The Role of PDGFs and PDGFRs in Colorectal Cancer.

Introduction. Colorectal cancer (CRC) is an important cause of morbidity and mortality worldwide. Angiogenesis was reported as one important mechanism activated in colorectal carcinogenesis. Tumor microenvironment associated angiogenesis involves a large spectrum of signaling molecules and deciphering their role in colorectal carcinogenesis still represents a major challenge. The aim of our study is to point out the diagnosis and prediction role of PDGF family and their receptors in colorectal carcinogenesis. Material and Methods. A systematic search in Medline and PubMed for studies reporting the role of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) in tumor biology related to CRC was made. Results. PDGFs are important growth factors for normal tissue growth and division, with an important role in blood vessel formation. PDGFs/PDGFRs signaling pathway has been demonstrated to be involved in angiogenesis mainly by targeting pericytes and vascular smooth muscle cells. High levels of PDGF-BB were reported in CRC patients compared to those with adenomas, while elevated levels of PDGFR α/ß in the stroma of CRC patients were correlated with invasion and metastasis. Moreover, PDGF-AB and PDGF-C were correlated with early diagnosis, cancer grading, and metastatic disease. Conclusions. Both PDGFs and PDGFRs families play an important role in colorectal carcinogenesis and could be considered to be investigated as useful biomarkers both for diagnosis and treatment of CRC.

Is there a correlation between peripheral blood expression of angiogenic transcriptional factors/receptors and colorectal cancer?

PURPOSE: The aim of this study was to evaluate whether there is a correlation between peripheral blood expression of angiogenic transcriptional factors/receptors and colorectal cancer (CRC). METHODS: Eighty six blood samples collected from patients with CRC (N=42), adenomas and/or hyperplastic polyps(AP, N=30) and individuals without colon pathology (control group/CTR, N=14) were used for this study. Twelve transcription factors and receptors were assessed by qRT-PCR in a case-control study. The molecules with a minimum of 30% differences in gene expression for CRC and AP compared to CTR were then analyzed separately for each sample. Gene expression was evaluated relatively to the CTR after normalization to the large ribosomal protein PO (RPLPO) housekeeping gene, and the differential expression between studied groups was assessed by ANOVA. RESULTS: Seven out of 12 genes presented differences in expression between 10-29% in CRC and/or AP compared to CTR. Considering the selection criteria, we further individually evaluated the levels of expression of 5 genes that had a minimum of 30% expression in the case-control study. Our data showed a significant up-regulation of platelet derived growth factor (PDGF) C in the blood of the patients with CRC compared to CTR (p=0.007). Likewise, clusterin (CLU) was significantly up-regulated both in CRC and AP groups compared to healthy subjects (p=0.01). For VEGFR1, PDGFRA and TGFB1 we didn't find significantly differential expression between any of the studied groups, even if increased levels were observed in both CRC and AP vs CTR. CONCLUSIONS: The results of our study indicated that increased blood level of PDGFC mRNA was associated with the presence of CRC (p=0.007). Additionally, high levels of circulating CLU mRNA were observed in both malignant and benign colorectal pathologies.

Can we change our microbiome to prevent colorectal cancer development?

BACKGROUND: Colorectal cancer represents an important disease as one of the major causes of death worldwide. Although a lot of genetic and epigenetic research has been conducted, all the pieces of the puzzle of colorectal cancer carcinogenesis have not yet been identified. New recent data has highlighted that gut microbiota could have an influence on colorectal carcinogenesis. Gut microbiota represents the microbe population living in the human intestine and contains tens of trillions of microorganisms. MATERIAL AND METHODS: A systematic search in Medline and PubMed for studies reporting the influence of gut microbiota and inflammation on patients with colorectal cancer was made. RESULTS: In this review we discuss many of the specific bacteria, as well as their metabolites which may have an important role in development of colorectal cancer. Furthermore, we emphasize the molecular mechanisms modulated by gut microbiota, which promote inflammation, toxic metabolites, DNA damaging and pro-carcinogenic compounds, as support for colorectal carcinogenesis. The interrelation between microbiota and inflammation is complex because bacteria and inflammation could mutually impact upon each other. In this context, both endogenous and exogenous miRNAs may have an important role to modulate tumor-related inflammation in colorectal cancer. CONCLUSIONS: Better understanding of the role of gut microbiota in colorectal carcinogenesis could provide promising new directions to improve both prevention and treatment of colorectal cancer. Moreover, the discovery of novel biomarkers in the gut microbiome in order to detect colorectal cancer in an early stage or even in a precancerous stage is of outmost importance.

Role of C5b-9 complement complex and response gene to complement-32 (RGC-32) in cancer.

