Role of ethnic variations in TNF-α and TNF-β polymorphisms and risk of breast cancer in India

TNF-α and -β, the multi-functional pro-inflammatory cytokines, are known to play important roles in both tumor progression and destruction based on their concentrations. Growth factors and various stimuli such as cytokines regulate proliferation of the breast epithelial cells. Therefore, the polymorphisms in the genes encoding these signaling molecules could affect the risk of breast cancer. We have investigated selected genetic polymorphisms in TNF-α promoter (rs1800629, −308 G>A and rs361525, −238 G>A) and TNF-β intron 1 (rs909253, +252 A>G) in ethnically two different case–control groups from India. The study included 200 cases and 200 controls from an Indo-European (North Indian) group, and 265 cases and 237 controls from a Dravidian (South Indian) group. Genotyping of a total of 902 individuals was done by direct DNA sequencing. None of the polymorphisms showed significant association with breast cancer in the Indo-European group; however, all the three polymorphisms showed strong association with breast cancer in the Dravidian group. Further, sub-group analysis in the Indo-European group showed no significant difference between pre-menopausal cases and controls or between post-menopausal cases and controls at any of the loci analyzed. However, all the polymorphisms in the Dravidian group were significantly associated with pre-menopausal but not with post-menopausal breast cancer. In conclusion, TNF-α and -β polymorphisms are strongly associated with breast cancer in the Dravidian but not in the Indo-European group.     

Silencing of IKKε using siRNA inhibits proliferation and invasion of glioma cells in vitro and in vivo

Recent studies implicated IKKε in the pathogenesis of many human cancers by promoting cell proliferation, increasing tumor angiogenesis and metastasis, and generating resistance to cell apoptosis. However, whether IKKε can influence the invasive ability and proliferation of glioma cells remains largely unknown. In this study, we showed that overexpression of IKKε is positively correlated to glioma pathological grade, suggesting that IKKε plays a role in tumor progression, rather than tumor initiation. Targeted knockdown of IKKε in human glioma cells using siRNA, was associated with inhibition of cell growth, cell cycle arrest and decreased cell invasion; however, notable apoptosis was not observed. Furthermore, we demonstrated that transposition of NF-κB p65 resulted in the alteration of these phenotypes. Tumor growth was attenuated in established subcutaneous gliomas in nude mice treated with IKKε siRNA in vivo. Collectively, our results suggest that deregulation of IKKε plays a pivotal role in the uncontrolled proliferation and malignant invasion of glioma cells in vitro and in vivo by targeting NF-κB. Silencing of IKKε using synthetic siRNAs may offer a novel therapeutic strategy for the treatment of glioma.     

The role and status of fuzheng in cancer prevention and treatment

Traditional Chinese medicine (TCM) treatment of cancer has a long history, and is an important part of cancer prevention and control in China. Fuzheng, also cal ed reinforcing healthy qi and supplementing the root, is the most funda-mental principle of TCM in cancer prevention and control. In recent decades, this treatment has been thoroughly studied and widely applied, and played a crucial role in cancer prevention and treatment. With regard to the treatment of malignant tumors, Chinese medicine is mainly used in the fol owing areas:improving symptoms, enhancing the quality of life, reducing postop-erative recurrence and metastasis, increasing ef icacy and decreasing toxicity together with radiotherapy and chemotherapy treatments, and to some extent prolonging the survival of advanced tumors.     

TNF-α in promotion and progression of cancer

Tumour necrosis factor alpha is a member of the TNF/TNFR cytokine superfamily. In common with other family members, TNF-α is involved in maintenance and homeostasis of the immune system, inflammation and host defence. However, there is a ‘dark side’ to this powerful cytokine; it is now clear that, especially in middle and old age, TNF-α is involved in pathological processes such as chronic inflammation, autoimmunity and, in apparent contradiction to its name, malignant disease. This article will discuss the involvement of TNF-α in the inflammatory network that contributes to all stages of the malignant process, and consider the possibility that TNF-α may be a target for cancer therapy.     

