Published online Jul 21, 2014. doi: 10.3748/wjg.v20.i27.8986
Revised: March 17, 2014
Accepted: April 5, 2014
Published online: July 21, 2014
Processing time: 262 Days and 22.8 Hours
The Tenth International Gastric Cancer Congress (IGCC) was held in Verona, Italy, from June 19 to 22, 2013. The meeting enclosed various aspects of stomach tumor management, including both tightly clinical approaches, and topics more related to basic research. Moreover, an overview on gastrointestinal stromal tumors was provided too, although here not discussed. Here we will discuss some topics related to molecular biology of gastric cancer (GC), inherent to prognostic, diagnostic and therapeutic tools shown at the conference. Results about well known subjects, such as E-cadherin loss of expression/function, were presented. They revealed that other mutations of the gene were identified, showing a continuous research to improve diagnosis and prognosis of stomach tumor. Simultaneously, new possible molecular markers with an established role for other neoplasms, were discussed, such as mesothelin, stomatin-like protein 2 and Notch-1. Hence, a wide overview including both old and new diagnostic/prognostic tools was offered. Great attention was also dedicated to possible drugs to be used against GC. They included monoclonal antibodies, such as MS57-2.1, drugs used in other pathologies, such as maraviroc, and natural extracts from plants such as biflorin. We would like to contribute to summarize the most impressive studies presented at the IGCC, concerning novel findings about molecular biology of gastric cancer. Although further investigations will be necessary, it can be inferred that more and more tools were developed, so as to better face stomach neoplasms.
Core tip: Gastric cancer (GC) is one of the most common tumors in the world, although scientists’ knowledge about this neoplasm grew in the last years. In June, an international meeting (10th International Gastric Cancer Congress), focused on GC management, was held in Verona (Italy). It gave an overview about the state-of-the-art stomach tumor treatments, including chemotherapy, surgical therapies and nutritional support. Moreover, several new possible prognostic markers were shown. Here we report a summary of novel findings taken from some molecular biology sessions, focused on prognosis and treatment of GC.
- Citation: Penon D, Cito L, Giordano A. Novel findings about management of gastric cancer: A summary from 10th IGCC. World J Gastroenterol 2014; 20(27): 8986-8992
- URL: https://www.wjgnet.com/1007-9327/full/v20/i27/8986.htm
- DOI: https://dx.doi.org/10.3748/wjg.v20.i27.8986
Gastric cancer (GC) represents one of the most frequent cause of cancer death[1,2], although most of the mechanisms leading to its development have been clarified. Helicobacter pylori (H. pylori) infection, salted/smoked food consumption and E-cadherin mutations[2-4] are the main causes of stomach tumor, according to multifactoriality characterizing almost all neoplasms. Improving early diagnosis is one of the most yearned target, because of possible misunderstanding of first GC symptom. Therapies are based above all on surgery and, however, the use of drugs was recently supported by GC gene expression analysis, which led to performing target specific treatments[5,6]. Reflecting the need of a multidisciplinary approach, the (10th IGCC) predisposed several sessions in which the authors were allowed to present their results in a well targeted context. Discussed topics ranged from surgical techniques, to patient nutrition, to diagnosis and chemotherapy. We focused our attention on subjects related to possible diagnostic/prognostic factors and to molecular targeted therapies. As we report, together with novel findings about well characterized molecules, a role in GC development of markers involved in other neoplasms growth was also found. Moreover, discussed therapies provided interesting starting points, as the results obtained with natural extracts of Capraria biflora on a GC cell line and the treatment of a mouse model of peritoneal metastases with maraviroc, an Food and Drug Administration (FDA) approved drug used for human immunodeficiency virus (HIV) patients. Hence we can assert that the 10th IGCC gave an all-round view about GC, showing the most important trend in this neoplasm management.
Many studies about E-cadherin (also known as CDH1) have been performed over the past several years. Its role in GC development is ascertained by now[7-9] and several germline mutations were effectively well characterized[7]. Yet, Sugimoto et al[10] reported the first case of a de novo large genomic deletion of CDH1 associated with early-onset diffuse GC. The patient, with a deletion of the exon 11, was a 41-year-old man with no familial history of GC. His son was a carrier of the same deletion, hence according to authors’ conclusions, CDH1 mutational status should be considered also in the absence of familial history of GC. Again, the investigation of CDH1 mutational status led also to decision of profilactic gastrectomy, as shown by Biffi et al[11]. Authors presented a case of 41-year-old female patient positive for germline CDH1 mutation, who had previously undergone surgical resection of a lobular breast cancer. The case reported by authors was the first Italian prophylactic surgical intervention, whereas in the United States this kind of radical management in carriers is usually performed[12-15].
