Genetic analysis of caveolin-1 and eNOS genes in colorectal cancer.

Caveolae are involved in physical compartmentalization between different groups of signaling events. Its main component, CAV1, modulates different pathways in cellular physiology. The emerging evidence pointing to the role of CAV1 in cancer led us to study whether different alleles of this gene are associated with colorectal cancer (CRC). Since one of the most characterized enzymes regulated by CAV1 is eNOS, we decided to include both genes in this study. We analyzed five SNPs in 360 unrelated CRC patients and 550 controls from the general population. Two of these SNPs were located within eNOS and three within the CAV1 gene. Although haplotype distribution was not associated with CRC, haplotype TiA (CAV1) was associated with familiar forms of CRC (p<0.05). This was especially evident in CRC antecedents and nuclear forms of CRC. If both CG (eNOS) and TiA (CAV1) haplotypes were taken together, this association increased in significance. Thus, we propose that CAV1, either alone or together with eNOS alleles, might modify CRC heritability.

Angiogenesis-related gene expression profile with independent prognostic value in advanced ovarian carcinoma.

BACKGROUND Ovarian carcinoma is the most important cause of gynecological cancer-related mortality in Western societies. Despite the improved median overall survival in patients receiving chemotherapy regimens such as paclitaxel and carboplatin combination, relapse still occurs in most advanced diseased patients. Increased angiogenesis is associated with rapid recurrence and decreased survival in ovarian cancer. This study was planned to identify an angiogenesis-related gene expression profile with prognostic value in advanced ovarian carcinoma patients. METHODOLOGY/PRINCIPAL FINDINGS RNAs were collected from formalin-fixed paraffin-embedded samples of 61 patients with III/IV FIGO stage ovarian cancer who underwent surgical cytoreduction and received a carboplatin plus paclitaxel regimen. Expression levels of 82 angiogenesis related genes were measured by quantitative real-time polymerase chain reaction using TaqMan low-density arrays. A 34-gene-profile which was able to predict the overall survival of ovarian carcinoma patients was identified. After a leave-one-out cross validation, the profile distinguished two groups of patients with different outcomes. Median overall survival and progression-free survival for the high risk group was 28.3 and 15.0 months, respectively, and was not reached by patients in the low risk group at the end of follow-up. Moreover, the profile maintained an independent prognostic value in the multivariate analysis. The hazard ratio for death was 2.3 (95% CI, 1.5 to 3.2; p<0.001). CONCLUSIONS/SIGNIFICANCE It is possible to generate a prognostic model for advanced ovarian carcinoma based on angiogenesis-related genes using formalin-fixed paraffin-embedded samples. The present results are consistent with the increasing weight of angiogenesis genes in the prognosis of ovarian carcinoma.

Bcl-xL is overexpressed in hormone-resistant prostate cancer and promotes survival of LNCaP cells via interaction with proapoptotic Bak.

Androgen-sensitive prostate cancer cells turn androgen resistant through complex mechanisms that involve dysregulation of apoptosis. We investigated the role of antiapoptotic Bcl-xL in the progression of prostate cancer as well as the interactions of Bcl-xL with proapoptotic Bax and Bak in androgen-dependent and -independent prostate cancer cells. Immunohistochemical analysis was used to study the expression of Bcl-xL in a series of 139 prostate carcinomas and its association with Gleason grade and time to hormone resistance. Expression of Bcl-xL was more abundant in prostate carcinomas of higher Gleason grades and significantly associated with the onset of hormone-refractory disease. In vivo interactions of Bcl-xL with Bax or Bak in untreated and camptothecin-treated LNCaP and PC3 cells were investigated by means of coimmunoprecipitation. In the absence of any stimuli, Bcl-xL interacts with Bax and Bak in androgen-independent PC3 cells but only with Bak in androgen-dependent LNCaP cells. Interactions of Bcl-xL with Bax and Bak were also evidenced in lysates from high-grade prostate cancer tissues. In LNCaP cells treated with camptothecin, an inhibitor of topoisomerase I, the interaction between Bcl-xL and Bak was absent after 36 h, Bcl-xL decreased gradually and Bak increased coincidentally with the progress of apoptosis. These results support a model in which Bcl-xL would exert an inhibitory effect over Bak via heterodimerization. We propose that these interactions may provide mechanisms for suppressing the activity of proapoptotic Bax and Bak in prostate cancer cells and that Bcl-xL expression contributes to androgen resistance and progression of prostate cancer.

Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition.

