A Novel Oncolytic Herpes Capable of Cell-Specific Transcriptional Targeting of CD133± Cancer Cells Induces Significant Tumor Regression.

The topic of cancer stem cells (CSCs) is of significant importance due to its implications in our understanding of the tumor biology as well as the development of novel cancer therapeutics. However, the question of whether targeting CSCs can hamper the growth of tumors remains mainly unanswered due to the lack of specific agents for this purpose. To address this issue, we have developed the first mutated version of herpes simplex virus-1 that is transcriptionally targeted against CD133+ cells. CD133 has been portrayed as one of the most important markers in CSCs involved in the biology of a number of human cancers, including liver, brain, colon, skin, and pancreas. The virus developed in this work, Signal-Smart 2, showed specificity against CD133+ cells in three different models (hepatocellular carcinoma, colorectal cancer, and melanoma) resulting in a loss of viability and invasiveness of cancer cells. Additionally, the virus showed robust inhibitory activity against in vivo tumor growth in both preventive and therapeutic mouse models as well as orthotopic model highly relevant to potential clinical application of this virus. Therefore, we conclude that targeting CD133+ CSCs has the potential to be pursued as a novel strategy against cancer. Stem Cells 2018;36:1154-1169.

RalA is overactivated in medulloblastoma.

Medulloblastoma (MDB) represents a major form of malignant brain tumors in the pediatric population. A vast spectrum of research on MDB has advanced our understanding of the underlying mechanism, however, a significant need still exists to develop novel therapeutics on the basis of gaining new knowledge about the characteristics of cell signaling networks involved. The Ras signaling pathway, one of the most important proto-oncogenic pathways involved in human cancers, has been shown to be involved in the development of neurological malignancies. We have studied an important effector down-stream of Ras, namely RalA (Ras-Like), for the first time and revealed overactivation of RalA in MDB. Affinity precipitation analysis of active RalA (RalA-GTP) in eight MDB cell lines (DAOY, RES256, RES262, UW228-1, UW426, UW473, D283 and D425) revealed that the majority contained elevated levels of active RalA (RalA-GTP) as compared with fetal cerebellar tissue as a normal control. Additionally, total RalA levels were shown to be elevated in 20 MDB patient samples as compared to normal brain tissue. The overall expression of RalA, however, was comparable in cancerous and normal samples. Other important effectors of RalA pathway including RalA binding protein-1 (RalBP1) and protein phosphatase A (PP2A) down-stream of Ral and Aurora kinase A (AKA) as an upstream RalA activator were also investigated in MDB. Considering the lack of specific inhibitors for RalA, we used gene specific silencing in order to inhibit RalA expression. Using a lentivirus expressing anti-RalA shRNA we successfully inhibited RalA expression in MDB and observed a significant reduction in proliferation and invasiveness. Similar results were observed using inhibitors of AKA and geranyl-geranyl transferase (non-specific inhibitors of RalA signaling) in terms of loss of in vivo tumorigenicity in heterotopic nude mouse model. Finally, once tested in cells expressing CD133 (a marker for MDB cancer stem cells), higher levels of RalA activation was observed. These data not only bring RalA to light as an important contributor to the malignant phenotype of MDB but introduces this pathway as a novel target in the treatment of this malignancy.

Increased colorectal cancer incidence in Iran: a systematic review and meta-analysis.

BACKGROUND: Colorectal cancer is the third most common cancer in Iran. The increasing trend of colorectal cancer incidence in Iran and the close relationship with the geographical location are the underlying reasons for this study. DATA SOURCE: Eleven databases, including MEDLINE, EMBASE, SCOPUS, and four other databases, for articles in Persian were searched from April 2014 to October 2014. Additional data were obtained from an online survey of the Central Library of Tabriz Faculty of Medicine. STUDY ELIGIBILITY CRITERIA: In this systematic review and meta-analysis, we included studies reporting different measures of incidence, age-standardized incidence rates, and crude incidence rates. All rates (per 100,000 person-years) were standardized to the world standard population. STUDY APPRAISAL AND SYNTHESIS METHODS: A preliminary review of the title and abstracts of these articles was used to exclude any that were clearly irrelevant. The full text review determined whether the article was relevant to our topic. All the potentially relevant manuscripts were reviewed by two other investigators (S.D., M.G.). A total of 39 studies (10 Persian and 29 English articles) from different provinces and diverse areas of Iran, were analyzed in this study using comprehensive meta-analysis software. For accuracy studies, we used estimated rates for males and females with 95 % confidence intervals. RESULTS: Age-standardized incidence rates were obtained based on the random effects model and were 8.16 (95 % CI: 6.64 to 9.68) and 6.17 (95 % CI: 5.01 to 7.32) for males and females, respectively. The random crude rates were 5.58 (95 % CI: 4.22 to 6.94) for males and 4.01 (95 % CI: 3.06 to 4.97) for females. CONCLUSIONS: Colorectal cancer incidence rates rise due to individual and environmental risk factors as well as improvement in the registry system and increase in access to health services. A more executed organized and structured system for collecting cancer data, in all cities and rural areas of the country, is an essential priority.