Complement system activation plays an important role in both innate and acquired immunity, with the activation of complement and the subsequent formation of C5b-9 terminal complement complex on cell membranes inducing target cell death. Recognition of this role for C5b-9 leads to the assumption that C5b-9 might play an antitumor role. However, sublytic C5b-9 induces cell cycle progression by activating signal transduction pathways and transcription factors in cancer cells, indicating a role in tumor promotion for this complement complex. The induction of the cell cycle by C5b-9 is dependent upon the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/FOXO1 and ERK1 pathways in a Gi protein-dependent manner. C5b-9 also induces response gene to complement (RGC)-32, a gene that plays a role in cell cycle promotion through activation of Akt and the CDC2 kinase. RGC-32 is expressed by tumor cells and plays a dual role in cancers, in that it has both a tumor suppressor role and tumor-promoting activity. Thus, through the activation of tumor cells, the C5b-9-mediated induction of the cell cycle plays an important role in tumor proliferation and oncogenesis.

Systemic sclerosis-polymyositis overlap syndrome associated with autoimmune hepatitis and cerebral vasculitis.

Autoimmune hepatitis (AIH) is a chronic disorder characterized by persistent hepatocellular inflammation and necrosis. AIH overlap syndromes with other autoimmune diseases have been reported, including connective tissue diseases (CTD). Reports of AIH in systemic sclerosis (SSc), however, are scarce and have been particularly described in the limited SSc subtype. We report a case of systemic sclerosis-polymyositis overlap syndrome that developed AIH and subsequently, cerebral vasculitis. To our knowledge, this is the first report of such a complex mosaic of autoimmunity. We also review the literature regarding scleroderma-related AIH.

Epigenetic modifications induced by RGC-32 in colon cancer.

First described as a cell cycle activator, RGC-32 is both an activator and a substrate for CDC2. Deregulation of RGC-32 expression has been detected in a wide variety of human cancers. We have now shown that RGC-32 is expressed in precancerous states, and its expression is significantly higher in adenomas than in normal colon tissue. The expression of RGC-32 was higher in advanced stages of colon cancer than in precancerous states or the initial stages of colon cancer. In order to identify the genes that are regulated by RGC-32, we used gene array analysis to investigate the effect of RGC-32 knockdown on gene expression in the SW480 colon cancer cell line. Of the 230 genes that were differentially regulated after RGC-32 knockdown, a group of genes involved in chromatin assembly were the most significantly regulated in these cells: RGC-32 knockdown induced an increase in acetylation of histones H2B lysine 5 (H2BK5), H2BK15, H3K9, H3K18, and H4K8. RGC-32 silencing was also associated with decreased expression of SIRT1 and decreased trimethylation of histone H3K27 (H3K27me3). In addition, RGC-32 knockdown caused a significantly higher percentage of SW480 cells to enter S phase and subsequently G2/M. These data suggest that RGC-32 may contribute to the development of colon cancer by regulating chromatin assembly.

The long-term evolution of chronic hepatitis B acquired in childhood.

UNLABELLED: The AIM of this study was to assess the long-term evolution of chronic hepatitis B acquired in childhood. METHODS: The study was carried out in 2007 - 2008 on a group of 77 adult patients who were diagnosed with chronic hepatitis B in childhood. The actual assessment included epidemiological, clinical, biological and virological data, ultrasound examination in all patients and liver histology in 3 patients. RESULTS: From the 77 patients, 69 were HBeAg positive and the other 8 patients were anti-HBe positive when the diagnosis was made in their childhood. Thirty-seven patients from the HBeAg positive group and 2 patients from the anti-HBe group had been treated in childhood with IFN-alpha and the other 38 patients remained untreated (32 patients with HBeAg positive and 6 patients anti-HBe positive). Overall, 78.26% seroconverted to anti-HBe (87.50% untreated and 70.27% of patients treated with IFN). After a median follow-up period of 13 years, 36 patients from the HBeAg positive group (48.65% of treated patients and 56.25% of untreated ones) became inactive carriers. Seroconversion to anti-HBs, in the HBeAg positive group, occurred in 10.14% of cases (8.1% in treated patients) without statistical significance. Three patients from the whole group developed cirrhosis but none developed hepatocellular carcinoma. CONCLUSION: The long-term outcome in our patients with CHB acquired in childhood did not differ between treated and untreated patients.

Role of response gene to complement 32 in diseases.

The role of response gene to complement (RGC)-32 as a cell cycle regulator has been attributed to its ability to activate cdc2 kinases and to induce S-phase entry and mitosis. However, recent studies revealed novel functions for RGC-32 in diverse processes such as cellular differentiation, inflammation, and fibrosis. Besides responding to C5b-9 stimulation, RGC-32 expression is also induced by growth factors, hormones, and cytokines. Transforming growth factor beta activates RGC-32 through Smad and RhoA signaling, thus initiating smooth muscle cell differentiation. Accumulating evidence has drawn attention to the deregulated expression of RGC-32 in human malignancies, hyper-immunoglobulin E syndrome, and fibrosis. RCG-32 expression is up-regulated in cutaneous T cell lymphoma and colon, ovarian, and breast cancer, but down-regulated in invasive prostate cancer, multiple myeloma, and drug-resistant glioblastoma. A better understanding of the mechanism by which RGC-32 contributes to the pathogenesis of these diseases will provide new insights into its therapeutic potential. In this review we provide an overview of this field and discuss the most recent research on RGC-32.