Nearby novel discoveries related to well-known markers, such as CDH1, novel potential diagnostic and prognostic tools were described.
Santos-Sousa et al[16] presented an emerging role for mesothelin, a glycosylphosphatidylinositol-anchored cell surface protein overexpressed both in mesothelioma[17-19] and in ovarian cancer[18-20]. They found that mesothelin expression in GC tissue specimens was correlated with tumor location, macroscopic appearance, Lauren histological classification and stage. Moreover, its cytoplasmic expression was correlated with lymphatic invasion and associated with poorer survival. In 2012, Baba et al[21] discussed the role of mesothelin in GC development and its possible usefulness as a prognostic factor. They found that patients positive for mesothelin expression in gastric tissues showed broader nodal involvement and deeper tumor invasion. Yet, when the analysis was limited to only advanced GC cases, a higher survival rate was found in mesothelin positive patients. Considering the papers of Santos-Sousa et al[16] and of Baba et al[21], it can be inferred that mesothelin is an independent prognostic factor of GC, as stressed from authors themselves. But the first authors showed its cytoplasmic placement as a key element in exerting prognostic role, whereas the second ones referred its expected cell membrane localization. Hence further studies are necessary to better answer questions about mesothelin expression and localization so as to improve our knowledge on its role in GC development.
Few contributions were presented about the role of cell cycle regulators in stomach tumor development. Very interesting were the results presented by Kim et al[22], which focused their attention on p16 protein, whose expression was found lost in other neoplasms[23-26]. The same result was obtained in intestinal histotype of GC from the analysis performed by the authors, who showed that loss of p16 expression was related to a higher rate of cancer recurrence and poorer 5-year disease-free survival. This finding led the authors to hypothesize a role of loss of p16 expression in GC development, which is similar to data observed in other cancers.
Stomatin-like protein 2 (SLP-2) is a protein belonging to the stomatin superfamily, which has been found overexpressed in several kind of tumors[27]. Its overexpression is generally associated with poor prognosis in esophageal squamous cell carcinoma, human gallbladder cancer and HER2 negative breast cancer[27-29]. Liu et al[30] confirmed SLP-2 as a prognostic tool to manage GC. High level of SLP-2 expression was significantly associated with the depth of invasion, lymph node and distant metastases, and tumor node metastasis (TNM) stage in GC. Notch1 is another possible marker overexpressed in GC, as shown in two independent cohort studies performed by Chu et al[31]. Both of them showed that higher Notch1 expression was correlated with a shorter survival time, while lower Notch-1 expression was correlated with a better survival of GC patients. These results suggest that Notch1, whose prognostic role was found in other tumors[32,33], has a predictive role in clinical outcomes of GC patients too. Moreover, the authors highlighted the dependence of Notch1 prognostic value on p65 status, hypothesizing a role as a promising novel target for GC therapy.
An unexpected result was reported by Chen et al[34]. They found that CD44 positive expression in surgical specimens of primary GC was not correlated with clinicopathological features and survival outcomes. These data may be considered surprising because CD44 is a well-recognized tumor marker[35-37]. It may be possible that GC development is independent from CD44 expression levels, although it has to be mentioned that in 2013, a paper of Hirata et al[38] was published, in which the authors found a correlation between expression of a CD44 variant and GC recurrence.