Overactivation of Ras signaling pathway in CD133+ MPNST cells.

Cancer stem cells (CSCs) are believed to be the regenerative pool of cells responsible for repopulating tumors. Gaining knowledge about the signaling characteristics of CSCs is important for understanding the biology of tumors and developing novel anti-cancer therapies. We have identified a subpopulation of cells positive for CD133 (a CSC marker) from human primary malignant peripheral nerve sheath tumor (MPNST) cells which were absent in non-malignant Schwann cells. CD133 was also found to be expressed in human tissue samples and mouse MPNST cells. CD133+ cells were capable of forming spheres in non-adherent/serum-free conditions. The activation levels of Ras and its downstream effectors such as ERK, JNK, PI3K, p38K, and RalA were significantly increased in this population. Moreover, the CD133+ cells showed enhanced invasiveness which was linked to the increased expression of ß-Catenin and Snail, two important proteins involved in the epithelial to mesenchymal transition, and Paxilin, a focal adhesion protein. Among other important characteristics of the CD133+ population, endoplasmic reticulum stress marker IRE1α was decreased, implying the potential sensitivity of CD133+ to the accumulation of unfolded proteins. Apoptotic indicators seemed to be unchanged in CD133+ cells when compared to the wild (unsorted) cells. Finally, in order to test the possibility of targeting CD133+ MPNST cells with Ras pathway pharmacological inhibitors, we exposed these cells to an ERK inhibitor. The wild population was more sensitive to inhibition of proliferation by this inhibitor as compared with the CD133+ cells supporting previous studies observing enhanced chemoresistance of these cells.

Identifying the main barriers for participation in a population-based colorectal cancer screening programme in East Azerbaijan, Iran.

Background: Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death worldwide. However, CRC is considered as one of the most preventable cancers by which the mortality rates reduce about 60% through implementing the screening programmes. The present study aimed to evaluate the main barriers of CRC screening in a defined population. Method: Healthy individuals from all regions of the state were invited to participate in different healthcare centres. They were assessed by a provided online risk assessment tool, which was completed for all recruited subjects, and has been developed to assess the CRC risk based on personal and family history of adenoma, CRC, and other high-risk diseases. Research team staff assessed all individuals by this tool and then eligible people according to their lifetime risk of CRC were included in the study. There was not any age restriction in this study. Colonoscopy and three stool-based tests including faecal occult blood test, faecal immunochemical test and stool DNA tests were performed. Results: Overall, 725 cases including 425 (58.6%) males and 300 (41.4%) females participated in the study. Lack of knowledge and attitude about screening programmes was the most common barrier, especially among women (68% for women versus 58% for men) and those from rural areas (88% in rural versus 55% in urban areas). Fear of colonoscopy and procedure complications and pain (48%), discomfort and anxiety from inserting a tube into the bowel (65% among females versus 43% among males) were reported commonly. Embarrassment and dignity were other complaints, especially in women (62% in females versus 35% in males). Conclusion: Increasing knowledge and attitude about the aims and benefits of screening programmes, acceptable and convenient communication of health systems with the general population are considered to be the key elements in the success and implementation of any screening programme.

Cross-cultural validation of stool Based Colorectal cancer screening methods in the North West of Iran.