Cancer mortality in Romania, 1955-2004. Digestive sites: esophagus, stomach, colon and rectum, pancreas, liver, gallbladder and biliary tree.

AIM: Until recently, gastric cancer was the most frequent digestive neoplasia in our country. Our study presents the first synthesis of data regarding mortality rates from digestive cancers, for a period covering 50 years, in Romania. METHODS: Age-standardized mortality rates /100,000 population, general and/or per gender, concerning six digestive cancers, were identified from the statistics of IARC/OMS (Lyon, France) (years 1955-2002) and of the Ministry of Public Health (Bucharest, Romania) (year 2004). For 2002, incidence and mortality rates per sex from digestive cancers were available and case fatality ratios could be calculated as an approximation of survival rates, as well as sex ratio. RESULTS: Age standardized mortality rates per sex and cancer site registered the following changes: esophageal cancer increased from 2.03/0.62 (M/F) to 2.8/0.5; gastric cancer registered a decrease, from 33.14/18.77 to 17.0/6.6; colorectal cancer increased from 4.65/4.57 to 13.6/9.0; pancreatic cancer increased from 5.50/2.92 to 8.1/4.2 and liver cancer (including peripheric cholangiocarcinoma) increased from 1.77/0.83 to 8.8/3.9. In our population, the case fatality ratio appeared to be better only in colorectal cancer, 0.61 in males and 0.62 in females, respectively. Sex ratio was highest for esophageal cancer (males/females 5.8/1) and lowest for colorectal cancer (1.5/1). CONCLUSIONS: Our study found opposite trends in the mortality rates from digestive cancers, with gastric cancer rates decreasing and the other five digestive cancers increasing. A new hierarchy of digestive cancers has been drawn up, with colorectal cancer as the main cause of death, and gastric cancer in second position, followed by pancreatic, liver, esophageal, and gallbladder and biliary tree cancers.

Trends of mortality rates from gastric cancer and colorectal cancer in Romania, 1955-2003.

BACKGROUND: Steady and persisting falls in gastric cancer (GC) mortality rates have been observed worldwide in the last 50 years, and in Romania too. Colorectal cancer (CRC) is presently the most frequent digestive neoplasia in the Western countries. An increase of CRC incidence and mortality rates has been reported recently in Eastern European countries, including Romania. METHODS: Mortality data from GC and CRC, derived from population based mortality statistics, have been available on a national scale for 1955-2003. The data were identified from the statistics of the Ministry of Health (Bucharest, Romania) and of IARC/OMS (Lyon, France). GC and CRC mortality rates global and/or per gender were registered by time intervals. After 1995, only data on general mortality rates were available. RESULTS: Between 1955-59 and 1990-92, GC mortality rates/100,000 decreased from 33.14 to 17.70 in males and from 18.77 to 7.00 in females. Between 1995 and 2003, general mortality rates/100,000 from GC remained stable (17.54 and 17.74, respectively). Between 1955-59 and 1990-92, CRC mortality rates/100,000/gender increased from 4.65 to 10.10 in males and from 4.57 to 7.40 in females. Between 1995 and 2003, CRC general mortality rates/100 000 increased from 14.90 to 19.20. CONCLUSIONS: Our study reports opposite trends in GC and CRC mortality rates in the period under study, with GC declining and CRC increasing. A male predominance was registered in both neoplasms under study, more obvious in GC (male/female ratio: 2-3/1) than in CRC (male/female ratio: 1.5/1).

Pill esophagitis.

Pill esophagitis is a rare clinical diagnosis. We report a series of two patients who experienced ulcerative esophagitis while taking doxycycline (patient 1) and alendronate (patient 2). Both patients presented with retrosternal pain, odynophagia and dysphagia. Symptoms developed after 3 days of treatment with doxycycline in patient 1 and after 3 months of treatment with alendronate in patient 2. Endoscopy revealed ulcerative lesions in the mid-esophagus, sparing the distal esophagus. Biopsies showed inflammatory infiltrate (patient 1) and ulceration and hyperplastic cells (patient 2). Patient 1 recovered completely endoscopically after discontinuation of the antibiotic and a one month course of sucralfate treatment. Patient 2 did not accept the discontinuation of alendronate therapy. She also had a course of one month treatment with sucralfate. At one, two and even at seven months after the first diagnosis, endoscopy still showed the persistence of millimetric defects of epithelisation. She is still under endoscopical survey. In conclusion, doxycycline and alendronate can cause chemical esophagitis when taken improperly. In adults and elderly patients exclusion of esophageal carcinoma by histology is necessary. Continuation of treatment with the offending drug can delay healing. Pill esophagitis is a preventable cause of morbidity that consists of giving simple advice of how and when to take medication.