人宫颈癌基因在消化系肿瘤中的表达及其临床意义

人宫颈癌基因（HCCR）是在宫颈癌中发现的一个新的癌基因，可能通过负向调节p53而促进肿瘤发生。目的：检测HCCR在人胃癌、结肠癌、肝癌中的表达，探讨其与肿瘤临床病理特征的关系。方法：以免疫共沉淀法检测HCCR在消化系肿瘤患者外周血中的表达，以细胞免疫荧光和免疫细胞化学染色检测HCCR在消化系肿瘤细胞株中的定位和表达．以免疫组化方法检测HCCR在肿瘤组织中的表达，并分析其与肿瘤临床病理特征的关系。结果：HCCR在消化系肿瘤患者外周血中有表达，肿瘤细胞株中其表达定位于细胞膜和细胞质。HCCR在人胃癌、结肠癌、肝癌组织中的阳性表达率显著高于相应正常或癌旁组织（P〈0．05）。HCCR的阳性表达率与胃癌部位和肝癌组织学分级显著相关（P〈0．05），与其他肿瘤临床病理特征均不相关。结论：HCCR在人消化系肿瘤细胞和组织中表达较强，可能与肿瘤的发生、发展有关，有望成为消化系肿瘤诊断的标记物。     

Somatic alterations in mitochondrial DNA and mitochondrial dysfunction in gastric cancer progression

Energy metabolism reprogramming was recently identified as one of the cancer hallmarks.One of the underlying mechanisms of energy metabolism reprogramming is mitochondrial dysfunction caused by mutations in nuclear genes or mitochondrial DNA(mtDNA).In the past decades,several types of somatic mtDNA alterations have been identified in gastric cancer.However,the role of these mtDNA alterations in gastric cancer progression remains unclear.In this review,we summarize recently identified somatic mtDNA alterations in gastric cancers as well as the relationship between these alterations and the clinicopathological features of gastric cancer.The causative factors and potential roles of the somatic mtDNA alterations in cancer progression are also discussed.We suggest that point mutations and mtDNA copy number decreases are the two most common mtDNA alterations that result in mitochondrial dysfunction in gastric cancers.The two primary mutation types(transition mutations and mononucleotide or dinucleotide repeat instability)imply potential causative factors.Mitochondrial dysfunction-generated reactive oxygen species may be involved in the malignant changes of gastric cancer.The search for strategies to prevent mtDNA alterations and inhibit the mitochondrial retrograde signaling will benefit the development of novel treatments for gastric cancer and other malignancies.     

Low-dose aspirin affects the clinicopathological features of gastric cancer

BACKGROUND/AIMS: There have been investigations on the chemopreventive effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in gastric cancer and also on the association between cyclo-oxygenase 2 expression and the clinicopathological features of gastric cancer. However, it is not yet clear whether the cardioprotective properties of low-dose aspirin could affect the biological behavior of gastric cancer. This study was aimed at investigating the association between the use of low-dose aspirin and clinicopathological features of gastric cancer in human. METHOD: A case-control study was performed retrospectively by comparing the clinicopathological parameters between two groups of gastric cancers, 47 (30.5%) low-dose aspirin users and 107 (69.5%) non-aspirin users who were diagnosed and underwent operation for gastric cancers. RESULTS: The gastric cancers of aspirin user group showed favorable clinicopathological features, such as earlier tumor stage (overall stage, T and N stage: p < 0.001, <0.001, and 0.002, respectively), smaller size (p = 0.03), and intestinal type rather than diffuse type (p = 0.004). But these differences were significant only in non-cardiac cancer while cardiac cancer patients showed no significant association with low-dose aspirin usage (overall stage, T stage, N stage, tumor size, and histological type: p <0.001, <0.001, 0.003, 0.035, and 0.004, respectively, by Cochran-Mantel-Haenszel statistics). CONCLUSION: The use of low-dose aspirin might affect the clinicopathological features in gastric cancers, and possibly have a favorable protective effect on the progression of gastric cancer in a subset of non-cardiac gastric cancer patients.     

