Ciência e terapia do câncer

Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive malignant neoplasm that typically involves the abdominal or pelvic peritoneum in children and young adults. This tumor is characterized by the presence of a specific EWS-WT1 fusion gene, which is the result of recurrent chromosomal translocation, t(11;22)(p13;q12). EWS encodes a putative RNA binding protein of unknown function with an N-terminal domain that mediates potent transcriptional activation when fused to heterologous DNA binding domains. WT1 is a tumor suppressor gene initially identified based on its inactivation in Wilms tumor. The chimeric proteins resulting from these chromosomal translocations usually possess gain-of-function transcriptional activities and define histologically and biologically distinct tumor types. EWS-WT1 has two isoforms of EWS-WT1(-KTS) and EWS-WT1(+KTS). Previous studies have identified several EWS-WT1(-KTS) target genes, most of which are involved in growth factor signaling. In the current study, using an exogenous EWS-WT1(-KTS) induction system along with the selection from candidates for target genes based on the microarray data, we identified fibroblast growth factor receptor 4 (FGFR4) as a potential EWS-WT1(-KTS) target and this induction accompanied with increased phosphorylation form of Akt and MAPK, suggesting a post-transcriptional modulation by EWS-WT1(-KTS). In addition, CTNNB1 was also identified as a potential EWS-WT1(-KTS) target that defines epithelial characteristics of DSRCT. Furthermore, up-regulation of CTNNB1 driven by EWS-WT1(-KTS) was independent of FGFR4 regulation. Expressions of FGFR4 and CTNNB1 in DSRCT clinical samples were confirmed by immunohistochemistry. This study provides regulatory mechanism of FGFR4 in DSRCT and also novel insights into the acquisition of epithelial characteristics in DSRCT.

Background: MDM2 is an important negative regulator of the TP53 pathway, over expressed in many cancers as oncoprotein. Polymorphisms in the promoter region of the MDM2 gene have been shown to alter protein expression and may, thus play an important role in carcinogenesis.
 
Aim and methods: To test our hypothesis that the MDM2 promoter polymorphisms are associated with risk of non small cell lung cancer, we conducted a hospital-based, case–control study of 136 Indian patients diagnosed with NSCLC and 136 cancer-free controls and investigated the association between genetic variation in the promoter region of MDM2 (c.–51309G4T, rs2279744:g.G4T) and the risk of developing NSCLC by tetra-primer ARMS-PCR and ASO-PCR.
 
Results: Compared with the MDM2-2580TT genotype, we found that the MDM2-309G variant genotypes were associated with an increased risk of NSCLC in Indian patients [OR 3.88 (1.82-8.27) RR 1.94 (1.27-2.96) RD 32.6 (15.7-49.6) p 0.0004 for GG and OR 2.60 (1.49-4.57) RR 1.52 (1.20-1.93) RD 23.16 (10.3-36.0) p 0.0009 for GT genotype]. GG genotype was found to be associated with poor survival outcome of NSCLC patients and in addition significant association was observed with stage (p 0.01) and metastasis status (p 0.002) of NSCLC patients.
 
Conclusion: Genetic polymorphism in cell cycle regulatory genes MDM2 contribute to the risk of developing NSCLC in Indian Patients. In addition G allele was associated with an increased risk and poor survival outcome than T allele.

Background: The soluble fraction of the CD44 protein (CD44sol) appears to be a possible candidate screening marker for the early diagnosis of head and neck tumors. The aim of our study was to ascertain the levels of CD44sol in the saliva of patients with laryngeal carcinoma and compare them with those of a control group of individuals to assess the reliability of the test as diagnostic marker.
 
Methods: Ninety-two individuals with suspected laryngeal cancer who were submitted to biopsy were selected for the study. Forty adults who underwent surgery for head and neck benign disease were recruited to form a control group. The sampling of saliva was performed on the day before the laryngeal biopsy in the patient group and on the day before surgery in the control group. CD44sol levels were detected using the ELISA method.
 