Background: Globally, colorectal cancer (CRC) is the third most common cancer and the second leading cause of death from cancer. Incidence and mortality from CRCboth can be reduced and prevented using screening and early detection programs. The current study aimed to assess the feasibility of the colorectal cancer screening program in Northwest of Iran. Methods: The study designed as a cross-cultural analytic study, to evaluate the diagnostic accuracy of stool-based tests compared with colonoscopy, during 2016-2020. All individuals first were assessed with our CRC risk assessment tool, then eligible volunteers entered the study. Colonoscopy was performed on all participants, also stool-based tests including traditional guaiac, high-sensitivity guaiac-based, fecal immunochemical test (FIT), and multitarget stool DNA (Mt-sDNA) panel tests were performed. Results: Mt-sDNA test panel had a sensitivity of 77.8% (95% CI: 40-97.2)for detecting colorectal cancer with a specificity of 91.2% (95% CI:85.4-95.2). The FIT test alone had a lower sensitivity (66.7%; 95% CI:29.9-92.5) and almost the same specificity of 93.9% (95% CI: 88.7-97.2) for cancer detection. Mt-sDNA test had better diagnostic accuracy than the FIT (AUC = 0.85 vs 0.80), and is a more useful screening test. Positive and negative predictive values for cancer detection for both Mt-sDNA and FIT tests were almost the same results, however Mt-sDNA test had better NPV results than the FIT test alone. Conclusion: Our results showed that both Mt-sDNA panel and the FIT test had acceptable cut-off points for cancer detection, however, Mt-sDNA test had better diagnostic accuracy.

Impact of RAS/RAF mutations on clinical and prognostic outcomes in metastatic colorectal cancer.

Introduction: Early-activated RAS/RAF mutation status is a key molecular finding in colorectal cancer (CRC), while these mutations have been proposed as predictive and prognostic biomarkers. The present study has been designed as a longitudinal study to evaluate and summarize the different genotypes of metastatic CRC (mCRC), and assessing any association with the disease prognosis and clinicopathological characteristics. This study was performed in two main referral hospitals of Tabriz University of Medical Sciences, over three years (2016-2018). Methods: Mutations were detected by Idylla tests of KRAS/NRAS/BRAF among a total of 173 mCRCs, using surgically-resected specimens or biopsied samples. To evaluate the factors associated with overall survival (OS) and prognosis, the Cox proportional hazards model was used in two steps to estimate the outcome measures (hazard ratio, or HR) with a 95% confidence interval (CI). Results: The nominal 1 to 5-year OS rates were 78%, 65%, 55%, 46%, and 42%, respectively. KRAS mutations in codon 12 was an independent significant prognostic factor, as the patients with codon 12 mutations had a significantly lower OS (P Log-rank=0.049) and a higher hazard of mortality (HR=2.30; 95% CI: 0.95-5.58; P =0.066). Also, the mCRC patients with liver metastasis (HR=2.49; 95% CI: 1.49-12.52; P =0.002) and tumors of the distal colon (HR=3.36; 95% CI: 1.07-10.49; P =0.037) had a significantly worse prognosis. Conclusion: KRAS mutation in codon 12 was an independent significant poor prognostic factor, and patients with liver metastasis had a significantly worse prognosis. Routinely performing specific oncogenic tests may help improve the patients' prognosis and life expectancy.

Ras signaling influences permissiveness of malignant peripheral nerve sheath tumor cells to oncolytic herpes.

Lack of expression of neurofibromin in neurofibromatosis 1 and its lethal derivative, malignant peripheral nerve sheath tumors (MPNSTs), is thought to result in the overactivation of the Ras signaling pathway. Our previous studies have shown that cells with overactivation in the Ras pathway are more permissive to infection with herpes simplex virus 1 and its mutant version R3616. In this study, we show that among five different mouse MPNST cell lines, only the ones with elevated levels of Ras signaling are highly permissive to infection with oncolytic herpes G207. Specific inhibitors of the Ras, ERK, and JNK pathways all reduced the synthesis of viral proteins in MPNST cells. The cell lines that contained lower levels of Ras and decreased activation of downstream signaling components underwent an enhancement in apoptosis upon exposure to G207. Additionally, mouse SW10 Schwann cells were able to become infected by parental herpes but were found to be resistant to G207. The immortalization of these cell lines with the expression of SV40 large T antigen increased the levels of Ras activation and permissiveness to oncolytic herpes. A Ras/Raf kinase inhibitor reduced the synthesis of both herpes simplex virus-1 and G207 proteins in SW10 cells. The results of this study, therefore, introduce Ras signaling as a divergent turning point for the response of MPNST cells to an assault by oncolytic herpes.

Gene silencing for epidermal growth factor receptor variant III induces cell-specific cytotoxicity.

Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively active mutant form of EGFR that is expressed in 40% to 50% of gliomas and several other malignancies. Here, we describe the therapeutic effects of silencing EGFRvIII on glioma cell lines in vitro and in vivo. A small interfering RNA molecule against EGFRvIII was introduced into EGFRvIII-expressing glioma cells (U87Delta) by electroporation resulting in complete inhibition of expression of EGFRvIII as early as 48 h post-treatment. During EGFRvIII silencing, a decrease in the proliferation and invasiveness of U87Delta cells was accompanied by an increase in apoptosis (P < 0.05). Notably, EGFRvIII silencing inhibited the signal transduction machinery downstream of EGFRvIII as evidenced by decreases in the activated levels of Ras and extracellular signal-regulated kinase. A lentivirus capable of expressing anti-EGFRvIII short hairpin RNA was also able to achieve progressive silencing of EGFRvIII in U87Delta cells in addition to inhibiting cell proliferation, invasiveness, and colony formation in a significant manner (P < 0.05). Silencing EGFRvIII in U87Delta cultures with this virus reduced the expression of factors involved in epithelial-mesenchymal transition including N-cadherin, beta-catenin, Snail, Slug, and paxillin but not E-cadherin. The anti-EGFRvIII lentivirus also affected the cell cycle progression of U87Delta cells with a decrease in G(1) and increase in S and G(2) fractions. In an in vivo model, tumor growth was completely inhibited in severe combined immunodeficient mice (n = 10) injected s.c. with U87Delta cells treated with the anti-EGFRvIII lentivirus (P = 0.005). We conclude that gene specific silencing of EGFRvIII is a promising strategy for treating cancers that contain this mutated receptor.

Combination treatment of all-trans retinoic acid (ATRA) and γ-secretase inhibitor (DAPT) cause growth inhibition and apoptosis induction in the human gastric cancer cell line.

Current medication for gastric cancer patients has a low success rate with resistance and side effects. According to recent studies, γ-secretase inhibitors is used as therapeutic drugs in cancer. Moreover, all-trans retinoic acid (ATRA) is a natural compound proposed for the treatment/chemo-prevention of cancers. The aim of this study was to explore the effects of ATRA in combination with N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT) as γ-secretase inhibitor on viability and apoptosis of the AGS and MKN-45 derived from human gastric cancer. AGS and MKN-45 gastric cancer cell lines were treated with different concentrations of ATRA or DAPT alone or ATRA plus DAPT. The viability, death detection and apoptosis of cells was examined by MTT assay and Ethidium bromide/acridine orange staining. The distribution of cells in different phases of cell cycle was also evaluated through flow cytometry analyses. In addition, caspase 3/7 activity and the expression of caspase-3 and bcl-2 were examined. DAPT and ATRA alone decreased gastric cancer cells viability in a concentration dependent manner. The combination of DAPT and ATRA exhibited significant synergistic inhibitory effects. The greater percentage of cells were accumulated in G0/G1 phase of cell cycle in combination treatment. The combination of DAPT and ATRA effectively increased the proportion of apoptotic cells and the level of caspase 3/7 activities compared to single treatment. Moreover, augmented caspase-3 up-regulation and bcl-2 down-regulation were found following combined application of DAPT and ATRA. The combination of DAPT and ATRA led to more reduction in viability and apoptosis in respect to DAPT or ATRA alone in the investigated cell lines.

Main Risk Factors Association with Proto-Oncogene Mutations in Colorectal Cancer

Objective: Although several factors have been shown to have etiological roles in colorectal cancer, few investigations have addressed how and to what extent these factors affect the genetics and pathology of the disease. Precise relationships with specific genetic mutations that could alter signaling pathways involved in colorectal cancer remain unknown. We therefore aimed to investigate possible links between lifestyle, dietary habits, and socioeconomic factors and specific mutations that are common in colorectal cancers. Methods: Data were retrieved from a baseline survey of lifestyle factors, dietary behavior, and SES, as well as anthropometric evaluations during a physical examination, for 100 confirmed primary sporadic colorectal cancer patients from Northwest Iran. Results: High socioeconomic status was significantly associated with higher likelihood of a KRAS gene mutation (P < 0.05) (odds ratio: 3.01; 95% CI: 0.69­13.02). Consuming carbohydrates and alcohol, working less, and having a sedentary lifestyle also increased the odds of having a KRAS mutation. Conclusion: Although research has not yet described the exact relationships among genetic mutations with different known risk factors in colorectal cancer, examples of the latter may have an impact on KRAS gene mutations.

Association of clinicopathologic characteristics and outcomes with EZH2 expression in patients with breast cancer in East Azerbaijan, Iran.

