Krebswissenschaft und -therapie

Sodium/glucose co-transporter 1 (SGLT1) is an active glucose transporter that takes up glucose into cells independent of the extracellular concentration of glucose. This transporter plays a critical role in maintaining glucose homeostasis at both physiological and pathological levels. The expression level of SGLT1 in normal and diseased human prostatic tissue has not been determined. We produced two rabbit polyclonal antibodies against human SGLT1, one each for immunohistochemical and Western blot analyses, and characterized the expression of SGLT1 in human prostate tissues: normal prostate (n=3), benign prostatic hyperplasia (BPH) (n=53), prostatic intraepithelial neoplasia (PIN) (n=9), and prostate cancer (PCa) (n=44). In normal prostate tissue, SGLT1 was weakly expressed exclusively in the epithelium. The transporter was significantly increased in the basal cells and stromal cells of BPH, increased in the epithelial cells of PIN, and frequently overexpressed in stromal cells and universally overexpressed in the tumor cells of PCa. The pattern of expression was shown as membranous/ cytoplasmic staining in low-grade cancer cells and nuclear envelope staining in high-grade cancer cells. The SGLT1-positive stromal cells of BPH and PCa tissues were negative for tenascin, a marker of reactive stromal cells. We concluded that SGLT1 is up-regulated in BPH and PCa, and SGLT1 may serve as a potential therapeutic target for treating these prostate disorders.

The tumor suppressor gene FBXW7 is mutated in numerous types of human cancers leading to loss of its function and/or expression. However the clinic significance of FBXW7 alterations remains largely unknown. Here, we carried out a meta-analysis of 10 gene expression microarray studies for a total 1900 patients of breast cancer with clinic information to evaluate the prognostic impact of FBXW7 mRNA expression. The FBXW7 mRNA levels significantly reduced in breast cancer compared to normal tissues. In addition, significant difference in the FBXW7 mRNA levels was found among molecular subtypes (normal-like, luminal A, luminal B, ERBB2 and basal). ERBB2 and basal tumors had significantly lower average FBXW7 mRNA level than normal-like tumors, whereas luminal A and B tumors have the lowest average FBXW7 mRNA level. The patients with higher FBXW7 mRNA level significantly increased disease-free survival, particularly in the group of patients with ER negative and basal subtype tumors. Moreover, higher FBXW7 mRNA level also significantly increased overall survival in the patients with ER negative tumors. But we strikingly found opposite effect of FBXW7 expression on overall survival in different subtypes. The patients with higher FBXW7 mRNA level significantly decreased overall survival in normal-like subtype while the patients with higher FBXW7 mRNA level significantly increased overall survival in ERBB2 and Basal subtype. Taken together, our results suggest that FBXW7 mRNA levels were a prognostic factor for disease-free and overall survival according to ER status and molecular subtypes.

Patients with advanced hepatocellular carcinoma (HCC) have a poor prognosis. Their median survival time was reported to be 2.7-4 months if they were left untreated. Hepatic arterial infusion chemotherapy (HAIC) has been regarded as one of the effective therapeutic modalities. So, the aim of this study was to evaluate survival and therapeutic responses of HAIC for advanced HCC. From January 2004 to November 2011, we retrospectively reviewed the data of patients with advanced HCC who received 2 sessions of HAIC or more. Tumor response thereto was measured by the abdominal CT scan at each session of HAIC using Modified Response Evaluation Criteria in Solid Tumors. 54 patients were enrolled. Their mean age was 57 year-old and 47 patients were male. 33 patients were under Child-Turcotte-Pugh Class A, 17 were under Class B, and 4 were under Class C. The causes of HCC were HBV (70.3%), HCV (11.1%), and alcoholics (13.0%). On average, patients received 4.2 sessions of HAIC. At the time of completing 2 sessions of HAIC, the median survival time of patients who achieved complete response (CR) or partial response (PR) (Group A) was 190 days, while that of patients who had stable disease (SD) or progressive disease (PD) (Group B) was 96 days (p=0.265). At the time of completing 4 sessions of HAIC, the median survival time of Group A and Group B was 302 days and 111 days, respectively (p=0.009). Advanced HCC without potal vein tumor thrombosis (PVTT) showed better therapeutic responses than advanced HCC with PVTT (p=0.021). HAIC can be a useful therapeutic modality for patients with advanced HCC. Presence of PVTT can be an independent predictive factor for therapeutic response of HAIC. However, prospective studies for identifying predictive factors of better prognosis of advanced HCC are still needed.