Results: The levels of CD44sol were significantly higher in the patient group than they were in the control group (31.4 ± 27.3 vs. 9 ± 7.1 ng/mL). CD44sol levels were not related to smoking and drinking habits. Analysis of the clinical data revealed an absence of significant differences between the study groups according to tumor site, histological grade, and clinical stage of T and N. The salivary levels of CD44sol were higher in advanced-stage (stages III and IV) compared with early-stage disease (43.2 ± 32.2 vs. 32.2 ± 20.5 ng/mL). Sensitivity and specificity were calculated based on the ROC curve and exhibited best accuracy using a predictive probability cut-off point of 10 ng/mL, with corresponding estimates of sensitivity and specificity of 89.5% and 83.3%, respectively.
 
Discussion: The determination of CD44sol levels in the saliva of patients with laryngeal carcinoma using ELISA seems to be a promising diagnostic test in terms of high sensitivity and specificity, low cost and noninvasiveness of the technique.

Cutaneous wound healing is a complex process involving blood clotting, inflammation, tissue formation, and tissue remodeling. Many experimental and clinical studies have demonstrated varied, but in most cases beneficial, effects of exogenous growth factors on the healing process. The use of targeted anti-cancer agents is increasing. It is common to utilize a multi-modal treatment approach towards solid tumors, often including surgical resection, and it has become apparent that some targeted agents can impair wound healing or cause increasing risk of perioperative complications. There are limited data regarding the wound healing process of anti-cancer target drugs blocking the EGF/EGFR system. The aim of this paper is to review and to comment the effects of anti- EGF/EGFR drugs on the skin wound healing process after programmed or emergency surgical procedures. A review of the current literature, including our own results, was undertaken. We included the monoclonal antibodies cetuximab, panitumumab, nimotuzumab; the small tyrosine kinase molecules erlotinib and gefitinib; and the EGFbased cancer vaccine; CIMAvax and the EGFR-based cancer vaccine; HER-1 vaccine. Apparently, there are no deleterious effects of the anti-EGF/EGFR drugs in the wound healing post-operative process. Taking into account that treatment with anti-EGF/EGFR drugs inhibits tumor cell proliferation, and the lack of deleterious effects of these EGF/EGFR specific inhibitors in the wound healing post-operative process; we suggest that these kinds of drugs could be maintained and their effects tested, with very special surveillance during the post-surgical period.

Apoptosis occurs normally during development and aging as a homeostatic mechanism to maintain cell populations. Dysregulation of apoptosis can disrupt the equilibrium between cell growth and cell death leading to the development of cancer. Thus, the investigation of new biological apoptotic activators could play an important role in cancer therapy. In the present study, Cerastes cerastes and Vipera lebetina snake venoms were evaluated for their ability to activate apoptosis in cancer cells where test venoms exhibited a concentration and time dependent cytotoxic effect on breast cancer (MCF-7) cells. Typical apoptotic morphological features were demonstrated in venom treated cells detected via transmission electron microscope. In addition, flow cytometric analysis showed an increase in the percentage of apoptotic cells post 24 h treatment relative to venom concentrations. At the molecular level, test venoms induced apoptosis were mediated by up regulation of pro-apoptotic genes (p53 & Bax) and down regulation of anti-apoptotic gene (Bcl-2) in MCF-7 cells, indicating that these venoms could serve as apoptotic stimulators, presenting a novel and potential therapeutic strategy for cancer treatment.

Introduction: Clear cell RCC is the most common type of RCC that occurs in adults and it has the worst prognosis among the common epithelial tumors of these organs. The CD34 is an endothelial antigen that has been used to highlight the microvessel density (MVD) as a direct marker of neoangiogenesis degree.
 
Objective: To establish the correlation between CD34 and other prognostic factors like Fuhrman nuclear degree and tumoral size. Material and methods: Tumour samples from 17 patients with histopathology diagnosis of clear cell RCC were examined by immunohistochemical staining for CD34. The CD34 expression was analyzed by Anova and Student Newman Multiple Comparison Test and Tuckey like post test, and finally we used a Spearman Correlation to compare with the others prognostic factors analysed and Kaplan Meier survival analysis for the disease free survival of the patients.
 
Results and conclusion: There is a negative correlation between the MVD and the Fuhrman nuclear grade, whereas R = -0,46; and p < 0,05 and there is a positive correlation between the MVD and the maximum tumoral diameter, whereas R = 0,47 and p < 0,05. In conclusion, we found that a high MVD is related with a low Fuhrman nuclear grade and a high tumoral size. The possible significance of this study can be that in fact we need more than one parameter to predict the biological behavior of the clear cell CCR.