Mitochondrial DNA alterations and mitochondrial dysfunction in the progression of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is one of the most common malignancies and is ranked third in mortality among cancer-related diseases.Mitochondria are intracellular organelles that are responsible for energy metabolism and cellular homeostasis,and mitochondrial dysfunction has been regarded as a hallmark of cancer.Over the past decades,several types of mitochondrial DNA(mtDNA)alterations have been identified in human cancers,including HCC.However,the role of these mtDNA alterations in cancer progression is unclear.In this review,we summarize the recent findings on the somatic mtDNA alterations identified in HCC and their relationships with the clinicopathological features of HCC.Recent advances in understanding the potential roles of somatic mtDNA alterations in the progression of HCC are also discussed.We suggest that somatic mtDNA mutations and a decrease in the mtDNA copy number are common events in HCC and that a mitochondrial dysfunction-activated signaling cascade may play an important role in the progression of HCC.Elucidation of the retrograde signaling pathways in HCC and the quest for strategies to block some of these pathways will be instrumental for the development of novel treatments for this and other malignancies.     

The relationship between tissue factor and cancer progression: insights from bench and bedside

It is now widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers, including pancreatic, colorectal, and gastric cancer, often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Reciprocally, components from the coagulation cascade also influence cancer progression. The primary initiator of coagulation, the transmembrane receptor tissue factor (TF), has gained considerable attention as a determinant of tumor progression. On complex formation with its ligand, coagulation factor VIIa, TF influences protease-activated receptor-dependent tumor cell behavior, and regulates integrin function, which facilitate tumor angiogenesis both in vitro and in mouse models. Furthermore, evidence exists that an alternatively spliced isoform of TF also affects tumor growth and tumor angiogenesis. In patient material, TF expression and TF cytoplasmic domain phosphorylation correlate with disease outcome in many, but not in all, cancer subtypes, suggesting that TF-dependent signal transduction events are a potential target for therapeutic intervention in selected types of cancer. In this review, we summarize our current understanding of the role of TF in tumor growth and metastasis, and speculate on anticancer therapy by targeting TF.     

Lymph node metastasis as a significant prognostic factor in gastric cancer: a multiple logistic regression analysis

BACKGROUND: In Japan, the standard treatment policy for all potentially curable patients with gastric cancer is radical resection including extensive lymphadenectomy. This treatment strategy has been used for both early and advanced gastric cancers, and substantial increases in survival time have been reported. In advanced gastric cancer, lymphatic spread is reported to be one of the most relevant prognostic factors for gastric cancer resected for cure. The purpose of this study was to determine the factors affecting lymph node involvement and to establish guidelines for the extent of lymph node dissection most appropriate for the treatment of gastric cancer. METHODS: The clinicopathological features of 926 patients with gastric cancer were reviewed. Information on the clinicopathological features was obtained from the database of gastric cancer at the Department of Gastroenterological Surgery, Sendai National Hospital. Univariate and multivariate analyses of data for patients with gastric cancer tumors were performed to evaluate the prognostic significance of clinicopathological features. The independent risk factors influencing lymph node metastasis were determined by multiple logistic regression analysis. RESULTS: The following clinicopathologic factors were found to be correlated with prognosis of gastric cancer: (1) macroscopic type, (2) depth of invasion, (3) cancer-stromal relationship, (4) histological growth pattern, (5) lymph node involvement, (6) lymphatic invasion, (7) vascular invasion and (8) tumor site. However, a multivariate analysis revealed that macroscopic type, depth of invasion, lymph node involvement and tumor site are independent risk factors for the prognosis of gastric cancer patients. Among these factors, the prognosis of patients with gastric cancer was most strongly influenced by lymph node involvement (odds ratio, 4.632). According to a multiple logistic regression model, depth of cancer invasion and lymphatic invasion was significantly correlated with lymph node metastases. CONCLUSIONS: Lymph node involvement has the strongest influence on the prognosis of gastric cancer. Among the clinicopathological factors, depth of invasion and microscopically lymphatic invasion are important factors in predicting lymph node metastases. Thus, the ability to perform gastrectomy with dissection of lymph nodes is a basic requirement for gastric cancer surgeons.     

Somatic mutations of mitochondrial DNA in digestive tract cancers

BACKGROUND: Somatic mutations of mitochondrial DNA (mtDNA) have been reported to play an important role in the carcinogenesis of several human cancers. However, there are few reports on mtDNA mutations in digestive tract cancers, including esophageal, gastric and colorectal cancers. The present study examined somatic mtDNA mutations in these cancers. METHODS: Samples of 82 esophageal cancers, 96 gastric cancers and 138 colorectal cancers were collected. Mutations in the D310 mononucleotide repeat of mtDNA were examined by microsatellite assay. RESULTS: Frequencies of mtDNA mutations were similar in each digestive tract cancer: 14% (7/51) in esophageal cancers, 15% (14/94) in gastric cancers and 8% (11/133) in colorectal cancers. There were no significant relationships between mtDNA mutations and clinicopathological features, such as patient age or sex, tumor location, depth of tumor invasion and lymph node metastasis in each digestive tract cancer. CONCLUSIONS: The results suggest that mtDNA mutations play a role in the development but not progression in each digestive tract cancer, and that the role of mtDNA mutations might be similar among the digestive tract cancers.     