Expression and Significance of Coxsackie and Adenovirus Receptor in Renal-Cell Carcinoma

OBJECTIVE To investigate the expression of Coxsackie and Adenovirus receptor (CAR) in renal-cell carcinoma and the relationship of the CAR to the biological behavior of the carcinomas.METHODS The immunohistochemical SP method was used to detect the expression of Coxsaekie and Adenovirus receptor in 48 cases of renalcell carcinoma and in 12 cases of normal renal tissue 2 cm away from the tumor tissue.RESULTS The positive rates of CAR were 100% in 12 cases of para-tumcr normal renal tissue and 35.4% in 48 cases of renal-cell carcinoma respectively. The difference of CAR expression between them was significant (P＜0.05). The grades of the tumor were as follows: 22 in Grade Ⅰ, 17in Grade Ⅱ and 9 in Grade Ⅲ with the CAR positive rate being 54.5%,23.5% and 11.1%, respectively. There was a negative correlation between CAR expression and tumor grading (P＜0.05). In addition, the number of the cases in stages Ⅰ to ⅣV were 19, 13, 11 and 5 respectively, with the respective positive rates being 57.9%, 30.8%, 18.2% and 0.0%, i.e. there also was a negative relationship between CAR expression and the stage (P＜0.05).CONCLUSION CAR expression is down-regulated in renal-cell carcinoma compared with normal tissue. The level of CAR may be a sensitive predictor of differentiation, invasion and metastasis. Loss of CAR expression correlates with the invasive phenotype in our analysis of renal-cell carcinoma.     

in Vitro and in Vivo Inhibitory Effects of α-Mangostin on Cholangiocarcinoma Cells and Allografts

We investigated the anti-cholangiocarcinoma effect of α-mangostin from Garcinia mangostana pericarp extract (GM) in a human cholangiocarcinoma (CCA) cell line and a hamster CCA allograft model. In vitro, human CCA cells were treated with GM at various concentrations and for different time periods; then cell-cycle arrest and apoptosis were evaluated using flow cytometry, and metastatic potential with wound healing assays. In vivo, hamster allografts were treated with GM, gemcitabine (positive control) and a placebo (negative control) for 1 month; tumor weight and volume were then determined. Histopathological features and immunostaining (CK19 and PCNA) characteristics were examined by microscopy. The present study found that α-mangostin could: inhibit CCA cell proliferation by inducing apoptosis through the mitochondrial pathway; induce G1 cell-cycle arrest; and inhibit metastasis. Moreover, α-mangostin could inhibit CCA growth, i.e. reduce tumor mass (weight and size) and alter CCA pathology, as evidenced by reduced positive staining for CK19 and PCNA. The present study thus suggested that α-mangostin is a promising anti-CCA compound whose ready availability in tropical countries might indicate use for prevention and treatment of CCA.     

Incidence of craniopharyngioma in Denmark (n?=?189) and estimated world incidence of craniopharyngioma in children and adults

We studied the incidence of craniopharyngioma in Denmark during the period 1985-2004 and estimated worldwide incidence rates (IR) of craniopharyngioma based on a literature review. Craniopharyngioma patients diagnosed during the period 1985-2004 were identified from the Danish National Patient Registry, the Danish Cancer Registry and regional registries. Medical records were reviewed. Danish population data were obtained from Statistics Denmark. European and World population data were obtained from EU and WHO homepages. Prior studies providing data on craniopharyngioma IRs were identified via PubMed and, if appropriate, were included in a weighted analysis estimating overall and children's IRs of craniopharyngioma. IRs are given as new cases per million per year. We identified 189 patients with new verified (162) or probable craniopharyngioma. The overall WHO World-standardised incidence rate was 1.86 (1.60-2.14) for all ages and 2.14 (1.53-2.92) for children (age <15?years). Peak incidence rates were observed in age groups 5-9 and 40-44?years. Fifteen prior studies (including 1,232 craniopharyngioma cases) were identified. Seven and 11 studies, respectively, were eligible for weighted all-ages and childhood population IR analyses, yielding summary IRs of 1.34 (1.24-1.46) (all ages) and 1.44 (1.33-1.56) (children). We have provided a detailed survey of the incidence of craniopharyngioma in Denmark during a recent 20-year period. Overall IR of craniopharyngioma in Denmark was 1.86 (1.60-2.14) as compared to 2.14 (1.53-2.92) among children. Weighted estimates of craniopharyngioma world IRs were 1.34 (1.24-1.46) in all ages and 1.44 (1.33-1.56) among children.     