BACKGROUND: Recently, it was found that the overexpression and mutation status of EZH2 affect cancer progression and patient outcome in several human tumors. We aimed to evaluate the clinicopathologic significance of EZH2 in patients with breast cancer. METHODS: This was an analytical descriptive study of surgical specimens of primary breast tumors. Specimens were analyzed immunohistochemically for EZH2, estrogen receptor, progesterone receptor, Ki-67, P53, and human epidermal growth factor receptor 2 (HER2) expressions. Regression analysis was performed to calculate hazard ratios (HRs) and 95% CIs. Kaplan-Meier and Cox regression models were used to estimate the overall survival (OS) and disease-free survival (DFS). RESULTS: We included 100 patients with breast cancer (mean age 51.05±9.54 years). The multivariate regression analysis showed that HER2-positive patients had approximately twice the levels of EZH2 expression compared with HER2-negative patients (HR 2.16, 95% CI 0.48-11.49). The likelihood of EZH2 expression was significantly higher in patients with lymph node involvement than in those without (HR 8.44, 95% CI 3.06-23.33; P≤0.05). EZH2 expression did not have any significant effect on the OS, although the mean OS in high EZH2 expression was shorter than for those with low EZH2 expression (655 vs 787 days; log-rank P=0.336). The mean DFS was 487 days for patients with high EZH2 expression compared with 908 days for those with low EZH2 expression (log-rank P=0.188). CONCLUSION: There was no association found between EZH2 expression and OS and DFS in our patients. Further studies involving larger sample sizes, and conducted in different populations, are needed to validate this hypothesis.

A novel KRAS gene mutation report in sporadic colorectal cancer, from Northwest of Iran.

While the role of KRAS gene mutations has been widely accepted for predicting responses to anti-EGFR therapy in patients with colorectal cancer, although this study was based on observation of a single case it gives hope that some KRAS gene mutation may have favorable prognosis. More studies are required on patients with similar mutation to validate this finding.

Ral signaling pathway in health and cancer.

The Ral (Ras-Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.

Differential modulation of malignant peripheral nerve sheath tumor growth by omega-3 and omega-6 fatty acids.

Neurofibromatosis type 1 (NF1) is a common genetic disorder of the nervous system resulting in neurofibromas and malignant peripheral nerve sheath tumors (MPNST). In this study, we report the modulation of murine and human MPNST cell growth by the fatty acids docosahexaenoic acid (DHA) and arachidonic acid (AA). DHA demonstrated a tendency to stimulate cell growth at low doses and induce apoptosis at high doses, paralleled by the activation of ERK and caspase-3. Furthermore, high-dose DHA reversed the stimulation of MPNST cell growth by a number of growth factors suggested to have a pathogenic effect in NF1 and inhibited MPNST growth in vivo. AA was found to have a reciprocal activity in vitro, stimulating MPNST cell growth at comparable concentrations and reducing DHA activation of ERK. These findings introduce fatty acids as a possible regulator of MPNST development in NF1 patients.

Association between proto-oncogene mutations and clinicopathologic characteristics and overall survival in colorectal cancer in East Azerbaijan, Iran.

BACKGROUND: Colorectal cancer (CRC) is the third-most common cancer in Iran. The increasing incidence of CRC in the past three decades has made it a major public health burden in the country. This study aimed to determine any relationship of specific mutations in CRCs with clinicopathologic aspects and outcome of patients. MATERIALS AND METHODS: This study was conducted on 100 CRC patients by the case-only method. Polymerase chain-reaction products were analyzed by Sanger sequencing, and sequence results were compared with the significant KRAS and BRAF gene mutations in the My Cancer Genome database. Logistic regression models were used to detect associations of clinicopathologic characteristics with each of the mutations. Kaplan-Meier and Cox regression models were constructed to estimate overall survival in patients. RESULTS: A total of 26 subjects (26%) had heterozygote-mutant KRAS, and mutations were not detected in the amplified exon of BRAF in both tumor and normal tissues of the 100 CRCs. Rectal tumors had 1.53-fold higher likelihood of KRAS mutations than colon tumors, and men had 1.37-fold higher odds than women. The presence of metastasis increased the likelihood of KRAS mutations 2.36-fold over those with nonmetastatic CRCs. Compared to patients with KRAS wild-type cancers, those with KRAS mutations had significantly higher mortality (hazard ratio 3.74, 95% confidence interval 1.44-9.68; log-rank P=0.003). CONCLUSION: Better understanding of the causality of CRC can be established by combining epidemiology and research on molecular mechanisms of the disease.

