Recent advances in cancer immunotherapy: Modulation of tumor microenvironment by Toll-like receptor ligands.

Immunotherapy is considered a promising approach for cancer treatment. An important strategy for cancer immunotherapy is the use of cancer vaccines, which have been widely used for cancer treatment. Despite the great potential of cancer vaccines for cancer treatment, their therapeutic effects in clinical settings have been limited. The main reason behind the lack of significant therapeutic outcomes for cancer vaccines is believed to be the immunosuppressive tumor microenvironment (TME). The TME counteracts the therapeutic effects of immunotherapy and provides a favorable environment for tumor growth and progression. Therefore, overcoming the immunosuppressive TME can potentially augment the therapeutic effects of cancer immunotherapy in general and therapeutic cancer vaccines in particular. Among the strategies developed for overcoming immunosuppression in TME, the use of toll-like receptor (TLR) agonists has been suggested as a promising approach to reverse immunosuppression. In this paper, we will review the application of the four most widely studied TLR agonists including agonists of TLR3, 4, 7, and 9 in cancer immunotherapy.

Mediterranean fever (MEFV) gene profile and a novel missense mutation (P313H) in Iranian Azari-Turkish patients.

BACKGROUND: Familial Mediterranean fever (FMF) is common in Azari-Turkish people, one of the biggest ethnic groups in Iran. In this study, we sought to investigate the mutation spectrum of the MEFV gene and any genotype-phenotype correlations. METHODS AND MATERIALS: 400 unrelated Azari-Turkish FMF patients were analyzed in this study. Mutations in exons 2, 3, 5, and 10 of the MEFV gene were investigated using direct Sanger sequencing, and their correlations with the clinical features of the patients were analyzed. RESULTS: At least one mutation was detected in 248 (62%) patients. The most common mutations were M694V (26.25%) and E148Q (24.75%), respectively. Abdominal pain (65.2%) and fever 204 (51%) were the most frequent clinical problems in all subjects. The analysis recognized a novel missense mutation in the coding region of the MEFV gene, named P313H, which is the first report of a new mutation in exon 2 of the MEFV gene in an Azari-Turkish family. CONCLUSION: Genotype-phenotype correlations obtained from this study would be helpful in the diagnosis and management of FMF patients in clinical situations. This novel missense mutation may provide useful evidence for further studies of FMF pathogenesis.

Dysregulated KDR and FLT1 Gene Expression in Colorectal Cancer Patients.

BACKGROUND: Colorectal cancer (CRC) is one of the most commonly-diagnosed malignancies throughout the world and the fourth-leading cause of cancer deaths globally. Angiogenesis and the resultant tumor neovascularization is a well-known cancer hallmark. Here we investigated the expression of FLT1 and KDR, the influential genes in angiogenesis regulation, in CRC patients. METHODS: We assessed FLT1 and KDR mRNA expression in 47 CRC samples and matched adjacent noncancerous tissues (ANCT) by quantitative real-time PCR. The Spearmen correlation coefficient and receiver operating characteristic (ROC) curves were also examined. RESULTS: Both genes were expressed at significantly greater levels in CRC tissues than in ANCT (p < 0.05). A significant association was found between KDR expression and disease stage and lymph status in CRC patients. Furthermore, the Spearman correlation demonstrated a moderate correlation between FLT1 and KDR expression in CRC samples. Finally, ROC curve analysis demonstrated that FLT1 had the greatest sensitivity (85.1%), while the greatest specificity was achieved by a combination of the two genes. CONCLUSION: The dysregulated FLT1 and KDR expression, in addition to the observed correlation and ROC curve results, indicate the critical importance of angiogenesis among the cancer pathways in CRC. These data can broaden our current knowledge of angiogenesis in CRC to improve disease diagnosis and patient treatment.

Expression Patterns of CXCL12 and its Receptor in Colorectal Carcinoma.

BACKGROUND: Stromal cell-derived factor-1 (also called CXCL12) and its receptor, CXCR4, have a key role in the pathogenesis and tumorigenesis of various cancers. The aims of the current study were to quantitatively examine the expression of CXCR4 and CXCL12 genes in colorectal cancer and to correlate their expression degree with clinicopathological features. METHODS: Tumor tissue samples were collected from 47 patients with CRC. Total RNA was isolated from resection tissues and real-time PCR analysis was performed to examine mRNA levels of CXCL12 and CXCR4 genes. RESULTS: No significant differences were observed for both CXCL12 and CXCR4 between tumor tissues and the adjacent non-affected tissues, although a borderline significant correlation (p = 0.052) were detected between gene expression of CXCL12 and CXCR4 in tumor tissues. Our results also indicated that there was no significant correlation between expression pattern of CXCL12/CXCR4 and clinicopathological variables. CONCLUSIONS: Our data showed that CXCL12 and CXCR4 are expressed simultaneously in colorectal carcinoma tissues, suggesting that expression of these chemokines and corresponding receptors may play a pivotal role in colorectal tumorigenesis, although it cannot be as a predictive factor for disease progression.