Role of HIF-1α in response of tumors to a combination of hyperthermia and radiation in vivo

Purpose: Mild temperature hyperthermia (MTH) increases blood flow and oxygenation in tumours. On the other hand, high-dose-per-fraction irradiation damages blood vessels, decreases blood flow and increases hypoxia in tumours. The radiation-induced hypoxia in tumours activates hypoxia-inducible factor-1α (HIF-1α) and its target genes, such as vascular endothelial growth factor (VEGF), promoting revascularization and recurrence. In the present study, we examined the hypothesis that MTH inhibits radiation-induced upregulation of HIF-1α and its target genes by increasing tumour oxygenation.

Materials and methods: FSaII fibrosarcoma tumours grown subcutaneously in the legs of C3H mice were used. Tumours were irradiated with 15?Gy using a ⁶⁰Co irradiator or heated at 41?°C for 30?min using an Oncothermia heating unit. Blood perfusion and hypoxia in tumours were assessed with Hoechst 33342 and pimonidazole staining, respectively. Expression levels of HIF-1α and VEGF were determined using immunohistochemical techniques. Apoptosis of tumour cells was quantitated via TUNEL staining and the effects of treatments on tumour growth rate were assessed by measuring tumour diameters.

Results: Irradiation of FSaII tumours with a single dose of 15?Gy led to significantly decreased blood perfusion, increased hypoxia and upregulation of HIF-1α and VEGF. On the other hand, MTH at 41?°C for 30?min increased blood perfusion and tumour oxygenation, thereby suppressing radiation-induced HIF-1α and VEGF in tumours, leading to enhanced apoptosis of tumour cells and tumour growth delay.

Conclusion: MTH enhances the anti-tumour effect of high-dose irradiation, at least partly by inhibiting radiation-induced upregulation of HIF-1α.     

Renal handling of 2′-deoxyadenosine and adenosine in humans and mice

Summary In a child lacking adenosine deaminase and in patients treated with deoxycoformycin (a potent inhibitor of the enzyme), apparent renal secretion of 2-deoxyadenosine (dAdo) and reabsorption of adenosine (Ado) were observed. The renal clearance of dAdo in humans was approximately five-fold that of creatinine, whereas the renal clearance of Ado was only one-fifth that of creatinine. In mice treated with deoxycoformycin, a similar paradigm was observed. Specifically, plasma levels of Ado and dAdo were elevated to detectable levels and apparent renal secretion and reabsorption of these purine nucleosides became manifest. Thus, the mouse may serve as a suitable model to study the renal handling of these two compounds. The active renal secretion of dAdo may occur because the compound has not been appreciably synthesized by mouse kidney in situ, and ion-trapping of dAdo in acid urine could not explain the net secretion. The differential transport of these similar purine nucleosides suggests a very selective transport system in mammalian kidney. Although carrier-mediated, facilitated diffusion of purine nucleosides across cell membranes is a well-known phenomenon, the present data indicate the existence of (an) active transport sysem(s) for the transepithelial secretion of dAdo, and possibly for the reabsorption of Ado.The abbreviations used in this paper are ADA adenosine aminohydrolase EC 3.5.4.4 - Ado adenosine - dAdo 2-deoxyadenosine - DCF 2-deoxycoformycin - HPLC high-performance liquid chromatography - PBS 0.14 M NaCl plus 0.01 M phosphate buffer, pH 7.4 - PNPase purine nucleoside: orthophosphate ribosyltransferase EC 2.4.2.1 - SCID: ADA^- severe combined immunodeficiency disease associated with ADA deficiency     

Expression of Coxsackie and Adenovirums and its Significance in Human Lung Cancer