Background: Apoptotic inhibitor gene survivin regulates apoptosis and cell cycle progression. Functional polymorphism in the promoter region of survivin influences its expression may lead to the development of several cancers including lung cancer. Our study aimed to investigate the association of survivin-31G>C polymorphism with the risk of NSCLC in Indian population.
 
Methods: A hospit al-based case control study of 136 cases and 136 age-gender matched healthy controls was performed by PCR-RFLP.
 
Results: Our findings reveal that a statistically increased risk and poor survival was associated with the BIRC5 -31CC genotype (OR 3.13, 95% CI 1.57- 6.25) compared to the genotype containing G allele GC (OR 1.22, 95% CI 0.69-2.14). In addition significant association was found with stage and distant metastasis status of NSCLC patients.
 
Conclusions: Our results conclude that the function polymorphism (-31G>C) in the promoter of survivin gene is associated with risk and susceptibility to NSCLC.

Cancer cells compared to their normal counterparts reveal different metabolic needs and this differential requirement of metabolic intermediates and their subsequent consequences require an elaborate understanding of cancer cell metabolism and increased energy production in these cells. Nevertheless these metabolic differences have provided opportunities for developing novel therapeutic approaches for the cancer diagnosis and treatment. In addition enhanced proliferative capacities of tumor cells associated with aberrations of many signal transduction pathways resulting from genetic or epigenetic alterations has made it possible to develop countless targeted therapeutics for several types of malignancies. However at present most of our understanding about the dysregulated cancer cell metabolism is at physiological stages. With advancement in technology development, we may eventually be able to differentiate the metabolic differences between normal cells and cancerous at the single-tumor level that may influence the development of personalized cancer medicine. In this review, the focal point will be the recent developments in understanding the crucial role of metabolic enzymes, oncogenes and tumor suppressor genes in progression of cancer and their targeting to establish the most appropriate therapeutic strategies for better clinical outcome.

Rationale: In 2009 we reported the results of a pharmaco-epidemiological, retrospective observational cohort study in colorectal carcinoma (CRC) patients UICC stage I-III, receiving chemo- and/or radiotherapy together with European Viscum album L. (“Viscum”) extract (Iscador®) as supportive care (n = 429) versus the conventional treatment (n = 375) after R0 resection (J. Soc. Int. Oncol. 7: 173-145). The endpoints have been therapy induced adverse effects, disease symptoms and disease-free survival (DSF).   Objective: Here, we present the secondary and confirmatory analysis of this original data set with respect to the host tree specificity of Viscum.   Results: Patients receiving the extract from Viscum harvested from oak (Quercus) trees, Iscador® Qu (Isc- Qu), in a supportive care mode simultaneously with chemo- and/or radiotherapy (n = 106) showed a significant improvement in therapy induced adverse effects, and, most remarkable, a significant delay of metastasis formation and longer DFS compared to conventionally treated patients (n = 212) (control). To make the analysis more robust, patients treated by the chemo- and/or radiotherapy protocols were also analyzed and stratified for the UICC I-III stages. Accordingly to the overall Kaplan-Meier analysis result, patients receiving Isc-Qu as supportive care presented significantly longer median time to distant metastases formation (metastasis-free survival, MFS) within the course of the observational cohort study (133+ months (Isc-Qu) versus 94 months (control), p (Log Rank) = 0.002. In the Cox regression analysis, the confounder-adjusted hazard ratio, HR, (95% confidence interval) came up to HR (metastasis) = 0.31 (0.13-0.711), p = 0.006. This result indicates an estimated 69% metastasis-hazardreduction in the Isc-Qu group relative to the controls. In summary, patients concomitantly treated by Iscador® showed fewer persisting disease- and therapy-induced symptoms and the DSF hazard ratio suggested a survival benefit.   Clinical implication: This secondary and confirmatory analysis of the original data set suggests that a mistletoe (Viscum) preparation, harvested from oak (Quercus) trees (Isc-Qu), appears to be a naturally tailored molecular composition to target CRC patients by reducing therapy-related adverse effects, improving the cancerrelated symptoms and showing a potential to increasing the metastases-free survival.   Limitations: The effect on prolonged survival should be interpreted with some caution because the applied study design shares some potential risk for bias common to all non-randomized observational studies. Also, potential biases were tried to minimize by systematic multivariable adjusting of end point criteria for baseline imbalance, treatment regimen, and other potential confounders.

