Prospective study of serum retinol, β-carotene, β-cryptoxanthin, and lutein/zeaxanthin and esophageal and gastric cancers in China

Objective: This study examined the relationship between pretrial serum concentrations of retinol, -carotene, -cryptoxanthin, and lutein/zeaxanthin and the subsequent risk of developing esophageal squamous cell carcinoma and gastric cardia or non-cardia adenocarcinoma in subjects selected from a randomized nutritional intervention trial in Linxian, China, a region with epidemic rates of esophageal and gastric cardia cancer. Methods: We used a stratified case–cohort design to select cohort members for inclusion in this study. In all we measured serum concentrations of the above vitamins in 590 esophageal, 395 gastric cardia, and 87 gastric non-cardia case subjects as well as in 1053 control subjects. Relative risks (RRs) were estimated using Cox proportional hazards models. Results: Median values in our cohort were low for serum retinol (33.6 g/dl), -carotene (4.3 g/dl), and -cryptoxanthin (3.5 g/dl) , but were high for lutein/zeaxanthin (40.0 g/dl). Gastric cardia cancer incidence fell 10% for each quartile increase in serum retinol (RR = 0.90, 95% CI = 0.83–0.99). For esophageal cancer, an inverse association with retinol levels was found only in male non-smokers (RR = 0.79 per quartile increase, 95% CI = 0.63–0.99). For gastric non-cardia cancer, an inverse association was limited to subjects 50 years old or younger (RR = 0.58 per quartile, 95% CI = 0.31–0.96). For -cryptoxanthin there was a borderline significant protective association for gastric non-cardia cancer (RR = 0.88 per quartile, 95% CI = 0.76–1.0). In contrast, we found the incidence of gastric non-cardia cancer increased (RR = 1.2 per quartile, 95% CI = 1.0–1.3) with increasing concentration of serum lutein/zeaxanthin. Conclusions: In this population, we found that low retinol and high lutein/zeaxanthin concentrations increased the risks of gastric cardia and gastric non-cardia cancer respectively. We found that there were no strong associations between any of the other analytes and any of the cancer sites.     

APC and β-catenin protein expression patterns in HNPCC-related endometrial and colorectal cancers

Objective: The adenomatous polyposis coli (APC) and β-catenin (CTNNB1) genes are the two major components of the Wnt signaling pathway that has been shown to play an important role in the formation of certain cancers. The overactivation of the pathway, which results in abnormal accumulation of β-catenin protein in nuclei, contributes to most colorectal cancers (CRCs), both sporadic and hereditary, as well as sporadic endometrial cancers (ECs). Here, we studied the involvement of APC and β-catenin in hereditary nonpolyposis colorectal cancer (HNPCC)-related ECs, and compared the expression patterns to those in HNPCC-related CRCs. Materials and methods: Nineteen ECs and 31 CRCs derived from HNPCC patients were immunohistochemically stained with anti-APC- and anti-β-catenin –antibodies. Results: Tumor-specific loss of APC was observed in 16 of endometrial cancers (3 of 19) and in 39 of colorectal cancers (12 of 31). Consistently, the loss of APC expression was associated with nuclear β-catenin staining. Altogether, aberrant β-catenin localization was observed in 53 of ECs (10 of 19) as compared to 84 of CRCs (26 of 31) (P=0.02).Conclusion: Our results suggest a frequent overactivation of the Wnt signaling pathway in hereditary endometrial cancer. In accordance with studies on sporadic cancers, abnormal accumulation of β-catenin protein in nuclei occurred much less frequently in HNPCC-related ECs than CRCs, which may reflect organ-specific differences in their pathogenesis.     

Alterations of E-cadherin and β-catenin in gastric cancer

Background  

The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression.     

Expression of FRAT1 and β-catenin in human brain glioma and their significances

Objective: To investigate the expression of FRAT1 and β-catenin in human brain glioma, analyze the correlation between the expression and clinical pathological grades and the correlation of the two genes. Methods: FRAT1 and β-catenin were detected by immunohistochemistry in 84 human brain glioma tissues and 6 human normal brain tissues. Results: 66.7% (56/84) and 77.4% (65/84) of human brain glioma tissues expressed FRAT1 and β-catenin protein, whereas no FRAT1 and β-catenin protein expression was detected in human normal brain tissues. The expression levels of FRAT1 and β-catenin increased markedly with the ascending of pathologic grade of tumor specimens (r = 0.55, P < 0.01, r = 0.70, P < 0.01), there was a positive correlation between FRAT1 and β-catenin (r = 0.77, P < 0.01). Conclusion: FRAT1 and β-catenin over-expression maybe closely related with occurrence and development of human brain gliomas. The results provide important supplements for the research of Wnt/β-catenin pathway. Meanwhile, FRAT1 may act as a valuable biomarker for molecular diagnosis of glioma and a potential target for gene therapy of glioma.     