OBJECTIVE To study the relationship between the coxsackie and adenovirus receptor （CAR） and the development of human lung cancer. To optimize adenovirus vector-based gene therapy. METHODS The expression of CAR in 112 cases of lung cancer was examined using immunohistochemistry. At the same time, the relationship between CAR expression and clinicopathologic characteristics was analyzed, RESULTS ：lhere is a little expression of CAR in normal lung tissue. Compared with paraneoplastic epithelial tissue of the lung, the expression of CAR is generally up-regulated in tumor tissues showing a significant dif- ference （P〈0.01）. The positive rate of CAR expression in squamous cell carcinoma was 43.1%, and in adenocarcinoma 70.2%, with the difference between the two rates being statistically significant （P〈0.01）. Compared to the paraneoplastic tissues, the difference in CAR positive expression was 35.4% for squamous cell carcinoma and 38.3% for adenocarcinoma. But the difference in different stages of squamous cell carcinoma had no statistical significance （P〉0.05）. However, the expression of CAR was at a high level in the bronchioalveolar carcinomas as 80.4% were CAR positive. This research showed that there was a specially high expression of CAR in adenocarcinomas. CONCLUSION CAR is expressed in human lungs at a low level and up-regulated in the tumor tissues, suggesting that there is a relationship between adenocarcinoma and CAR. This research provides a basis for planning a regimen of gene therapy using an adenovirus vector,     

Differential effects of tumor–platelet interaction in vitro and in vivo in glioblastoma

An elevated platelet count is considered an independent predictor of short survival in glioblastoma and various other tumor entities. Prothrombotic activity of the tumor microcirculation resulting in platelet activation and release of cytokines from activated platelets has been suggested to play a role. This study was designed to analyze the effects of platelet-released cytokines on glioblastoma and endothelial cell proliferation and migration in vitro, and the influence of platelet count on glioblastoma growth and angiogenesis in vivo. In cultured human glioblastoma, umbilical cord and cerebral microvascular endothelial cells platelet-released cytokines significantly stimulated proliferation and migration as well as sprouting and formation of capillary-like structures. In vivo, glioblastoma cells were implanted in mice followed by platelet depletion starting 1 or 8 days later. Tumor volume, proliferative index, and vessel density analyzed 14 days after engraftment did not differ between animals with a normal and a low platelet count. Likewise, no effect of platelet depletion over 20 days upon the volume of intracerebrally growing tumors was observed in mice. Additionally, proliferative activity and vessel density determined in tumor samples from patients operated upon glioblastoma did not show any correlation with the patients’ preoperative platelet count. Thus, we conclude that distinct proliferation- and chemotaxis-stimulating effects of platelet-derived cytokines can be achieved in vitro, while the platelet count does not exert a major influence on tumor growth and tumor angiogenesis in GBM in vivo.     

Expression of E2F-1, Rb and ER in Peripheral Papilloma and Ductal Carcinoma in Situ of the Breast and its Significance

OBJECTIVE To investigate the correlation of E2F-1, Rb and ER expression with peripheral papilloma (Peri-PM) and ductal carcinoma in situ of the breast (DCIS), and further explore some molecular mechanisms of the canceration of Peri-PM. METHODS Imunohistochemistry was used to examine the expression of E2F-1, Rb and ER in 60 Peri-PM, 60 Peri-PM with atypical ductal hyperplasia (Peri-PM with ADH) and 60 DCIS. Normal breast tissues were selected as a control group. RESULTS Based on immunohistochemical staining, the positive rate of E2F-1 expression in Peri-PM, Peri-PM with ADH and DCIS was 21.7%, 46.7% and 78.3% respectively. The positive rate of Rb expression was 83.3 %, 53.9% and 21.7% and the ER expression was 86.7%,61.7% and 55.0%. Significant differences were found among the 3 groups (Peri-PM, Peri-PM with ADH and DCIS) (P<0.05). Significant differences existed between any 2 groups (P<0.05) except for the rate of ER positive expression comparing Peri-PM with ADH verus DCIS (P>0.05). The expression of E2F-1 was nega- tively correlated with ER and Rb, and at the same time the expression of ER was positively correlated with Rb. Following the degree of breast epithelial hyperplasia involved and its development into carcinoma, the positive rate of E2F-1 expression displayed an elevating tendency, but that of Rb and ER expression showed a tendency to decline. CONCLUSION The interaction of the 3 indexes studied may play an im- portant role in the conversion of precancerous lesions to early in situ breast carcinoma, and the evaluation of these indexes might provide a valuable basis for screening high-risk cases of Peri-PM.     

