet "Information Network on Rare Cancers" project were adopted: rare cancers are entities (defined as a combination of topographical and morphological codes of the ICD-O-3) having an incidence rate of less than 6 per 100,000 per year in the European population. This monograph presents 198 rare cancers grouped in 14 major groups. Crude incidence rates were estimated as the number of all new cancers occurring in 2000-2010 divided by the overall population at risk, for males and females (also for gender-specific tumours).The proportion of rare cancers out of the total cancers (rare and common) by site was also calculated. Incidence rates by sex and age are reported. The expected number of new cases in 2015 in Italy was estimated assuming the incidence in Italy to be the same as in the AIRTUM area. One- and 5-year relative survival estimates of cases aged 0-99 years diagnosed between 2000 and 2008 in the AIRTUM database, and followed up to 31 December 2009, were calculated using complete cohort survival analysis. To estimate the observed prevalence in Italy, incidence and follow-up data from 11 CRs for the period 1992-2006 were used, with a prevalence index date of 1 January 2007. Observed prevalence in the general population was disentangled by time prior to the reference date (≤2 years, 2-5 years, ≤15 years). To calculate the complete prevalence proportion at 1 January 2007 in Italy, the 15-year observed prevalence was corrected by the completeness index, in order to account for those cancer survivors diagnosed before the cancer registry activity started. The completeness index by cancer and age was obtained by means of statistical regression models, using incidence and survival data available in the European RARECAREnet data. RESULTS: In total, 339,403 tumours were included in the incidence analysis. The annual incidence rate (IR) of all 198 rare cancers in the period 2000-2010 was 147 per 100,000 per year, corresponding to about 89,000 new diagnoses in Italy each year, accounting for 25% of all cancer. Five cancers, rare at European level, were not rare in Italy because their IR was higher than 6 per 100,000; these tumours were: diffuse large B-cell lymphoma and squamous cell carcinoma of larynx (whose IRs in Italy were 7 per 100,000), multiple myeloma (IR: 8 per 100,000), hepatocellular carcinoma (IR: 9 per 100,000) and carcinoma of thyroid gland (IR: 14 per 100,000). Among the remaining 193 rare cancers, more than two thirds (No. 139) had an annual IR <0.5 per 100,000, accounting for about 7,100 new cancers cases; for 25 cancer types, the IR ranged between 0.5 and 1 per 100,000, accounting for about 10,000 new diagnoses; while for 29 cancer types the IR was between 1 and 6 per 100,000, accounting for about 41,000 new cancer cases. Among all rare cancers diagnosed in Italy, 7% were rare haematological diseases (IR: 41 per 100,000), 18% were solid rare cancers. Among the latter, the rare epithelial tumours of the digestive system were the most common (23%, IR: 26 per 100,000), followed by epithelial tumours of head and neck (17%, IR: 19) and rare cancers of the female genital system (17%, IR: 17), endocrine tumours (13% including thyroid carcinomas and less than 1% with an IR of 0.4 excluding thyroid carcinomas), sarcomas (8%, IR: 9 per 100,000), central nervous system tumours and rare epithelial tumours of the thoracic cavity (5%with an IR equal to 6 and 5 per 100,000, respectively). The remaining (rare male genital tumours, IR: 4 per 100,000; tumours of eye, IR: 0.7 per 100,000; neuroendocrine tumours, IR: 4 per 100,000; embryonal tumours, IR: 0.4 per 100,000; rare skin tumours and malignant melanoma of mucosae, IR: 0.8 per 100,000) each constituted <4% of all solid rare cancers. Patients with rare cancers were on average younger than those with common cancers. Essentially, all childhood cancers were rare, while after age 40 years, the common cancers (breast, prostate, colon, rectum, and lung) became increasingly more frequent. For 254,821 rare cancers diagnosed in 2000-2008, 5-year RS was on average 55%, lower than the corresponding figures for patients with common cancers (68%). RS was lower for rare cancers than for common cancers at 1 year and continued to diverge up to 3 years, while the gap remained constant from 3 to 5 years after diagnosis. For rare and common cancers, survival decreased with increasing age. Five-year RS was similar and high for both rare and common cancers up to 54 years; it decreased with age, especially after 54 years, with the elderly (75+ years) having a 37% and 20% lower survival than those aged 55-64 years for rare and common cancers, respectively. We estimated that about 900,000 people were alive in Italy with a previous diagnosis of a rare cancer in 2010 (prevalence). The highest prevalence was observed for rare haematological diseases (278 per 100,000) and rare tumours of the female genital system (265 per 100,000). Very low prevalence (<10 prt 100,000) was observed for rare epithelial skin cancers, for rare epithelial tumours of the digestive system and rare epithelial tumours of the thoracic cavity. COMMENTS: One in four cancers cases diagnosed in Italy is a rare cancer, in agreement with estimates of 24% calculated in Europe overall. In Italy, the group of all rare cancers combined, include 5 cancer types with an IR>6 per 100,000 in Italy, in particular thyroid cancer (IR: 14 per 100,000).The exclusion of thyroid carcinoma from rare cancers reduces the proportion of them in Italy in 2010 to 22%. Differences in incidence across population can be due to the different distribution of risk factors (whether environmental, lifestyle, occupational, or genetic), heterogeneous diagnostic intensity activity, as well as different diagnostic capacity; moreover heterogeneity in accuracy of registration may determine some minor differences in the account of rare cancers. Rare cancers had worse prognosis than common cancers at 1, 3, and 5 years from diagnosis. Differences between rare and common cancers were small 1 year after diagnosis, but survival for rare cancers declined more markedly thereafter, consistent with the idea that treatments for rare cancers are less effective than those for common cancers. However, differences in stage at diagnosis could not be excluded, as 1- and 3-year RS for rare cancers was lower than the corresponding figures for common cancers. Moreover, rare cancers include many cancer entities with a bad prognosis (5-year RS <50%): cancer of head and neck, oesophagus, small intestine, ovary, brain, biliary tract, liver, pleura, multiple myeloma, acute myeloid and lymphatic leukaemia; in contrast, most common cancer cases are breast, prostate, and colorectal cancers, which have a good prognosis. The high prevalence observed for rare haematological diseases and rare tumours of the female genital system is due to their high incidence (the majority of haematological diseases are rare and gynaecological cancers added up to fairly high incidence rates) and relatively good prognosis. The low prevalence of rare epithelial tumours of the digestive system was due to the low survival rates of the majority of tumours included in this group (oesophagus, stomach, small intestine, pancreas, and liver), regardless of the high incidence rate of rare epithelial cancers of these sites. This AIRTUM study confirms that rare cancers are a major public health problem in Italy and provides quantitative estimations, for the first time in Italy, to a problem long known to exist. This monograph provides detailed epidemiologic indicators for almost 200 rare cancers, the majority of which (72%) are very rare (IR<0.5 per 100,000). These data are of major interest for different stakeholders. Health care planners can find useful information herein to properly plan and think of how to reorganise health care services. Researchers now have numbers to design clinical trials considering alternative study designs and statistical approaches. Population-based cancer registries with good quality data are the best source of information to describe the rare cancer burden in a population