Pharmacokinetics and metabolism of β-2′-deoxythioguanosine and 6-thioguanine in man

Summary Resistance to the antileukemic agent 6-thioguanine (TG) inevitably develops in animal tumors. However, a new agent, -2-deoxythioguanosine (-TGdR) can overcome TG resistance in animal tumor models and is therefore of potential clinical use. The pharmacokinetics of radiolabeled TG were compared with those of -TGdR in patients with cancer after intravenous administration. [³⁵S]--TGdR (5.4 mg/kg, 200 mg/m², 200 Ci total) was administered to five patients; the radiolabel in the plasma declined with an initial half-life (t_1/2) of 14 min and a terminal t_1/2 of 19.3 h. Within 24 h, 65% of the radiolabel was excreted in the urine. In contrast, after administration of [³⁵S]-6-TG (3.4 mg/kg, 125 mg/m², 200 Ci total) the average initial t_1/2 was 40 min while the terminal phase t_1/2 was 28.9 h. Urinary excretion of the radiolabel was 75% of the dose 24 h after administration. Both thiopurines were rapidly and extensively degraded and excreted as 6-thioxanthine, inorganic sulfate, S-methyl-6 thioxanthine, and 6-thiouric acid in addition to other products. Small amounts of unchanged drug were also excreted. These studies suggest that -TGdR is merely a latent form of TG.Deceased, to whose memory this paper is dedicated     

Increased concentrations of transforming growth factor β1 and β2 in the plasma of patients with glioblastoma

Summary Recently, several in vitro studies have demonstrated production of the potent immunosuppressive cytokine transforming growth factor β (TGF-β)2 in glioblastoma cell lines. Systematic studies of the concentration of TGF-β isoforms in the plasma of patients harboring intracerebral tumors do not exist.In the present study, the concentrations of TGF-β1 and TGF-β2 in platelet-poor plasma of 21 patients with glioblastoma before and after extensive resection were measured by specific ELISA systems and related to survival.The plasma concentrations of latent TGF-β1 of patients with glioblastoma prior to surgery were significantly higher in comparison to healthy control probands, but not to patients with multiple sclerosis (MS). Furthermore, latent TGF-β2 was found to be significantly increased in the plasma of patients with glioblastoma in comparison to healthy control probands and patients with MS. After extensive resection of the tumor, the value of latent TGF-β2 evidently decreased.Interestingly, the concentration of latent TGF-β2 prior to surgery was correlated with survival and a strong relationship was found between the survival and the difference of latent TGF-β2 levels prior to surgery minus the TGF-β2 concentrations 7 days after surgery. A higher difference in these plasma concentrations >6 ng/ml vs. <6 ng/ml clearly correlates with a longer survival time. In conclusion, this study suggests that glioblastoma does secret TGF-β2 in vivo and that TGF-β2 may play an important role in glioblastoma patients.     

Significance of β-tubulin Expression in Breast Premalignant Lesions and Carcinomas

OBJECTIVE To explore the expression of β-tubulin in premalignant lesions and carcinomas of the breast,and to observe the relationship of its expression with breast cancer pathological features. METHODS The expression of β-tubulin was detected immunohistochemically in 50 specimens of premalignant lesions of the breast(ADH and Peri-PM with ADH),50 specimens of breast in situ ductal carcinomas(DCIS),and 50 specimens of invasive ductal carcinomas(IDC).Thirty specimens of normal breast tissues served as a control group. RESULTS Immunohistochemical analysis showed that:the differences among the 4 groups(normal breast tissues,breast premalignant lesions,DCIS and IDC,P<0.05)were significant, and there were also statistically significant differences between any 2 groups(P<0.05)except for the β-tubulin positive expression comparing DCIS versus IDC(P>0.05).In addition,β-tubulin was expressed at a higher level in Peri-PM with ADH compared to ADH(P<0.05).Following the degree of breast epithelial hyperplasia involved,and its development into carcinoma,the β-tubulin positive expression displayed an elevating tendency. We also found a significant positive relationship of β-tubulin expression with lymph node metastasis(P<0.05),but no significant correlation with histological grading and nuclear grade. CONCLUSION Centrosome defects may be an early event in the development of breast cancer and they can also promote tumor progression.Studies of aberrations of centrosomal proteins provide a new way to explore the mechanism of breast tumorigenesis.     