Expression of E-Cadherin and the PTEN Gene in Relation to Invasion and Metastasis of Gastric Carcinomas

Objective To observe the expression of PTEN and E-Cadherin in gastric carcinomas (GCs): and to investigate the relationship between their expression and the pathology and prognosis of patients with GC. Methods The proposed markers were detected inmmunohistochemicaily by using the SABC method in 100 post-operated specimens of GC. The results were statically analyzed by the chi-square and log rank tests. Results Both E-Cadherin and PTEN proteins were expressed in noncancerous rnucosa. They were reduced or lost in GCs. The abnormal rate of expression of E-Cadherin was 42.0%. The decreased rate of expression in the diffuse-type GC (48.6%) was significantly higher than in the intestinaltype GC (26.7%, P< 0.05). The abnormal expression of E-Cadherin closely correlated to the depth of invasion (P< 0.05). The degree of loss of the PTEN protein was 59.0% in GCs. In the diffuse-type GC, the rate of toss of PTEN was (65.7%) which was significantly higher than that in the intestinal-type GC (43.3%,P< 0.05). The rate of loss of PTEN (64.5%) in GCs with lymph node metastasis was significantly higher than that in GCs without metastasis (41.7%, P< 0.05). The prognosis of patients with a loss of PTEN protein was worse than the patients with positive expression of PTEN (P=0.0066). E-Cadherin was normally expressed in 65.9% of GCs with positive expression of PTEN. Conclusion The loss of E-Cadherin and PTEN markers correlated with infusion and metastasis of GC. The expression of PTEN showed a close relationship to the prognosis of patients. Detection of the 2 markers together aided in the correct prediction of the prognosis of the GC patients and provided information for clinical treatment.     

Expression of Cyclooxygenase-1 and –2 and Clinicopathologic Features of Colorectal Cancer in Northern Thailand

Two isoforms of cyclooxygenase, COX-1 and COX-2, have been identified and shown to be involved in ‍tumorigenesis. Although, overexpression of COX-2 in human cancers has been repeatedly reported, no data have ‍hitherto been available for Thai patients. To cast light on the role(s) of COX enzymes in the development and ‍progression of colorectal cancers and to determine the incidence of COX-2 overexpression, the expression levels of ‍COX-1 and COX-2 proteins using Western blot analysis in tumor tissues and adjacent normal tissues obtained from ‍44 Thai patients with colorectal cancer. ‍Compared with paired normal tissues, COX-2 was overexpressed in 13 of 44 colorectal tumor tissues (29.5%). ‍Overall, COX-2 levels in colorectal tumor specimens were significantly correlated with histological differentiation, ‍in particular in the tumors with poor differentiation (p<0.05). In addition, overexpression of COX-2 was found more ‍frequently in colorectal tumors with lymphatic invasion, regional lymph node metastasis and larger size, ‍althoughwithout statistical significance. In contrast to the relatively consistent alteration in COX-2 expression, the ‍level of COX-1 expression was quite varied in tumor tissues. Forty-eight percent of colorectal tumors exhibited a ‍decreased level of COX-1 in comparison to normal tissues and overexpressed in 23%. Thus both isoforms may both ‍play roles in promoting tumorigenesis. However, there was no significant relationship between the alteration of ‍COX-1 protein levels and any pathological features of tumors. ‍     