Low-dose all-trans retinoic acid enhances cytotoxicity of cisplatin and 5-fluorouracil on CD44(+) cancer stem cells.

Cis-diamminedichloridoplatinum(II)(CDDP)-based combination chemotherapy is frequently used in gastrointestinal cancer. The synergistic mechanism of all-trans retinoic acid (ATRA), cisplatin (CDDP) and 5-fluorouracil (5-FU) in combination remains unclear. Despite their potent antitumor properties, resistance to CDDP and 5-FU develops frequently in tumors. To clarify this mechanism, we determined the sensitivity to each drug and their combination in two gastrointestinal cancer stem cells (CSCs) subpopulation. Here, we report the identification and separation of CD44(+) cells from human gastric carcinoma (AGS) and human esophageal squamous cell carcinoma (KYSE-30) cancer cell lines by magnetic activated cell sorting (MACS). We allowed the CD44(±) cells to grow 6 days at a subtoxic concentration of ATRA and then treated with different concentration of CDDP and 5-FU for 24h. The cytotoxicity was examined by cell proliferation MTT assay. Additionally, AO/EB staining was used for detection of apoptotic cells. In order to determine whether the growth inhibition was also associated with changes in cell cycle distribution, cell cycle analysis was performed using flow cytometry. Low concentration of ATRA (1µM, 6days) followed by 5-FU and CDDP was found to be more effective than either drugs alone, thus resulting in synergistic cytotoxicity in Kyse-30 and AGSCD44(±) cells. Furthermore, there was an indication that the combination of ATRA with 5FU and CDDP caused an increase in cell cycle arrest in G2/M and G0/G1. We conclude that low concentration of ATRA enhances the cytotoxicity of CDDP and 5FU by facilitating apoptosis and cell cycle arrest in gastrointestinal CSCs and provide a rational basis for the design of novel, well-tolerated CDDP- and 5FU-based chemotherapy in human gastrointestinal carcinoma.

Colorectal cancer in iran: molecular epidemiology and screening strategies.

Purpose. The increasing incidence of colorectal cancer (CRC) in the past three decades in Iran has made it a major public health burden. This study aimed to report its epidemiologic features, molecular genetic aspects, survival, heredity, and screening pattern in Iran. Methods. A comprehensive literature review was conducted to identify the relevant published articles. We used medical subject headings, including colorectal cancer, molecular genetics, KRAS and BRAF mutations, screening, survival, epidemiologic study, and Iran. Results. Age standardized incidence rate of Iranian CRCs was 11.6 and 10.5 for men and women, respectively. Overall five-year survival rate was 41%, and the proportion of CRC among the younger age group was higher than that of western countries. Depending on ethnicity, geographical region, dietary, and genetic predisposition, mutation genes were considerably diverse and distinct among CRCs across Iran. The high occurrence of CRC in records of relatives of CRC patients showed that family history of CRC was more common among young CRCs. Conclusion. Appropriate screening strategies for CRC which is amenable to early detection through screening, especially in relatives of CRCs, should be considered as the first step in CRC screening programs.

Sulindac derivatives inhibit cell growth and induce apoptosis in primary cells from malignant peripheral nerve sheath tumors of NF1-patients.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are neoplasms leading to death in most cases. Patients with Neurofibromatosis type 1 have an increased risk of developing this malignancy. The metabolites of the inactive prodrug Sulindac, Sulindac Sulfide and Sulindac Sulfone (Exisulind) are new chemopreventive agents that show promising results in the treatment of different cancer types. In this study we examined the antineoplastic effect of these compounds on primary cells derived from two MPNSTs of Neurofibromatosis type 1 patients. RESULTS: Exisulind and Sulindac Sulfide showed a dramatic time- and dose-dependent growth inhibitory effect with IC50-values of 120 microM and 63 microM, respectively. The decrease in viability of the tested cells correlated with induction of apoptosis. Treatment with 500 microM Exisulind and 125 microM Sulindac Sulfide for a period of 2 days increased the rate of apoptosis 21-27-fold compared to untreated cells. Reduced expression of RAS-GTP and phosphorylated ERK1/2 was detected in treated MPNST cells. Moreover, elevated levels of phosphorylated SAPK/JNK were found after drug treatment, and low activation of cleaved caspase-3 was seen. CONCLUSIONS: Our results suggest that this class of compounds may be of therapeutic benefit for Neurofibromatosis type 1 patients with MPNST.