Expression and significance of TGF － β1 and TPR Ⅱin human pancreatic ductal adenocarcinoma

目的：对人胰腺癌中转化生长因子β1（TGF－β1）及其血型受体（TβRⅡ）的表达进行研究,探讨其与胰腺癌进展、转移的关系。方法：应用SABC免疫组化方法检测TGF－βl、TβR－Ⅱ在10例正常胰腺,13例慢性胰腺炎和36例胰腺癌中的表达。结果：1．TGF－β1、TβⅡ阳性率在正常胰腺均为10．0％,慢性胰腺炎中分别为7．7％、15．4％,胰腺癌中分别为44．4％、47．2％,胰腺癌中的阳性率明显高于前两组（P＜0．05））;2．TGF－β1、TβRⅡ的表达与胰腺癌患者的年龄、性别、肿瘤的大小、位置、组织学分级无关（P＞005）,与临床分期相关（P＜0．001）;3．TGF－β1、TβRⅡ在胰腺癌中共同阳性率为36．1％,其共同表达与胰腺癌的组织学分级和临床分期有关（P＜0．001）。结论：单独检测TGF－βl、TβRⅡ的表达对判断胰腺癌的进展、转移趋势有参考价值;二者共同表达对判断胰腺癌的恶性程度及进展、转移趋势有参考价值。     

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.     

Trans-Lycopene and β-Cryptoxanthin Intake and Stomach Cancer in Vietnamese Men: A Pilot Case-Control Study

Objective: To examine the association between dietary intake of Trans-Lycopene and β-Cryptoxanthin and stomach cancer in Vietnamese men. Methods: A case-control study including 80 male incident stomach cancer cases and 146 male controls was performed in a general hospital in Viet Nam. A validated semi-quantitative food frequency (SQFFQ) and demographic lifestyle questionnaire were designed, and venous blood samples were collected to determine H. pylori status by IgG ELISA. Nutrient intake was converted using the data of SQFFQ and the Nutritive Composition Table of Vietnamese Foods, updated in 2019. The respective associations between Trans-Lycopene and β-Cryptoxanthin intake and stomach cancer were examined using unconditional logistic regression analysis with adjustments for possible cofactors. Results: Both Trans-Lycopene and β-Cryptoxanthin intake and stomach cancer showed a significantly inverse association, tertile-3 versus tertile-1, (OR = 0.15, 95%CI: 0.06–0.35, p trend = 0.00) and (OR = 0.34, 95%CI: 0.14–0.79, p trend = 0.02, respectively). For Trans-Lycopene intake stratifying by H. pylori status remained the benefit effect against stomach cancer among H. pylori-negative participants (OR = 0.15, 95%CI: 0.03–0.69, p trend = 0.02) and H. pylori-positive participants (OR = 0.13, 95%CI: 0.04–0.42, p trend = 0.00). Conclusions: Both Trans-Lycopene and β-Cryptoxanthin intake showed a strong protective effect against stomach cancer. The findings suggest that these two types of fat-soluble micronutrients would be considered as an anti-cancer therapy for both primary and secondary prevention.     

Dietary β-carotene,cigarette smoking,and lung cancer in men

A cohort of 5,080 men living in a retirement community in California (United States) and initially free from lung cancer were followed from June 1981 to December 1989. At recruitment, each study participant completed a mailed questionnaire which requested information on the subject's medical history, use of cigarettes, and usual consumption frequencies during the preceding 12 months of 44 vegetable and fruit items. Men who had never smoked had the highest mean daily intake of -carotene (8,505 g), followed by past smokers (7,761 g) and then by current smokers (6,178 g). -Carotene intake of the subject's wife was correlated significantly with that of the husband in the 4,018 spouse pairs (r=0.46; P=0.0001). Among men with similar smoking habits, dietary -carotene intake significantly decreased with the spouse's smoking habit: never, past, and current smokers (P=0.004; test for linear trend). During 31,477 person-years of follow-up, 125 incident cases of lung cancer were observed among the cohort of 5,080 men. Age-adjusted relative risks for lung cancer were below unity (i.e., demonstrating a reduced risk) for higher relative to lower consumption of -carotene, of all vegetables and fruits, and of yellow vegetables alone. However, these relative risks approached or crossed the null value when adjusted for personal smoking.This study was supported by US Public Health Service grants CA-17054 and CA-32197 from the National Cancer Institute.     

Key signaling nodes in mammary gland development and cancer: β-catenin

β-Catenin plays important roles in mammary development and tumorigenesis through its functions in cell adhesion, signal transduction and regulation of cell-context-specific gene expression. Studies in mice have highlighted the critical role of β-catenin signaling for stem cell biology at multiple stages of mammary development. Deregulated β-catenin signaling disturbs stem and progenitor cell dynamics and induces mammary tumors in mice. Recent data showing deregulated β-catenin signaling in metaplastic and basal-type tumors suggest a similar link to reactivated developmental pathways and human breast cancer. The present review will discuss β-catenin as a central transducer of numerous signaling pathways and its role in mammary development and breast cancer.