LonP1 Differently Modulates Mitochondrial Function and Bioenergetics of Primary Versus Metastatic Colon Cancer Cells

Mitochondrial Lon protease (LonP1) is a multi-function enzyme that regulates mitochondrial functions in several human malignancies, including colorectal cancer (CRC). The mechanism(s) by which LonP1 contributes to colorectal carcinogenesis is not fully understood. We found that silencing LonP1 leads to severe mitochondrial impairment and apoptosis in colon cancer cells. Here, we investigate the role of LonP1 in mitochondrial functions, metabolism, and epithelial-mesenchymal transition (EMT) in colon tumor cells and in metastasis. LonP1 was almost absent in normal mucosa, gradually increased from aberrant crypt foci to adenoma, and was most abundant in CRC. Moreover, LonP1 was preferentially upregulated in colorectal samples with mutated p53 or nuclear \u3b2-catenin, and its overexpression led to increased levels of \u3b2-catenin and decreased levels of E-cadherin, key proteins in EMT, in vitro. LonP1 upregulation also induced opposite changes in oxidative phosphorylation, glycolysis, and pentose pathway in SW480 primary colon tumor cells when compared to SW620 metastatic colon cancer cells. In conclusion, basal LonP1 expression is essential for normal mitochondrial function, and increased LonP1 levels in SW480 and SW620 cells induce a metabolic shift toward glycolysis, leading to EMT

Prevalence of metabolic syndrome and of symptoms of anxiety and depression in patients undergoing colonoscopy

Introduction Metabolic syndrome (MetS) is defined by metabolic and cardio-vascular impairments and is frequently associated with anxiety and depressive disorders. Both MetS and anxiety-depressive syndromes feature similar systemic inflammatory alterations. Inflammation of the large bowel is also a key factor for the development of colorectal cancer (CRC). Objective To measure the prevalence of MetS and symptoms of anxiety and depression among patients undergoing colonoscopy. Methods Cross-sectional study. Patients undergoing colonoscopy aged 40 or more, with negative history for neoplasia or inflammatory bowel disease, were enrolled. Data collected: colonoscopy outcome, presence/absence of MetS (IDF and ATP III criteria), presence/absence of depressive and anxiety symptoms assessed with HADS. Results The sample was made up of 53 patients (female 24, 45.3%). Mean age was 60.66 ± 9.08. At least one adenoma was found to 23 patients (43.3%). Prevalence of MetS ranged from 34% to 36% (ATP III and IDF criteria, respectively). Prevalence of depressive and anxiety symptoms was 20% and 33%, respectively. Conclusion Prevalence of MetS, anxiety and depressive symptoms among patients undergoing colonoscopy was higher than in the general population