BACKGROUND ErbB2-positive breast cancer is characterized by highly aggressive phenotypes and reduced responsiveness to standard therapies. Although specific ErbB2-targeted therapies have been designed, only a small percentage of patients respond to these treatments and most of them eventually relapse. The existence of this population of particularly aggressive and non-responding or relapsing patients urges the search for novel therapies. The purpose of this study was to determine whether cannabinoids might constitute a new therapeutic tool for the treatment of ErbB2-positive breast tumors. We analyzed their antitumor potential in a well established and clinically relevant model of ErbB2-driven metastatic breast cancer: the MMTV-neu mouse. We also analyzed the expression of cannabinoid targets in a series of 87 human breast tumors. RESULTS Our results show that both Delta9-tetrahydrocannabinol, the most abundant and potent cannabinoid in marijuana, and JWH-133, a non-psychotropic CB2 receptor-selective agonist, reduce tumor growth, tumor number, and the amount/severity of lung metastases in MMTV-neu mice. Histological analyses of the tumors revealed that cannabinoids inhibit cancer cell proliferation, induce cancer cell apoptosis, and impair tumor angiogenesis. Cannabinoid antitumoral action relies, at least partially, on the inhibition of the pro-tumorigenic Akt pathway. We also found that 91% of ErbB2-positive tumors express the non-psychotropic cannabinoid receptor CB2. CONCLUSIONS Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.

Functional characterization of E- and P-cadherin in invasive breast cancer cells

BACKGROUND Alterations in the cadherin-catenin adhesion complexes are involved in tumor initiation, progression and metastasis. However, the functional implication of distinct cadherin types in breast cancer biology is still poorly understood. METHODS To compare the functional role of E-cadherin and P-cadherin in invasive breast cancer, we stably transfected these molecules into the MDA-MB-231 cell line, and investigated their effects on motility, invasion and gene expression regulation. RESULTS Expression of either E- and P-cadherin significantly increased cell aggregation and induced a switch from fibroblastic to epithelial morphology. Although expression of these cadherins did not completely reverse the mesenchymal phenotype of MDA-MB-231 cells, both E- and P-cadherin decreased fibroblast-like migration and invasion through extracellular matrix in a similar way. Moreover, microarray gene expression analysis of MDA-MB-231 cells after expression of E- and P-cadherins revealed that these molecules can activate signaling pathways leading to significant changes in gene expression. Although the expression patterns induced by E- and P-cadherin showed more similarities than differences, 40 genes were differentially modified by the expression of either cadherin type. CONCLUSION E- and P-cadherin have similar functional consequences on the phenotype and invasive behavior of MDA-MB-231 cells. Moreover, we demonstrate for the first time that these cadherins can induce both common and specific gene expression programs on invasive breast cancer cells. Importantly, these identified genes are potential targets for future studies on the functional consequences of altered cadherin expression in human breast cancer.

Prévention primaire et dépistage chez l'adulte: mise a jour 2014 [Primary prevention and screening in adults: update 2014].

Cet article propose une mise à jour des recommandations pour le bilan de santé et la prévention primaire et secondaire de nombreuses maladies cardiovasculaires et oncologiques. Les nouveautés pour le dépistage des cancers concernent essentiellement les cancers colorectal, du poumon et de la prostate. Pour la prévention des maladies cardiovasculaires, le dépistage de la sténose de l'artère carotidienne n'est toujours pas recommandé. Les preuves de la littérature sont insuffisantes pour recommander le dépistage de l'artériopathie coronarienne ou périphérique chez les patients asymptomatiques. Le partage de l'information et de la décision entre le médecin et le patient est à privilégier lorsqu'il existe une incertitude quant à l'efficacité d'une intervention. This article provides an update on the recommendations for the routine check-up and the primary and secondary prevention of cancer and cardiovascular disease. Changes for cancer screening affect mainly colorectal, lung and prostate cancers. In the area of cardiovascular disease prevention, screening for carotid artery stenosis is still not recommended. The current evidence is insufficient to recommend screening for coronary heart disease or peripheral artery disease in asymptomatic patients. Shared information and decision making between physician and patient is recommended when there is uncertainty regarding the effectiveness of an intervention.

Analysis of CXCL12 3 ' UTR G > A polymorphism in colorectal cancer

Colorectal cancer is one of the most prevalent cancers in developed countries. However, the genetic factors influencing its appearance remain far from being fully characterized. Recently, a G>A functional transition mapping the 3' untranslated region of the CXCL12 gene (rs1801157) has been found to be under-represented among rectal cancer patients when compared to colon cancer patients from a Swedish series. Here we present the results from an independent analysis of CXCL12 rs1801157 in a larger CRC series of Spanish origin in order to analyse the robustness of this association within a different European population. No significant difference was observed between controls and colon or rectal cancer patients. We were also unable to find a correlation between rs1801157 and different prognostic markers such as metastasis development or disease-free survival time. The epidemiologic data involving CXCL12 rs1801157 in colorectal cancer risk are discussed.