Epigenetic control of DNA expression was often found pivotal in etiogenesis of various cancers, since it leads to gene silencing and therefore to loss of expression of oncosuppressors too[39-41]. Calcagno et al[42] investigated the expression levels of enzymes with methyltransferase activity, showing that they may exert an important role in GC development. They found high levels of DNMT1, DNMT3A and DNMT3B (DNA-methyl-transferase 1, 3A and 3B) expression in gastric adenocarcinoma tissues, when compared to normal specimens. However, they found no correlation between DNMT1, DNMT3A and DNMT3B overexpression and clinicopathological features, drawing the conclusion that the increased expression may be placed in the early stage GC development. Besides, the same authors investigated the effects of hypermethylation in GC cell lines[43]. They treated two gastric adenocarcinoma cell lines, ACP02 (diffuse-type) and ACP03 (intestinal-type), with a demethylating agent and evaluated gene expression compared to untreated cells. The genes neuritin 1 (NRN1) and tumor necrosis factor alpha-induced protein (TNFAIP) were found upregulated in both GC cell lines compared to controls, while metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and small nucleolar RNA D (SNORD) were overexpressed only in intestinal-type GC cell line. They obtained these data as before by microarray assay and confirmed them by real-time PCR, finding new genes epigenetically altered in GC. Also, the overexpression of nonmuscle myosin IIA (NMIIA) may be associated with progression and poor prognosis of GC, as revealed by Liu et al[44], because high expression of this protein is significantly correlated with the depth of wall invasion, lymph node metastasis, distant metastasis and TNM stage. Another very interesting prognostic tool was presented by Choi[45], who found that in GC patients, the number of loss of eterozygosity (LOH) may be a determinant poor prognostic factor. The author analyzed LOH of 5 chromosomes having tumor suppressor genes such as p16, PTEN, Rb, E-cadherin and p53 in 100 surgically resected tumors. Patients with 2 or more LOHs displayed a poorer 5-year survival rate than those who had less than 2 LOHs. In particular, LOH in 17p13 (p53 locus) contributed to a lower survival rate. Therefore, the number and the type of LOH in GC may be useful prognostic indicators. A very innovative diagnostic tool was presented by Linē et al[46], who identified a tumor-associated autoantibody signature that can be used for the early detection of GC among high-risk individuals. The autoantibody production, which does not correlate with histotype, already occurs in early GC and it could be associated with shorter overall survival. H. pylori status, grade, localization and size of the primary tumor were not related to autoantibody signature. Diagnosis of GC at advanced stages is considered a major reason for lower five-year overall survival rate in developing countries[47]. Hence, early diagnosis of GC is fundamental for patient survival.
VEGF (vascular endothelial growth factor) has been largely investigated because of its active role in angiogenesis. It was found that its overexpression is a poorer prognostic marker in various neoplasms such as osteosarcoma[48], non-small cell lung carcinoma[49] and melanoma[50].
Some authors analyzed the expression levels of VEGFs either alone, or together with other possible prognostic factors. Kruszyna et al[51] showed that VEGF, hypoxia inducible factor-1 (HIF-1) and CXC chemokine receptor 4 (CXCR4) were up-regulated in tumoral, but not in normal specimens. Von Hippel-Lindau tumor suppressor (VHL) and HIF-prolyl hydroxylase 2 (PHD2) were, instead, expressed at very low levels in tumor tissues. All these results were found related with malignant tumor progression and lymph node metastasis, drawing attention to the possibility of considering VEGF, CXCR4, VHL and PHD2 as prognostic markers of GC. Noteworthy were also the results obtained by Partika et al[52]. Although in few patients, they observed the absence of VEGF within the GC tissue despite its high plasma concentration. The authors hypothesized that VEGF in somehow was quickly eliminated into the blood stream. Hence, further investigations may be useful to cast light on the possibility to use plasma levels of VEGF as a biomarker. Finally, Yingwei et al[53] investigated the expression levels of VEGF, EGF and their receptors in GC cell lines of different biological properties and the outcomes of their targeted inhibition. They found that EGF, EGFR, VEGF and VEGFR mRNA expression increased sequentially in SGC7901, BGC823, HGC27 and MGC803 cell lines, allowing them to increase their proliferation, motility and adhesion. Therefore, specific inhibition of VEGF and EGF may impair cellular properties related to tumoral phenotype, representing a possible therapeutic strategy for GC. On the other hand, Donizy et al[54] have not found any clinical significance of VEGF-C, VEGF-D, VEGFR-3 expression in GC patients. The only statistically significant parameter which they found related to poor prognosis and shorter long-term survival was the lower level of matrix metalloproteinase-2 (MMP-2). Hence it can be deduced that, although there are some exceptions, VEGF pathways may be considered as possible prognostic tools and/or therapeutic targets.
Interesting studies about prognostic significance of microsatellites instability (MSI) were also presented. Pascale et al[55] analyzed the differences in MSI between two groups of patients living in higher and lower Italian risk areas. The authors found that GC patients living in higher risk areas showed a higher rate of MSI than those in low-risk areas. These results stress the relationship among environment, genome and cancer, topic of investigations for a long time. Although not always demonstrated, it is undeniable that many authors contributed to reinforce the aforementioned relationship. The analysis performed by Pascale et al[55] is hence particularly interesting because it highlighted the clinical implications derived from possible impact of environment on human genome. Kim et al[56] presented similarly interesting results, related to role of MSI in GC medical evaluation. They studied the link between the MSI-high (MSI-H) and GC prognosis in patients who underwent gastrectomy. In few patients MSI-H was detected and there was no relationship with lymph node involvement. Yet, MSI-H correlated with a poorer prognosis than MSI-low (MSI-L) and microsatellite stable (MSS) context. It has to be noticed that in literature different results were reported too. Some authors showed that MSI-H was related to a better prognosis[57-59], whereas others reported no significant correlation between MSI and GC prognosis[60,61]. And in more recent reviews, the role exerted by MSI in GC development is discussed but not definitely clarified[62]. Hence it can be deduced that far from being well understood, the role of MSI in GC, although challenging cues were provided during the 10th IGCC, deserves further investigations in order to better clarify its role in GC development.