The aim of this study was to investigate the effect of ferrocene (FeCp₂) and ferrocenium salt (FeCp₂BF₄) on the viability of MCF7 breast cancer and MCF10A non-tumorigenic epithelial cells and the role of Reactive Oxygen Species (ROS) production in cell cytotoxicity. FeCp₂BF₄ displayed higher cytotoxicity than FeCp₂, and the cell type contributes toward complexes toxicity, as MCF7 cells displays greater toxicity than MCF10A cells. The mechanism of toxicity seems to involve the generation of ROS, with MCF7 cells producing higher levels than epithelial cells. In addition, the inhibition of ROS was found to be protective against ferrocene induced cell death. The findings of cancerous cell-induced cytotoxicity by ROS indicate a potential utility of ferrocenyl derivatives in the treatment of cancer.

We present an autopsy case of malignant granular cell tumor with an unusual clinical course. The patient had noticed a tumor on his neck 13 years prior to hospital admission. The tumor was resected and diagnosed as a malignant granular cell tumor fulfilling all 6 criteria proposed by Fanburg-Smith et al. Histologically, the tumor consisted of an extensive malignant area with adjacent small areas of benign granular cell tumor at the periphery. The patient received systemic chemotherapy and radiation, but little effect was noted. The tumor recurred 1.5 months after resection and grew rapidly. At autopsy, the tumor had metastasized to various organs, and carcinomatous lymphangiosis was present. Immunohistochemistry revealed diffuse S-100 protein expression but no expression of c-kit or EGFR and Ki-67 index in the malignant area was approximately 40%. This case report demonstrates the potential of benign granular cell tumors for malignant transformation.

The number of voxels with low signal intensity (Low DCE voxels) might be potentially related to treatment failure, which might be associated with the tumor oxygenation status. Our goal was to investigate whether at-risk voxels can be used to predict treatment outcome during radiation therapy for cervical cancer.
 
80 patients with Stage IB2–IVB cervical cancer were included. Four sequential MRI scans were performed at pre-RT, every 2–2.5 weeks during RT, and post-radiotherapy. 3D volumetric data including tumor regression and tumor perfusion from dynamic contrast enhanced MRI (DCE-MRI) were analyzed. Based on the signal intensity (SI) curves of the DCE-MRI, the low-DCE tumor voxels was obtained for individual patients. The predictive power of low DCE voxels in predicting the treatment outcomes was evaluated by Kaplan-Meier survival analysis. Correlation of low DCE voxels with hemoglobin (Hgb) was checked by Pearson Correlation.
 
The actuarial local control rate and survival rate in the patient group with a small number of low DCE voxels were 89.7% and 76.9%, compared with 75.6% and 51.2% in the patient group with a big number of low DCE voxels for the MRI study #1, and 94.1% and 80.4% compared with 62.1% and 34.5% for the MRI study #2, and 95.7% and 78.7% compared with 63.6% and 42.4% for the MRI study #3, respectively. Low DCE voxels were significantly correlated with Hgb.
 
At-risk voxels can be used to predict the outcomes and help understand tumor heterogeneity of response to RT. The Hgb level and tumor perfusion during RT influence the radioresponsiveness and survival in cervical cancer patients.

Background and purpose: Non-Hodgkin lymphomas are closely related diseases with distinctive morphologic, immunophenotypic, genetic, and clinical features. Genetic susceptibility studies of NHL are mandatory to identify at risk populations and to clarify important disease mechanisms. Caspase genes play a key role in regulation of apoptotic cell death, and dysregulation of this signaling pathway has been shown to participate in tumorigenesis. The current study aimed at defining the role of Caspase 8-D302H, Caspase 8-652 6N ins/del and Caspase 10-I522L genetic polymorphisms as risk factors for NHL and their possible role as genetic prognostic markers.   Methods: The present study included 100 Egyptian B-cell NHL patients and 100 healthy controls. Genotyping of the studied genes was performed by polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) technique. Data was analyzed using SPSS statistical package version 15.   Results: The study revealed that CASP8-D302H mutant genotypes were significantly higher in NHL patients when compared to the controls and conferred increased risk of NHL. For CASP8-652 6N ins/del and Casp10- I522L, there was no statistical difference in the distribution of the different genotypes between NHL cases and the controls. Furthermore, there were no statistical differences between NHL patients harboring the wild or mutant genotypes of the studied genes as regards their response to therapy.   Conclusions: CASP8-D302H genetic polymorphism represents a genetic risk factor for NHL in Egyptian population. Hopefully, better understanding of the functional consequences of caspase genes polymorphism would provide a foundation for future studies of the possible role of these genes in lymphomagenesis.