Rho/ROCK signaling in motility and metastasis of gastric cancer

Gastric cancer is one of the most frequent and lethal malignancies worldwide because of high frequency of metastasis. Tumor cell motility and invasion play fundamental roles in cancer metastasis. Recent studies have revealed that the Rho/Rho-associated protein kinases (ROCK) pathway plays a critical role in the regulation of cancer cell motility and invasion. In addition, the Rho/ROCK pathway plays important roles in invasion and metastasis on the basis of its predominant function of cell cytoskeletal regulation in gastric cancer. According to the current understanding of tumor motility, there are two modes of tumor cell movement: mesenchymal and amoeboid. In addition, cancer cell movement can be interchangeable between the mesenchymal and amoeboid movements under certain conditions. Control of cell motility through the actin cytoskeleton creates the potential for regulating tumor cell metastasis. In this review we discuss Rho GTPases and ROCK signaling and describe the mechanisms of Rho/ROCK activity with regard to motility and metastasis in gastric cancer. In addition, we provide an insight of the therapeutic potential of targeting the Rho/ROCK pathway.     

Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer

Despite a decrease in gastric cancer incidence, the development of novel biologic agents and combined therapeutic strategies, the prognosis of gastric cancer remains poor. Recently, the introduction of modern immunotherapy, especially using immune checkpoint inhibitors, led to an improved prognosis in many cancers. The use of immunotherapy was also associated with manageable adverse event profiles and promising results in the treatment of patients with gastric cancer, especially in heavily pretreated patients. These data have led to an accelerated approval of some checkpoint inhibitors in this setting. Understanding the complex relationship between the host immune microenvironment and tumor and the immune escape phenomenon leading to cancer occurrence and progression will subsequently lead to the identification of prognostic immune markers. Furthermore, this understanding will result in the discovery of both new mechanisms for blocking tumor immunosuppressive signals and pathways to stimulate the local immune response by targeting and modulating different subsets of immune cells. Due to the molecular heterogeneity of gastric cancers associated with differentclinico-biologic parameters, immune markers expression and prognosis, novel immunotherapy algorithms should be personalized and addressed to selected subsets of gastric tumors, which have been proven to elicit the best clinical responses. Future perspectives in the treatment of gastric cancer include tailored dual immunotherapies or a combination of immunotherapy with other targeted agents with synergistic antitumor effects.     

Adenoviral gene therapy in gastric cancer： A review

Gastric cancer is one of the most common malignancies worldwide. With current therapeutic approaches the prognosis of gastric cancer is very poor, as gastric cancer accounts for the second most common cause of death in cancer related deaths. Gastric cancer like almost all other cancers has a molecular genetic basis which relies on disruption in normal cellular regulatory mechanisms regarding cell growth, apoptosis and cell division. Thus novel therapeutic approaches such as gene therapy promise to become the alternative choice of treatment in gastric cancer. In gene therapy, suicide genes, tumor suppressor genes and anti-angiogenesis genes among many others are introduced to cancer cells via vectors. Some of the vectors widely used in gene therapy are Adenoviral vectors. This review provides an update of the new developments in adenoviral cancer gene therapy including strategies for inducing apoptosis, inhibiting metastasis and targeting the cancer cells.     

Estrogen receptors in gastric cancer:Advances and perspectives

Worldwide, gastric cancer is one of the most common malignancies with high mortality. Various aspects of thedevelopment and progression of gastric cancer continue to be extensively investigated in order to further our understanding and provide more effective means for the prevention, diagnosis, and treatment of the disease. Estrogen receptors(ERs) are steroid hormone receptors that regulate cellular activities in many physiological and pathological processes in different tissues. There are two distinct forms of ERs, namely ERα and ERβ, with several alternative-splicing isoforms for each. They show distinct tissue distribution patterns and exert different biological functions. Dysregulation of ERs has been found to be associated closely with many diseases, including cancer. A number of studies have been conducted to investigate the role of ERs in gastric cancer, the possible mechanisms underlying these roles, and the clinical relevance of deregulated ERs in gastric cancer patients. To date, inconsistent associations of different ERs with gastric cancer have been reported. These inconsistencies may be caused by variations in in vitro cell models and clinical samples, including assay conditions and protocols with regard to different forms of ERs. Given the potential of the deregulated ERs as diagnostic/prognostic markers or therapeutic targets for gastric cancer, it will be important to identify/confirm the association of each ER isoform with gastric cancer, to determine the specific roles and interactions that these individual ER isoforms play under specific conditions in the development and/or progression of gastric cancer, and to elucidate precisely these mechanisms. In this review, we summarize the achievements from early ER studies in gastric cancer to the most up-to-date discoveries, with an effort to provide a comprehensive understanding of the role of ERs roles in gastric cancer and its possible mechanisms. Furthermore, we propose directions for future investigations.     

Immune Response and the Tumor Microenvironment: How They Communicate to Regulate Gastric Cancer

Gastric cancer is the second most common cause of cancer-related death in the world. A growing body of evidence indicates that inflammation is closely associated with the initiation, progression, and metastasis of many tumors, including those of gastric cancer. In addition, approximately 60% of the world''s population is colonized by Helicobacter pylori, which accounts for more than 50% of gastric cancers. While the role of inflammation in intestinal and colonic cancers is relatively well defined, its role in stomach neoplasia is still unclear because of the limited access of pathogens to the acidic environment and the technical difficulties isolating and characterizing immune cells in the stomach, especially in animal models. In this review, we will provide recent updates addressing how inflammation is involved in gastric malignancies, and what immune characteristics regulate the pathogenesis of stomach cancer. Also, we will discuss potential therapeutics that target the immune system for the efficient treatment of gastric cancer.     

Hepsin在胃癌中表达下调并提示预后不良

背景:Ⅱ型跨膜丝氨酸蛋白酶hepsin在前列腺癌、卵巢癌、乳腺癌等多种原发肿瘤中呈高表达,并与肿瘤进展和预后不良相关。目的:探讨hepsin在胃癌中的表达模式及其与胃癌临床病理特征和预后的关系。方法:纳入40对原发性胃癌组织和相应正常胃黏膜,以cDNA微阵列技术筛选两者间的差异表达基因,并以real-time PCR进行验证。以免疫组化方法检测其中20例胃癌组织以及另100例胃癌组织石蜡切片中的hepsin蛋白表达,分析其表达与胃癌临床病理特征和预后的关系。结果:cDNA微阵列分析显示胃癌组织中的hepsin基因表达较正常胃黏膜显著下调(ratio=0.240),real-time PCR结果与cDNA微阵列分析一致(P=0.002)。83例(69.2%)胃癌组织hepsin蛋白表达阴性,其余为弱阳性表达。Kaplan-Meier曲线显示hepsin蛋白表达阴性者总体生存率显著低于hepsin蛋白表达弱阳性者(P<0.0001)。单因素分析显示hepsin蛋白表达与胃癌浸润深度(P=0.043)和患者总体生存率(P=0.018)相关,多因素Cox回归分析显示hepsin蛋白表达为胃癌预后的保护因素(RR=0.599,P=0.000)。结论:Hepsin在胃癌组织中表达下调,并与胃癌进展和预后不良相关。     

Gonadotropins and ovarian cancer

Ovarian epithelial cancer (OEC) accounts for 90% of all ovarian cancers and is the leading cause of death from gynecological cancers in North America and Europe. Despite its clinical significance, the factors that regulate the development and progression of ovarian cancer are among the least understood of all major human malignancies. The two gonadotropins, FSH and LH, are key regulators of ovarian cell functions, and the potential role of gonadotropins in the pathogenesis of ovarian cancer is suggested. Ovarian carcinomas have been found to express specific receptors for gonadotropins. The presence of gonadotropins in ovarian tumor fluid suggests the importance of these factors in the transformation and progression of ovarian cancers as well as being prognostic indicators. Functionally, there is evidence showing a direct action of gonadotropins on ovarian tumor cell growth. This review summarizes the key findings and recent advances in our understanding of these peptide hormones in ovarian cancer development and progression and their role in potential future cancer therapy. We will first discuss the supporting evidence and controversies in the "gonadotropin theory" and the use of animal models for exploring the involvement of gonadotropins in the etiology of ovarian cancer. The role of gonadotropins in regulating the proliferation, survival, and metastasis of OEC is next summarized. Relevant data from ovarian surface epithelium, which is widely believed to be the precursor of OEC, are also described. Finally, we will discuss the clinical applications of gonadotropins in ovarian cancer and the recent progress in drug development.     