Gene Expression Analyses of HER-2/neu and ESR1 in Patients with Breast Cancer

ABSTRACT Background: Her-2 and ESR1 genes, that interact in the cell signaling pathway, are the most important molecular markers of breast cancer, which have been amplified or overexpressed in 30% and 70%, respectively. This study was performed to evaluate the gene expression levels of Her-2 and ESR1 genes in tumor cells and its adjacent normal tissue of breast cancer patients and compared them whit clinical-pathological features. Methods: In total, 80 tissue specimens from 40 patients, with an average age of 48.47 years, were examined by Real-time PCR technique, and ultimately evaluated the expression level of Her-2 and ESR1genes. The data were analyzed by REST 2009 V2.0.13 statistical software. Results: HER2 and ESR1 overexpression was identified in 19 (48%) and 12 (30%) of 40 patients respectively, which was higher and lower than that recorded in international statistics, respectively. ESR1 overexpression was associated with Stage 3A and lymph node involvement 2 (N2) (P = 0.04 and P = 0.047, respectively). No significant correlation was observed between the expression of HER2 and ESR1 and other clinical-pathological features, however, the relative differences were identified in the expression levels of genes between main group and groups that were classified according to the clinical-pathological features and age. Conclusions: Overexpression of Her-2 and ESR1 genes in the patients of our study are higher and lower than international statistics, respectively, indicating the differences in genetic, environmental and ethnic factors that involved in the developing of breast cancer.

Gene Expression Analyses of HER-2/neu and ESR1 in Patients with Breast Cancer

ABSTRACT Background: Her-2 and ESR1 genes, that interact in the cell signaling pathway, are the most important molecular markers of breast cancer, which have been amplified or overexpressed in 30% and 70%, respectively. This study was performed to evaluate the gene expression levels of Her-2 and ESR1 genes in tumor cells and its adjacent normal tissue of breast cancer patients and compared them whit clinical-pathological features. Methods: In total, 80 tissue specimens from 40 patients, with an average age of 48.47 years, were examined by Real-time PCR technique, and ultimately evaluated the expression level of Her-2 and ESR1genes. The data were analyzed by REST 2009 V2.0.13 statistical software. Results: HER2 and ESR1 overexpression was identified in 19 (48%) and 12 (30%) of 40 patients respectively, which was higher and lower than that recorded in international statistics, respectively. ESR1 overexpression was associated with Stage 3A and lymph node involvement 2 (N2) (P = 0.04 and P = 0.047, respectively). No significant correlation was observed between the expression of HER2 and ESR1 and other clinical-pathological features, however, the relative differences were identified in the expression levels of genes between main group and groups that were classified according to the clinical-pathological features and age. Conclusions: Overexpression of Her-2 and ESR1 genes in the patients of our study are higher and lower than international statistics, respectively, indicating the differences in genetic, environmental and ethnic factors that involved in the developing of breast cancer.

Personalized Gene Expression Analyses of SMAD7 and KLF10 In Breast Cancer

Many cancer researchers use gene expression analysis for differentiation between tumor and normal cells for diagnostic, prognostic and therapeutic purposes. Most of studies compare either tumor cell lines by normal cell lines or tumor tissue of affected individuals by normal healthy control tissue. But expression of each special gene is unique in different individuals and also in different tissue of same individual. For this reason, here we compare the gene expression levels of SMAD7 and KLF10 in tumor cells and its adjacent normal tissue of breast cancer patients and compared them. For this purpose, a total of 40 tumor and matched tumor-free margin samples were obtained during surgery. The SMAD7 and KLF10 mRNA expression levels in tumor and marginal samples were examined by real-time quantitative PCR. Results are not concordant with previous studies and comparison of only SMAD7 or KLF10 is not useful for differentiating between tumor and margin cells, but ratio analysis of these two genes, SMAD7/ KLF10, can be indicative than study of one gene alone. We concluded that gene expression analysis of tumor cells with adjacent normal tissue are essential for precise identification and interpretation of cancer alterations and have important implications for the diagnostic and therapeutic management of cancer patients.

Bcl-2 gene expression in human breast cancers in iran.

BACKGROUND: Breast cancer is among the five most common cancers and ranks first among cancers diagnosed in Iranian women. Screening and treatment of this disease with molecular methods, especially regarding high incidences at early age and advanced stage, is essential. Several genes with altered expression have been identified by cDNA microarray studies in breast cancer, with the Bcl-2 gene indicated as a likely candidate. In this study, we studied Bcl-2 gene expression levels in parallel tumor and non-tumor breast tissues. MATERIALS AND METHODS: Forty samples including 21 tumor, 16 non tumor (marginal) and 3 benign breast tissues which were all pathologically diagnosed, were subjected to RNA extraction and polyA RT-PCR with the expression level of Bcl-2 quantified using real-time PCR. RESULTS: There is higher expression levels of the Bcl-2 gene in tumor samples compared with marginal samples, but not attaining significance(p>0.05). Bcl-2 expression in 14 (66.7%) of the cases of tumor samples and 9 (56.3%) cases of the marginal samples were positive. Comparison of the expression of the Bcl-2 gene in histological grade showed that a high expression of Bcl-2 was associated with a high histological grade (p<0.41). CONCLUSIONS: Our data suggests that dysregulated Bcl-2 gene expression is potentially involved in the pathogenesis of breast cancer. Using gene expression analysis may significantly improve our ability for screening cancer patients and will prove a powerful tool in the diagnosis and prognostic evaluation of the disease whilst aiding the cooperative group trials in the Bcl-2 based therapy project.