Dietary and Lifestyle Factors and Risk of Non-Hodgkin’sLymphoma in Oman

Background: The incidence of various types of cancers including the non-Hodgkin’s lymphoma (NHL) hasincreased during the recent years. Diet and lifestyle factors have been reported to play an important role inthe etiology of NHL. However, no such data are available from the Middle Eastern countries, including Oman.Materials and Methods: Forty-three histologically confirmed cases of non-Hodgkin’s lymphoma (NHL) diagnosedat the Sultan Qaboos University Hospital (SQUH) and the Royal Hospital (RH), Muscat, Oman and forty-threeage and gender matched controls were the subjects of this study. Frequency matching was used to select thecontrol population. Information on social and demographic data as well as the dietary intake was collected bypersonal interviews, using a 117-items semi-quantitative food frequency questionnaire. Results: A non-significantincreased risk of NHL was observed with higher body mass index (BMI) (OR=1.20, 95%CI: 0.45, 2.93), whereasa significantly decreased risk of NHL was associated with a higher educational level (OR=0.12, 95%CI: 0.03,0.53). A significantly increased risk was observed for higher intake of energy (OR=2.67, 95%CI: 0.94, 7.57),protein (OR=1.49, 95%CI: 0.54, 4.10) and carbohydrates (OR=5.32, 95%CI: 1.78, 15.86). Higher consumptionof daily servings from cereals (OR=3.25, 95%CI: 0.87, 12.09) and meat groups (OR=1.55, 95%CI: 0.58, 4.15)were also found to be associated with risk of NHL, whereas a significantly reduced risk was associated withhigher consumption of vegetables (OR=0.24, 95%CI: 0.07, 0.82). The consumption of fruits, milk and dairyproducts however showed no significant association with the risk of developing NHL. Conclusion: The resultssuggest that obesity, high caloric intake, higher consumption of carbohydrate and protein are associated withincreased risk of NHL, whereas a significantly reduced risk was observed with higher intake of vegetables.     

Expression and Clinical Significance of HMGB1 and RAGE in Cervical Carcinoma

OBJECTIVE To study the expression level and clinical significance of HMGB1 and RAGE in cervical squamous epithelial carcinoma. METHODS Real time quantitative polymerase chain reaction(qRT-PCR) was employed to examine the expression of HMGB1(high mobility group box protein1),and RAGE(receptor for advanced glycation endproducts)in 60 cervical squamous epithelial carcinomas(CSEC),their paraneoplastic tissues(PS)and 30 normal cervix tissues(NCS). RESULTS The expression of HMGB1 in the CSEC samples and PS was similar(P>0.05),but higher compared to NCS(P<0.05).Overexpression of HMGB1 in the CESC tissues was significantly correlated with the tumor (P<0.05),and the presence of metastasis(P<0.01),but not correlated with the tumor diameter or tumor grade.RAGE expression was not significantly different among these tissue types,and showed no significant correlation with the the tumor stage,diameter or grade.But there was a significant positive correlation between RAGE expression and CSEC metastasis. CONCLUSION The results suggest that HMGB1 may be related to the proliferation,progression and metastasis of CSEC.The relationship of HMGB1/RAGE may be of importance for CSEC metastasis.HMGB1 presents a new potential gene target for prevention and treatment of CSEC. Study of HMGB1/RAGE expression will offer an experimental foundation for understanding the pathogenesis of CSES.     

Roles of cyclin-dependent kinase 8 and β-catenin in the oncogenesis and progression of gastric adenocarcinoma

Gastric adenocarcinoma is a common cause of cancer-related death. The Wnt/β-catenin pathway plays an important role in various cancers. However, relatively little is known about the regulatory mechanism of β-catenin in stomach cancer. To determine the patterns of cyclin-dependent kinase (CDK) 8 and β-catenin expression and the relationship between CDK8 and β-catenin, we conducted a study of immuno-histochemical staining of tumor tissues (12 adenomas, 24 early gastric carcinomas, 24 advanced gastric carcinomas and 21 metastatic lymph nodes), together with Western blot analysis and CDK8 interference studies using gastric cancer cell lines. Gastric adenocarcinomas with CDK8 expression had distinct clinical, prognostic and molecular attributes. CDK8 expression and the delocalization of β-catenin expression showed a significant positive correlation with carcinogenesis and tumor progression, especially lymph node metastasis. Immunohisto-chemically, CDK8 expression in gastric adenocarcinoma was independently associated with β-catenin activation (p<0.05). β-catenin expression was suppressed by CDK8 interference in the gastric adenocarcinoma cell lines, SNU-601 and SNU-638. These data support the potential link between CDK8 and β-catenin, and suggest that CDK8 detection and β-catenin delocalization could be related to a poor prognosis. Moreover, the interference of CDK8 could be a promising therapeutic modality for gastric adenocarcinoma.