N-3 fatty acids, cancer and cachexia: a systematic review of the literature.

Use of n-3 fatty acids (FA) has been reported to be beneficial for cancer patients. We performed a systematic review of the literature in order to issue recommendations on the clinical use of n-3 FA in the cancer setting. A systematic search was performed in MEDLINE, EMBASE, Cochrane and Healthstar databases. We selected clinical trials or prospective observational studies including patients with cancer and life expectancy >2 months, in which enteral supplements with n-3 FA were administered. Parameters evaluated individually were clinical (nutritional status, tolerance, survival and hospital stays), biochemical (inflammatory mediators), and functional (functional status, appetite and quality of life (QoL)). Seventeen studies met the inclusion criteria; eight were of high quality. The panel of experts established the following evidence: (1) oral supplements with n-3 FA benefit patients with advanced cancer and weight loss, and are indicated in tumours of the upper digestive tract and pancreas; (2) the advantages observed were: increased weight and appetite, improved QoL, and reduced post-surgical morbidity; (3) there is no defined pattern for combining different n-3 FA, and it is recommended to administer > 1.5 g/day; and (4) better tolerance is obtained administering low-fat formulas for a period of at least 8 weeks. All the evidences were grade B but for 'length of treatment' and 'advantage of survival' it was grade C. Our findings suggest that administration of n-3 FA (EPA and DHA) in doses of at least 1.5 g/day for a prolonged period of time to patients with advanced cancer is associated with an improvement in clinical, biological and QoL parameters.

Differential prefrontal-like deficit in children after cerebellar astrocytoma and medulloblastoma tumor

BACKGROUND This study was realized thanks to the collaboration of children and adolescents who had been resected from cerebellar tumors. The medulloblastoma group (CE+, n = 7) in addition to surgery received radiation and chemotherapy. The astrocytoma group (CE, n = 13) did not receive additional treatments. Each clinical group was compared in their executive functioning with a paired control group (n = 12). The performances of the clinical groups with respect to controls were compared considering the tumor's localization (vermis or hemisphere) and the affectation (or not) of the dentate nucleus. Executive variables were correlated with the age at surgery, the time between surgery-evaluation and the resected volume. METHODS The executive functioning was assessed by means of WCST, Complex Rey Figure, Controlled Oral Word Association Test (letter and animal categories), Digits span (WISC-R verbal scale) and Stroop test. These tests are very sensitive to dorsolateral PFC and/or to medial frontal cortex functions. The scores for the non-verbal Raven IQ were also obtained. Direct scores were corrected by age and transformed in standard scores using normative data. The neuropsychological evaluation was made at 3.25 (SD = 2.74) years from surgery in CE group and at 6.47 (SD = 2.77) in CE+ group. RESULTS The Medulloblastoma group showed severe executive deficit (

Methylation alterations are not a major cause of PTTG1 misregulation.

BACKGROUND On its physiological cellular context, PTTG1 controls sister chromatid segregation during mitosis. Within its crosstalk to the cellular arrest machinery, relies a checkpoint of integrity for which gained the over name of securin. PTTG1 was found to promote malignant transformation in 3T3 fibroblasts, and further found to be overexpressed in different tumor types. More recently, PTTG1 has been also related to different processes such as DNA repair and found to trans-activate different cellular pathways involving c-myc, bax or p53, among others. PTTG1 over-expression has been correlated to a worse prognosis in thyroid, lung, colorectal cancer patients, and it can not be excluded that this effect may also occur in other tumor types. Despite the clinical relevance and the increasing molecular characterization of PTTG1, the reason for its up-regulation remains unclear. METHOD We analysed PTTG1 differential expression in PC-3, DU-145 and LNCaP tumor cell lines, cultured in the presence of the methyl-transferase inhibitor 5-Aza-2'-deoxycytidine. We also tested whether the CpG island mapping PTTG1 proximal promoter evidenced a differential methylation pattern in differentiated thyroid cancer biopsies concordant to their PTTG1 immunohistochemistry status. Finally, we performed whole-genome LOH studies using Affymetix 50 K microarray technology and FRET analysis to search for allelic imbalances comprising the PTTG1 locus. CONCLUSION Our data suggest that neither methylation alterations nor LOH are involved in PTTG1 over-expression. These data, together with those previously reported, point towards a post-transcriptional level of misregulation associated to PTTG1 over-expression.

Breast cancer prognostic classification in the molecular era: the role of histological grade.

Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers.