1. Introduction
Despite the progressive decrease observed in the past fifty years, gastric cancer (GC) is the fourth of the world rankings incidence of various types of cancer and is the second as a cause of cancer-related death. There is distinct geographical variation in gastric cancer incidence with the highest rates reported from Japan, Korea and Eastern Asia. Other high incidence areas are Eastern Europe and parts of Latin America, while Western Europe, Africa, Australia and the US generally have low incidence rates. In the last decade there has been a downward trend in the incidence and mortality from this cancer. The reasons are to be found in the improvement of food both as regards its preservation procedures and the variability in the diet and for the decrease of infection by Helicobacter
The most important epigenetic alterations are confined within the chromatin structure like chromatin remodeling, DNA methylation and histone modification. These molecular alterations are generally common in gastric cancer, independently from its classification (gastric or intestinal). Also genetic polymorphism represents a possible endogenous cause of cancer risk. However, it must be considered that genetic polymorphisms might influence the efficacy of gastric cancer therapy and the toxicity of anticancer drugs. Although the worldwide decline in incidence and recent diagnostic and therapeutic advances provided excellent survival for patients with early gastric cancer, the prognosis of patients with advances cancer is still poor. Over the past 15 years, integrated research, including genetic polymorphism and global analysis of gene expression has clarified detailed molecular mechanisms and the role of genetic and epigenetic abnormalities of cancer-related genes in the course of development and progression of gastric cancer. This review describes an outline of the molecular pathway of stomach carcinogenesis, as signaling pathways, H.
2. Risk factors and classification
The general decrease of gastric cancer frequency in developed countries is attributed to the changes in dietary habits and food preservation methods [1]. Chronic inflammation with gastric atrophy was shown to be the most important pathological entity with hypochlorhydria being the most important physiological abnormality. Alcohol and smoking are also thought to contribute to the etiology. Achlorhydria, pernicious anaemia and blood group A are also associated with a higher risk of gastric malignancy. However, following the discovery of H.
GC is characterized by two distinct histological type of adenocarcinoma (intestinal type and a diffuse type) each having different epidemiological and pathophysiological features [4]. The intestinal-type generally evolves through a relatively well-defined multistep process that starts from chronic gastritis and progresses to chronic atrophy, intestinal metaplasia and dysplasia [5, 6]. It is associated with H.
3. H. pylori infection
The pathogenesis of gastric cancer remains poorly understood although it is evident that several environmental factors, such as H.
H.
Among the targets of CagA strain there is also RUNX3, a tumor suppressor in many tissues and frequently inactivated in gastric cancer. Recently, it has been shown that H.
4. Molecular pathology
The bacterial, environmental and host genetic factors discussed above influence the development of gastric carcinoma. Genomic, proteomic and biotechnology could allow the identification of novel genes and molecules specifically up-regulated or down-regulated in gastric cancer. Advances in our understanding of the genetic and molecular bases of gastric cancer lead to improved diagnosis, personalized medicine and prevention of gastric cancer.
In the following section, we discuss some of the molecular mechanisms underlying the molecular pathway of stomach carcinogenesis and of the biological and clinical roles of recently identified genes involved in gastric cancer.
4.1 GKN1
Recently, a novel tissue-specific protein, gastrokine1 (GKN1), has been isolated from gastric mucosa cells of several mammalian species, including mouse [23]. The human GKN1 gene has been localized in a 6 kb region of the chromosome 2p13 and contains 6 exons [24]. GKN1 is found within the granules just under the apical plasma membrane, suggesting that it is a secreted rather than a membrane protein. GKN1 has been hypothesized to play an important role in maintaining the integrity of the gastric mucosa and mediating repair after injury. Oien et al. [25] demonstrated, by Northern blotting, that GKN1 mRNA was abundant only in normal human stomach, in all areas (cardia, body and antrum), but absent in gastric adenocarcinomas; gastro-oesophageal adenocarcinoma cell line and other normal and tumor gastro-intestinal tissues. Therefore, there is a transcriptional silencing of GKN1 gene in gastric cancer. Rippa et al. [26] recently demonstrated, by means of proteomic technology, that GKN1 protein is reduced in patients with
Our group has been studying the effect of GKN1 on gastric cancer cell lines (AGS and MKN28). We found by cytofluorimetry, Western blot and RT-PCR that overexpression of GKN1 in these cell lines stimulated the expression of Fas receptor. Moreover, compared to control cells, a significant increase of apoptosis, evaluated by TUNEL, was observed when GKN1 transfected cells were treated with a monoclonal antibody (IgM) anti-Fas. The activation of Fas expression was also observed by the overexpression of GKN1 in other cancer cell lines. GKN1-overexpressing gastric cancer cells exposed to FasL induced the activation of caspase-3 was as evaluated by Western blot and fluorescence assays [33]. In addition, MTT assay showed that recombinant GKN1 reduced cell proliferation of gastric cancer cells (AGS) compared to human embryonic kidney cell line (HEK 293) and non-gastric cancer cells, human lung epidermoid carcinoma cell line (H1355). Our data represent the first report for GKN1 as modulator of apoptotic signals and suggest that GKN1 might play an important role for tissue repair during the early stages of neoplastic transformation. In fact, it was seen that individuals with a lower expression of the protein have an increased risk to develop gastric diseases [34].
Finally, regarding the mechanism by which
4.2 E–cadherin and the Wnt system
The signal transduction pathway called Wnt is a central mechanism for regulating gene expression and is highly conserved in vertebrates and invertebrates. It includes a large family of ligands and plays a key role in many cellular processes, which ranging from regulation of embryogenesis control processes the proliferation of mature cells. In particular, it seems crucially involved in the processes of differentiation and proliferation of stem cell elements [36]. Central to these mechanisms is the process of regulation of expression of the β-catenin, an intracellular protein able to communicate on the surface of the cell with the system of cadherine, but also to act as nuclear transcription factor, including the Wnt/Wingless, epidermal growth factor (EGF), hepatocyte growth factor (HGF), and insulin-like growth factor (IGF) signaling pathways [37-40].
The Wnt signalling pathway can be activated trough the binding of Wnt ligands to their receptors Frizzled (Fz) and low-density lipoprotein receptor-related protein LRP5 and LRP6 (Figure 2). The binding induces an activation signal direct protein Dishevelled (DSH) and axin, that once activated, inhibit GSK3 kinase. Normally GSK3 phosphorylates β-catenin as part of a multiprotein complex that includes GSK3, APC and axin. The phosphorylation triggers the degradation of β-catenin through the process of ubiquitination (Figure 2, left panel). It follows that the inhibition Wnt-induced GSK3 interferes with the process of degradation of β-catenin and causes its cytoplasmic accumulation in a non-complexed form [41]. As consequence, β-catenin goes into the nucleus and regulates target gene transcription through association with the transcription factor TCF/ LEF (lymphoid enhancer binding factor) (Figure 2, right panel).
The translocation into the nucleus of β-catenin eventually leads to transcription of several genes including protagonists of carcinogenesis known protooncogenes such as c-myc and cyclin D1. In this regard, it is interesting that GSK3 can be inhibited through the PI3K/AKT pathway after toxin VacA stimulation [42]. This is a further element to support the correlation between infection by H.
4.3 RUNX3
Another potential candidate in the molecular carcinogenesis process of stomach cancers is represented by RUNX3, one of the first identified members of the RUNX family (mammalian Runt related genes) [56]. The RUNX gene family is composed of three members, RUNX1/AML1, RUNX2 and RUNX3 [57]. These are genes coding for a group of closely related proteins with DNA binding function. In humans, loss of RUNX3 by hypermethylation of the promoter CpG islands is observed in several different cancers, including 64% of gastric carcinomas [58]. This loss reaches 90% in patients with gastric cancer in advanced stage. Gastric epithelium of RUNX3 knockout mice exhibits hyperplasia, reduced rate of apoptosis and reduced sensitivity to TGFβ1, thus suggesting that the tumour suppressor activity of RUNX3 operates downstream of the TGFβ signaling pathways. RUNX3 methylation is also a feature of 8% of chronic gastritis, 28% of intestinal metaplasia and 27% of gastric adenomas. These observations suggest RUNX3 is a target for epigenetic gene silencing in gastric carcinogenesis [59, 60]. Another element of great interest that correlates RUNX3 to H.
4.4 Genomic instability
In gastric cancer the loss of genomic stability represents a key molecular step that occurs early in the carcinogenesis process and creates a permissive environment for the accumulation of genetic and epigenetic alterations in tumor suppressor genes and oncogenes. It iswidely accepted that gastric cancer can follow at least two major genomic instability pathways, chromosome instability (CIN) and microsatellite instability (MSI). CIN is defined as the loss of chromosomal material during dysfunctional chromosome replication, repair or segregation [63]. MSI, which results from an erroneous DNA mismatch repair system, has been well known to be involved in the carcinogenesis of hereditary nonpolyposis colon cancers and some of sporadic colorectal cancers [64, 65]. A variable fraction from 15% to 50% of sporadic gastric cancer ischaracterized by MSI as a result of genetic inactivation or mainly Mismatch Repair (MMR) genes epigenetics, including hMLH1 and hMSH2. The inactivation of MMR genes is not itself a transforming event and additional genetic changes are required for progression to malignancy. In particular, in gastric cancer MSI is observed with the presence of mutations in repetitive sequences of genes involved in the regulation of cell growth (TGF-βRII, IGF-IIR), in apoptosis (BAX) and DNA repair (hMSH6, hMSH3). These mutations can alter the gene expression and give an advantage in cell growth and in clonal expansion. GC with MSI represents a tumor subset with clinico-pathological specific features. In particular, MSI GC is an intestinal gastric cancer, with antral location, low prevalence of vascular invasion or lymph node infiltration and better prognosis.
5. The molecular aspect of gastric cancer as rational for new therapeutic targeted strategies
In recent years it has strengthened the tendency to identify therapeutic strategies different from classical chemotherapeutic approach. The reviewed signaling pathways are relevant contributors for gastric carcinogenesis and encompass a multitude of potential therapeutic targets. In particular, there are growing efforts designed to identify the molecular mechanisms whose inhibition can significantly reduce the clinical aggressiveness of tumor malignacy. This innovative approach has achieved major successes in rare neoplastic diseases such as chronic myeloid leukemia and gastrointestinal stromal tumors (GIST) where it was possible to effectively inhibit constitutionally activated receptor tyrosine kinase such as the KIT gene [66, 67]. Except for the inhibition of HER2 in breast carcinoma, the same success has not yet been achieved in other tumors hence the need to further investigate on the existence of new potential molecular targets. Under this aspect, GC is not an exception indeed it represents a disease for the possible application of targeted therapies.
5.1 HER 2
HER2 (Human Epidermal Growth Factor Receptor 2) also known as Neu, ErbB-2, CD340 (cluster of differentiation 340) or p185 is part of a large family of receptors of tyrosine kinase activities. Along with HER1, also known as EGFR, up-regulation of HER2 is an important event in molecular carcinogenesis of many cancers. Ligand binding to EGFR extracellular domain leads to its activation, with subsequent homodimerization leading to the phosphorylation of its intracellular tyrosine kinase domain. This will initiate a series of intracellular signals, including activation of the central Ras/Raf/mitogen activated protein kinases (MAPK) signaling pathway (Figure 3). Up to now, the best model known is constituted by breast carcinoma in which HER2 is amplified in about 20% of cases [68]. This amplification is correlated to an increase of the expression of the protein and thus in growth advantage [69]. The prognostic negative role played by the amplification of HER2 in breast cancer is balanced by the possibility to interfere with that oncogenetic mechanism through the use of molecular therapies targeted with humanized monoclonal antibodies (i.e. Trastuzumab) [70]. On the basis of the results obtained in the treatment of breast cancer and counting on the fact that gastric carcinomas show amplification of HER2 in approximately 20% of cases, clinical trials have been designed that demonstrated significant improvement in progression-free survival disease for patients with HER2 overexpression, treated with trastuzumab, particularly when associated to conventional chemotherapy [71-73]. It is interesting to note how the aberrations of HER2 are practically exclusive of gastric (and cardial) adenocarcinomas of intestinal type, while they are decidedly not represented in the forms of the diffuse type. As in the case of E-cadherin alterations, there is a correlation between morphological and molecular mechanism in the diffuse forms. The EGFR/MAPK pathway has also shown to be activated in gastric carcinomas with microsatellite instability [74].
5.2 VEGF
The mechanisms of angiogenesis have recently received a lot of interest in oncology and the inhibition of tumor angiogenesis has become a therapeutic option even feasible in gastric cancer [75]. The vascular endothelial growth factor (VEGF) is a dimeric heparin-binding glycoprotein and it is characterized by the ability to exert a powerful mitogenic action on endothelial cells, promoting their growth both in the primary tumor and in metastases, in the latter case after having stimulated the migration from home neoplastic primitive and secondary levels. A very recent study has shown a direct relationship between VEGF concentrations and new blood vessel development; gastric mucosal neovascularization was also reported to be significantly higher in the antrum of patients with H.
5.3 mTOR
The mammalian target of rapamycin (mTOR) pathway has become a major focus of preclinical and clinical cancer research [80]. mTOR is a central regulatory kinase that increases the production of proteins involved in key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis [81-83]. mTOR increases translation of proteins that drive cell growth and cell division, such as cyclin D1, and decreases translation of negative regulators of cell cycle progression [84]. It plays a role in cellular metabolism too by stimulating the surface expression of nutrient transporters [85]. mTOR consists in a double molecular complex (mTORC1 and mTORC2). mTORC1 is regulated by two components of the complex tuberous sclerosis (TSC1 and TSC2), which are controlled by the PI3K/AKT. mTORC2 instead regulates AKT cascade. Recently, because of their function in cell proliferation, these molecular complexes were considered ideal target for the design of drugs in oncology [86].
The efficiency of this approach has obtained a first success in a group of rare tumors known as PEComi [87]. However, significant results seem to be possible in the context of solid tumors. In fact, recent data show that the activation of mTOR in gastric cancer represents a key event observed in approximately 50% of cases [88]. Hence, the first attempts to use mTOR inhibitors to improve the efficiency of systemic therapies [89, 90].
6. Conclusions
In this review, we have summarized reports on genes, proteins and factors involved in gastric carcinogenesis based on currently available literature. Gastric carcinoma results from a complex interaction between bacterial, environmental, host-genetic and molecular mechanisms. It is evident that gastric cancer is the consequence of a multistep process involving different genetic and epigenetic changes in numerous genes. Host genetic background and environmental factors also play an important role in the pathogenesis of the disease. The majority of genetic alterations contributing to the malignant transformation were observed in growth regulatory genes, and in genes involved in cell cycle progression and arrest. In recent years, the analysis of molecular carcinogenesis gastric epithelial neoplasm has certainly provided information of great importance. It is understood that the molecular mechanisms involved in carcinogenesis of intestinal type are different from those prevailing in the development of diffuse one. The element of greater importance from a clinical point lies in the fact that the elucidation of these mechanisms is the prerequisite for exploring innovative therapeutic approaches. While the conventional forms of treatment seem to have reached the limit of effectiveness, it is possible that use of targeted therapies based on solid preclinical rational can translate into tangible clinical benefit. The reviewed signaling pathways are relevant contributors for gastric carcinogenesis and encompass a multitude of potential therapeutic targets. In addition to these signaling-related targets we included new data on
GKN1 as being involved in gastric cancer susceptibility phenotype.
Acknowledgments
This work was supported by funds from PON Ricerca e Competitivita` 2007–2013 (PON01_02782).
References
- 1.
Epidemiology of gastric cancer. World J GastroenterolCrew K. D Neugut A. I 2006 12 3 354 362 - 2.
HelicobacterHoughton J Wang T. C pylori and gastric cancer: a new paradigm fo inflammation-associated epithelial cancers. Gastroenterology.2005 128 6 1567 1578 - 3.
Recent advances in molecular pathobiology of gastric carcinoma. In: The diversity of gastric carcinoma. Springer-VerlagYasui W Oue N Kitadai Y Nakayama H 2005 2005 51 71 - 4.
The Two Histological Main Types of Gastric Carcinoma: Diffuse and So-Called Intestinal-Type Carcinoma. An Attempt at a Histo-Clinical Classification. Acta Pathologica et Microbiologica ScandinavicaLauren P 1965 64 31 49 - 5.
HelicobacterCorrea P pylori and gastric carcinogenesis. Am J Surg Pathol1995 S37 S43. - 6.
Human gastric carcinogenesis: a multistep and multifactorial process-First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer ResearchCorrea P 1992 52 6735 6740 - 7.
A review of the genomics of gastric cancer. Clin Gastroenterol HepatolHamilton J. P Meltzer S. J 2006 4 4 416 425 - 8.
Genomic and epigenetic profiles of gastric cancer: potential diagnostic and therapeutic applications. Surg TodayYamashita K andSakuramoto S Watanabe M 2011 41 1 24 38 - 9.
Cytogenetic and molecular aspects of gastric cancer: clinical implications. Cancer Lett,Panani A. D 2008 266 2 99 115 - 10.
Oncogenic Signaling in Gastric Cancer. Rijeka: In Tech;Costa N. R Sousa A Teixeira C Castro J Guimaraes N Santos-silva F 2011 - 11.
Genetic Instability in Gastric Cancer. Rijeka: In Tech;Hudler P Vogelsang M Komel R 2011 - 12.
HelicobacterGoldstone A. R Quirke P Dixon M. F pylori infection and gastric cancer.Journal of Pathology1996 179 129 137 - 13.
Epidemiology of HelicobacterNabewera H. M Logan R. P pylori infection: transmission, translocation and extragastric reservoirs. J Physiol Pharmacol1999 50 711 722 - 14.
Association between infection with HelicobacterForman D Newell D. G Fullerton F pylori and risk of gastric cancer: evidence from prospective investigation. BMJ1991 302 1302 1305 - 15.
Risk for gastric cancer in people with CagA positive or CagA negative HelicobacterParsonnet J Friedman G. D Oremtreich N Vogelman H pylori infection. Gut1997 40 297 301 - 16.
HelicobacterWatanabe T Tada M Nagai H pylori infection induces gastric cancer in Mongolian gerbils. Gastroenterology1998 115 642 648 - 17.
HelicobacterUemura N Okamoto S Yamamoto S Matsumura N Yamaguchi S Yamakido M Taniyama K Sasaki N Schlemper R. J pylori infection and the development of gastric cancer. New England Journal of Medicine2001 345 784 789 - 18.
Effect of eradication of HelicobacterFukase K Kato M Kikuchi S Inoue K Uemura N Okamoto S Terao S Amagai K Hayashi S Asaka M pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet2008 372 9636 392 397 - 19.
HelicobacterBlaser M. J Berg D. E pylori genetic diversity and risk of human disease. Journal of Clinical Investigation2001 107 767 773 - 20.
Implication of NF-kappaB in HelicobacterIsomoto H Mizuta Y Miyazaki M Takeshima F Omagari K Murase K Nishiyama T Inoue K Murata I Kohno S pylori -associated gastritis. American Journal of Gastroenterology2000 95 2768 2776 - 21.
Nuclear factor-kappaB p65 (RelA) transcription factor is constitutively activated in human gastric carcinoma tissue. Clinical Cancer ResearchSasaki N Morisaki T Hashizume K Yao T Tsuneyoshi M Noshiro H Nakamura K Yamanaka T Uchiyama A Tanaka M Katano M 2001 - 22.
Peek jr RM, Ito Y and Che LF. HelicobacterTsang Y. H Lamb A Romero-gallo J Huang B Ito K pylori CagA targets gastric tumor suppressor RUNX3 for proteasomemediated degradation. Oncogene2010 29 41 5643 5650 - 23.
A novel mitogenic protein that is highly expressed in cells of the gastric antrum mucosa. AJP Gastrointesinal and Liver PhysiologyMartin T. E Powell C. T Wang Z Bhattacharyya S Walsh-reitz M. M Agarwal K Toback F. G 2003 G332 G343. - 24.
Isolation of two novel genes, downregulated in gastric cancer. Japanese Journal of Cancer ResearchYoshikawa Y Mukai H Hino F Asada K Kato I 2000 91 459 463 - 25.
Gastrokine 1 is abundantly and specifically expressed in superficial gastric epithelium, down-regulated in gastric carcinoma, and shows high evolutionary conservation. Journal of PathologyOien K. A Mcgregor F Butler S Ferrier R. K Downie I Bryce S Burns S Keith W. N 2004 203 789 797 - 26.
La Monica G, Fiengo A, Siciliano RA, Cacace G, Malori A, Nardone G, Arcari P. Changes of protein expression in HelicobacterRippa E Martin G Rocco A pylori -infected human gastric mucosa. Current Topics in Peptide & Protein Research2007 8 35 43 - 27.
Gastrokine 1 expression in patients with and without HelicobacterNardone G Rippa E Martin G Rocco A Siciliano R. A Fiengo A Cacace G Malorni A Budillon G Arcari P pylori infection. Digestive and Liver Disease2007 39 122 129 - 28.
La Monica G, Caruso F, Arcari P. Molecular expression of gastrokine 1 in normal mucosa and in HelicobacterNardone G Martin G Rocco A Rippa E pylori related preneoplastic and neoplastic gastric lesions. Cancer Biology and Therapy2008 7 1890 1895 - 29.
Human stomachspecific gene, CA11, is down-regulated in gastric cancer. Internal Journal of OncologyShiozaki K Nakamori S Tsujie M Okami J Yamamoto H Nagano H Dono K Umeshita K Sakon M Furukawa H Hiratsuka M Kasugai T Ishiguro S Monden M 2001 19 701 707 - 30.
Down-regulated full-length novel gene GDDR and its effect on gastric cancer. Zhonghua Yi Xue Za ZhiDu J. J Dou K. F Peng S. Y Wang W. Z Wang Z. H Xiao H. S Guan W. X Liu Y. B Gao Z. Q 2003 10 1166 1168 - 31.
Gastrokine 1 functions as a tumor suppressor by inhibition of epithelial-mesenchymal transition in gastric cancers. Journal of Cancer Research and Clinical OncologyYoon J. H Kang Y. H Choi Y. J Park I. S Nam S. W Lee J. Y Lee Y. S Park W. S 2011 137 1697 1704 - 32.
Gastrokine 1 induces senescence throughXing R Li W Cui J Zhang J Kang B Wang Y Wang Z Liu S Lu Y 16 Rb pathway activation in gastric cancer cells. Gut2011 - 33.
La Monica G, Allocca R, Romano MF, De Palma M, Arcari P. Overexpression of gastrokine 1 in gastric cancer cells induces fas-mediated apoptosis. Journal of Cellular PhysiologyRippa E 2011 226 2571 2578 - 34.
Decreased expression of gastrokine 1 and the trefoil factor interacting protein TFIZ1/GKN2 in gastric cancer: influence of tumor histology and relationship to prognosis. Clinical Cancer ResearchMoss S. F Lee J. W Sabo E Rubin A. K Rommel J Westley B. R May F. E Gao J Meitner P. A Tavares R Resnick M. B 2008 14 13 4161 4167 - 35.
Inactivation of the Gastrokine 1 gene in gastric adenomas and carcinomas. Journal of PathologyYoon J. H Song J. H Zhang C Jin M Kang Y. H Nam S. W Lee J. Y Park W. S 2011 223 618 625 - 36.
WNT signaling pathway and stem cell signaling network. Clinical Cancer ResearhKatoh M Katoh M 2007 13 4042 4045 - 37.
From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends in GeneticsKemler R 1993 9 317 321 - 38.
Blivet-Van Eggelpoel MJ, et al. Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. OncogeneDesbois-mouthon C Cadoret A 2001 20 2 252 259 - 39.
The promise and perils of Wnt signaling through beta-catenin. ScienceMoon R. T Bowerman B Boutros M Perrimon N 2002 296 5573 1644 1646 - 40.
Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell.Lu Z Ghosh S Wang Z Hunter T 2003 4 6 499 515 - 41.
He X.Wnt/beta-catenin signaling: new (and old) players and new insights. Current Opinion in Cell BiologyHuang H 2008 20 119 125 - 42.
Hatakeyama Azuma T, Yamaoka Y, Yahiro K, Moss J, Hirayama T. HelicobacterNakayama M Hisatsune J Yamasaki E Isomoto H Kurazono H pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. Journal of Biological Chemistry2009 284 1612 1619 - 43.
Hofle r H. E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer ResearchBecker K. F Atkinson M. J Reich U Becker I Nekarda H Siewert J. R 1994 54 3845 3852 - 44.
Pignatelli M. E-cadherin-catenin cell-cell adhesion complex and human cancer. British Journal of SurgeryWijnhoven B. P Dinjens W. N 2000 87 992 1005 - 45.
The molecular histology of neoplasia: the role of the cadherin/catenin complex. HistopathologySmith M. E Pignatelli M 1997 31 107 111 - 46.
Catenins and their associated proteins in colorectal cancer. Histology and HistopathologyTucker E. L Pignatelli M 2000 15 251 260 - 47.
Dysfunction of E-cadherin due to mutation of beta-catenin in a scirrhous gastric cancer cell line. Nihon Rinsho.Kawanishi J Kato J Sasaki K Fujii S Watanabe N Niitsu Y 1995 53 7 1590 1594 - 48.
Dominant negative inhibition of the association between beta-catenin and c-erbB-2 by N-terminally deleted beta-catenin suppresses the invasion and metastasis of cancer cells. OncogeneShibata T Ochiai A Kanai Y Akimoto S Gotoh M Yasui N Machinami R Hirohashi S 1996 13 5 883 889 - 49.
Beta- and gamma-catenin mutations, but not E-cadherin inactivation, underlie T-cell factor/lymphoid enhancer factor transcriptional deregulation in gastric and pancreatic cancer. Cell Growth Differentation JournalCaca K Kolligs F. T Ji X Hayes M Qian J Yahanda A Rimm D. L Costa J Fearon E. R 1999 10 6 369 376 - 50.
Germline CDH1 deletions in hereditary diffuse gastric cancer families. Human Molecular GeneticsOliveira C Senz J Kaurah P Pinheiro H Sanges R Haegert A Corso G Schouten J Fitzgerald R Vogelsang H Keller G Dwerryhouse S Grimmer D Chin S. F Yang H. K Jackson C. E Seruca R Roviello F Stupka E Caldas C Huntsman D 2009 18 1545 1555 - 51.
Frequent loss of membranous E-cadherin in gastric cancers: A cross-talk with Wnt in determining the fate of beta-catenin. Clinical and Experimental MetastasisCheng X. X Wang Z. C Chen X. Y Sun Y Kong Q. Y Liu J Gao X Guan H. W Li H 2005 22 85 93 - 52.
Guilford P. E-cadherin deficiency initiates gastric signet-ring cell carcinoma in mice and man. Cancer ResearchHumar B Blair V Charlton A More H Martin I 2009 69 2050 2056 - 53.
Increased beta-catenin mRNA levels and mutational alterations of the APC and beta-catenin gene are present in intestinal-type gastric cancer. CarcinogenesisEbert M. P Fei G Kahmann S Müller O Yu J Sung J. J Malfertheiner P 2002 23 87 91 - 54.
Mutation analysis of APC gene in gastric cancer with microsatellite instability. World Journal of GastroenterolologyFang D. C Luo Y. H Yang S. M Li X. A Ling X. L Fang L 2002 8 787 791 - 55.
The risk of upper gastrointestinal cancer in familial adenomatous polyposis. GastroenterologyOfferhaus G. J Giardiello F. M Krush A. J Booker S. V Tersmette A. C Kelley N. C Hamilton S. R 1992 102 1980 1982 - 56.
Upstream and downstream targets of RUNX proteins. Journal of Cellular BiochemistryOtto F Lübbert M Stock M 2003 89 9 18 - 57.
Oncogenic potential of the RUNX gene family: ‘overview’. OncogeneIto Y 2004 23 4198 4208 - 58.
Causal relationship between the loss of RUNX3 expression and gastric cancer. CellLi Q. L Ito K Sakakura C Fukamachi H Inoue K Chi X. Z Lee K. Y Nomura S Lee C. W Han S. B Kim H. M Kim W. J Yamamoto H Yamashita N Yano T Ikeda T Itohara S Inazawa J Abe T Hagiwara A Yamagishi H Ooe A Kaneda A Sugimura T Ushijima T Bae S. C Ito Y 2002 109 113 124 - 59.
Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma. Laboratory InvestigationKim T. Y Lee H. J Hwang K. S Lee M Kim J. W Bang Y. J Kang G. H 2004 84 479 484 - 60.
Possible involvement of RUNX3 silencing in the peritoneal metastases of gastric cancers. Clinical Cancer Research.Sakakura C Hasegawa K Miyagawa K Nakashima S Yoshikawa T Kin S Nakase Y Yazumi S Yamagishi H Okanoue T Chiba T Hagiwara A 2005 11 18 6479 6488 - 61.
HelicobacterKatayama Y Takahashi M Kuwayama H pylori causes runx3 gene methylation and loss of expression in gastric epithelial cells, which is mediated by nitric oxide produced by macrophages. Biochemical and Biophysical Research Communications2009 388 496 500 - 62.
Loss of RUNX3 expression correlates with differentiation, nodal metastasis, and poor prognosis in gastric cancer. Annals of Surgical OncologyHsu P. I Hsieh H. L Lee J Lin L. F Chen H. C Lu P. J Hsiao M 2009 16 1686 1694 - 63.
Genetic instability in colorectal cancers. NatureLengauer C Kinzler K. W Vogelstein B 1997 386 623 627 - 64.
Microsatellite instability in cancer of the proximal colon. ScienceThibodeau S. N Bren G Schaid D 1993 260 816 819 - 65.
Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. NatureIonov Y Peinado M. A Malkhosyan S Shibata D Perucho M 1993 363 558 561 - 66.
ESMO Guidelines Working Group. Gastrointestinal stromal tumours: ESMO clinical recommendations for diagnosis, treatment and follow-up. Annals of OncologyCasali P. G Jost L Reichardt P Schlemmer M Blay J. Y 2009 suppl 4): 64-67. - 67.
Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. Journal of Clinical InvestigationWarren R. S Yuan H Matli M. R Gillett N. A Ferrara N 1995 95 1789 1797 - 68.
Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. ScienceSlamon D. J Clark G. M Wong S. G Levin W. J Ullrich A Mcguire W. L 1987 235 177 182 - 69.
EGFR and cancer prognosis. European Journal of CancerNicholson R. I Gee J. M Harper M. E 2001 S9 15 - 70.
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New England Journal of MedicineSlamon D. J Leyland-jones B Shak S Fuchs H Paton V Bajamonde A Fleming T Eiermann W Wolter J Pegram M Baselga J Norton L 2001 344 783 792 - 71.
Targeted HER2 treatment in advanced gastric cancer. OncologyJørgensen J. T 2010 78 26 33 - 72.
Di Fabio F, Siena S, Cascinu S, Rojas Llimpe FL, Ceccarelli C, Mutri V, Giannetta L, Giaquinta S, Funaioli C, Berardi R, Longobardi C, Piana E, Martoni AA. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Annals of OncologyPinto C 2007 18 510 517 - 73.
Cetuximab enhances the activities of irinotecan on gastric cancer cell lines through downregulating the EGFR pathway upregulated by irinotecan. Cancer Chemotherapy and PharmacologyLiu X Guo W. J Zhang X. W Cai X Tian S Li J 2011 68 4 871 878 - 74.
Oncogenic mutations in gastric cancer with microsatellite instability. European Journal of CancerCorso G Velho S Paredes J Pedrazzani C Martins D Milanezi F Pascale V Vindigni C Pinheiro H Leite M Marrelli D Sousa S Carneiro F Oliveira C Roviello F Seruca R 2011 47 3 443 451 - 75.
El- A phase II study of bevacizumab, oxaliplatin, and docetaxel in locally advanced and metastatic gastric and gastroesophageal junction cancers. Annals of OncologyRayes B. F Patel B Zalupski M Hammad N Shields A Heilbrun L Venkatramanamoorthy R Philip P 2010 21 10 1999 2004 - 76.
Del Vecchio Blanco C, Romano M. Vascular endothelial growth factor and neo-angiogenesis in H.Tuccillo C Cuomo A Rocco A Martinelli E Staibano S Mascolo M Gravina A. G Nardone G Ricci V Ciardiello F pylori gastritis in humans. Journal of Pathology2005 207 3 277 284 - 77.
Targeted cancertherapies in the twenty-first century: lessons from imatinib. Clinical Pharmacology & TherapeuticsStegmeier F Warmuth M Sellers W. R Dorsch M 2010 87 543 552 - 78.
del Aguila LF, Tognazzi K, Yeo KT, Manseau EJ, Dvorak HF. Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer ResearchClaffey K. P Brown L. F 1996 56 172 181 - 79.
Circulating VEGF levels in the serum of gastric cancer patients: correlation with pathological variables, patient survival, and tumor surgery. Annals of SurgeryKarayiannakis A. J Syrigos K. N Polychronidis A Zbar A Kouraklis G Simopoulos C Karatzas G 2002 236 37 42 - 80.
The TOR pathway: a target for cancer therapy. Nat Rev CancerBjornsti M. A Houghton P. J 2004 4 5 335 348 - 81.
Akt maintains cell size and survival by increasing mTORdependent nutrient uptake. Molecular Biology of the CellEdinger A. L Thompson C. B 2002 13 2276 2288 - 82.
mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Molecular and Cellular BiologyFingar D. C Richardson C. J Tee A. R Cheatham L Tsou C Blenis J 2004 24 200 216 - 83.
Targeting von Hippel-Lindau pathway in renal cell carcinoma. Clinical Cancer ResearchPatel P. H Chadalavada R. S Chaganti R. S Motzer R. J 2006 12 7215 7220 - 84.
Upstream and downstream of mTOR. Genes Development.Hay N Sonenberg N 2004 18 1926 1945 - 85.
TOR signaling in growth and metabolism. CellWullschleger S Loewith R Hall M. N 2006 124 471 484 - 86.
Current development of mTOR inhibitors as anticancer agents. Nature Reviews Drug DiscoveryFaivre S Kroemer G Raymando E 2006 5 671 688 - 87.
Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. Journal of Clinical OncologyWagner A. J Malinowska-kolodziej I Morgan J. A Qin W Fletcher C. D Vena N Ligon A. H Antonescu C. R Ramaiya N. H Demetri G. D Kwiatkowski D. J Maki R. G 2010 28 835 840 - 88.
Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of chinese patients with gastric cancer. Clinical Cancer ResearchYu G Wang J Chen Y Wang X Pan J Li G Jia Z Li Q Yao J. C Xie K 2009 15 1821 1829 - 89.
Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. Journal of Clinical OncologyO Donnell A Faivre S Burris H. A Rd Rea D Papadimitrakopoulou V Shand N Lane H. A Hazell K Zoellner U Kovarik J. M Brock C Jones S Raymond E Judson I 2008 26 1588 1595 - 90.
Synergistic antiproliferative effect of mTOR inhibitors in combination with 5-fluorouracil in scirrhous gastric cancer. Cancer SciMatsuzaki T Yashiro M Kaizaki R Yasuda K Doi Y Sawada T Ohira M Hirakawa K 2009 100 2402 2410