Contribution of galectin-1, a glycan-binding protein,to gastrointestinal tumor progression

Gastrointestinal cancer is a group of tumors that affect multiple sites of the digestive system, including the stomach, liver, colon and pancreas. These cancers are very aggressive and rapidly metastasize, thus identifying effective targets is crucial for treatment. Galectin-1(Gal-1) belongs to a family of glycan-binding proteins, or lectins, with the ability to cross-link specific glycoconjugates. A variety of biological activities have been attributed to Gal-1 at different steps of tumor progression. Herein, we summarize the current literature regarding the roles of Gal-1 in gastrointestinal malignancies. Accumulating evidence shows that Gal-1 is drastically up-regulated in human gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic ductal adenocarcinoma tissues, both in tumor epithelial and tumor-associated stromal cells. Moreover, Gal-1 makes a crucial contribution to the pathogenesis of gastrointestinal malignancies, favoring tumor development, aggressiveness, metastasis, immunosuppression and angiogenesis. We also highlight that alterations in Gal-1-specific glycoepitopes may be relevant for gastrointestinal cancer progression. Despite the findings obtained so far, further functional studies are still required. Elucidating the precise molecular mechanisms modulated by Gal-1 underlying gastrointestinal tumor progression, might lead to the development of novel Gal-1-based diagnostic methods and/or therapies.     

Clinical presentation, endoscopic features, treatment and prognosis of synchronous upper gastrointestinal malignancies

OBJECTIVE: To study the clinical presentation, endoscopic features and prognosis of patients with synchronous upper gastrointestinal (GI) cancers. METHODS: A prospective database review of consecutive patients with synchronous upper GI malignancies was performed in a tertiary university hospital endoscopy unit. Gender, age, symptoms and cancer sites, endoscopic and pathological findings, as well as the long‐term survival of these patients were analyzed. RESULTS: A total of 64 patients with a median age of 56 years were included, in which 81.3% were male, 71.9% presented with notable features, 68.8% had familial history of cancer, 56.3% of gastric cancers were at the gastric body, 92.9% of the duodenal malignancies at the duodenal bulb, all esophageal cancers at the middle and lower part of esophagus and a significant proportion of tumors in the synchronous malignancies group were poorly differentiated. In all patients, 20 underwent curative surgical treatment and the 5‐year survival rate was only 20%. CONCLUSIONS: Patients with synchronous upper GI cancers are mainly male and present with different anatomic distribution and endoscopic features. They carry a poor prognosis as compared with single primary cancer patients. This case series describes the clinical profiles and emphasizes the necessity of a thorough examination for additional cancers before treatment of upper GI cancer.     

重视胃癌和结直肠癌血清肿瘤标记物的临床价值

癌胚抗原（CEA）对胃癌和结直肠癌诊断的敏感性较低，相对特异性较高，其血清水平的监测有助于判断肿瘤的转移、根治疗效、复发和预后。糖链抗原（CA）72—4对胃癌、CA242和CA19—9对结直肠癌诊断的敏感性和特异性较高．可作为胃癌和（或）结直肠癌进展程度、术后疗效判断和预后评估的参考指标。血清胃癌抗原MG7和胃蛋白酶原对胃癌诊断有较高的敏感性和特异性，且对早期胃癌亦有较高的检出率。重视多种血清肿瘤标记物的联合检测．有利于提高肿瘤的诊断率。     

Role of autophagy in tumorigenesis,metastasis,targeted therapy and drug resistance of hepatocellular carcinoma

Autophagy is a "self-degradative" process and is involved in the maintenance of cellular homeostasis and the control of cellular components by facilitating the clearance or turnover of long-lived or misfolded proteins, protein aggregates, and damaged organelles. Autophagy plays a dual role in cancer, including in tumor progression and tumor promotion, suggesting that autophagy acts as a double-edged sword in cancer cells. Liver cancer is one of the greatest leading causes of cancer death worldwide due to its high recurrence rate and poor prognosis. Especially in China, liver cancer has become one of the most common cancers due to the high infection rate of hepatitis virus. In primary liver cancer, hepatocellular carcinoma (HCC) is the most common type. Considering the perniciousness and complexity of HCC, it is essential to elucidate the function of autophagy in HCC. In this review, we summarize the physiological function of autophagy in cancer, analyze the role of autophagy in tumorigenesis and metastasis, discuss the therapeutic strategies targeting autophagy and the mechanisms of drug-resistance in HCC, and provide potential methods to circumvent resistance and combined anticancer strategies for HCC patients.