One of the most challenging topics of the 10th IGCC, representing also one of the most innovative section of 10th IGCC, was referred to biomolecular analysis of therapeutic management of GC. Various authors obtained promising results, identifying novel potential therapeutic tools that could have a future clinical application. Liu et al[63] identified a novel immunological method that can not only detect GC cells and but also inhibit migration and invasion. In particular, a functional monoclonal antibody (mAb) MS57-2.1 against novel antigenic markers on the gastric cancer cell surface, MS57A and MS57B, was generated. Both antigens are membrane bound glycosylated enzymes and belong to the alkaline phosphatase family[64]. MS57-2.1 mAb was produced by hybridoma method and it was able to bind specifically to GC cell membrane with high affinity. Through this binding, a cellular signal inhibiting tumor cell migration and invasion was found activated in vitro and tumor metastasis impairment was detected in vivo. Hence, MS57-2.1 mAb could represent an effective novel tool in GC therapy because it may help to impair progression of tumoral phenotype. Other authors tested the effect of drugs both in vitro and in vivo experiments. In vitro, Calcagno et al[65] evaluated the cytotoxic and genotoxic potential of E-2-Benzo[D]thiazol in normal and gastric tumor cells (ACP02 - diffuse-type gastric adenocarcinoma cell line). Their results showed DNA damage and apoptosis in tumor cells, without significant damage to lymphocytes. These findings suggest E-2-Benzo[D]thiazol as a potential drug to improve GC management. Protein kinase D (PKD) inhibitor CID755673 may be another anti-neoplastic treatment for GC, as shown by Tsuboi et al[66]. PKD regulates multiple normal and abnormal biological processes, including angiogenesis[67,68]. VEGF pathway seems to be an important driver of tumorigenesis in GC, as previously reported[69,70], also in a paragraph above. Analysis of mechanism of action of CID755673, performed in MKN45 cell line, showed inhibition of PKD phosphorylation, induced by phorbol myristate acetate, and of VEGF secretion levels in a dose-dependent manner. Hence, PKD inhibitors may contribute to angiogenesis regression in GC. In an in vivo model, Graziosi et al[71] studied the effect of maraviroc, a chemokine CCR5-receptor antagonist, in GC treatment. Maraviroc is the first member of a new class of antiretroviral drugs, whose mechanism of action is pivoted on blocking R5-tropic HIV entry into CD4 cells[72,73]. It was approved by United States FDA to be used, in combination with other antiretroviral agents, for treatment of patients carrying both drug-sensitive and -resistant HIV strains[74]. In cancer, metastasis prevention induced by maraviroc was observed in hepatocellular carcinoma[75] and basal breast cancer[76,77]. In their study, Graziosi et al[71] analyzed a mouse model of peritoneal carcinomatosis in which maraviroc reduced both GC cell dissemination and tumor growth. These findings provide evidences for an important role of CCR5 in cancer cell invasiveness, suggesting also a possible use of maraviroc as a further therapy to reduce the risk of metastasis in GC patients. Finally, among the various possible chemotherapeutic strategies, it has to be mentioned the potential efficacy of biflorin, a prenyl-ortonaftoquinone obtained from the roots of Capraria biflora L., in ACP02 cell line. Calcagno et al[78] reported that biflorin exerts anticancer activity; it inhibits both tumor cell line growth in culture and tumor development in mice[79,80]. In fact, biflorin showed a powerful cytotoxic effect in vitro, inhibiting cell proliferation, migration and invasion. Moreover, after treatment, morphological analysis spotlighted cell death by necrosis. Results obtained by authors seemed to be focused on a possible reduction of MYC copy number in ACP02 and in the length of telomeres, to give a possible explanation for biflorin effects.
The 10th IGCC gave a complete overview about the state-of-the-art of stomach tumor management. Both in the basic research and in clinical activity, there has been a great knowledge improvement. In our opinion, original suggestions were particularly found in therapy and treatment sections. Treatment of GC with Maraviroc, generally used in HIV patients, may be a turning point, so as the promising possible use of biflorin. Yet, due to complexity of GC etiogenesis, further studies will be necessary and will have to be performed for a long period of time to reach the target of a gold standard therapy.
P- Reviewers: Chen JX, Fassan M, Fujiwara T, Lin ZH, Shimi SM, Wang XL, Zheng XF S- Editor: Wen LL L- Editor: Wang TQ E- Editor: Liu XM
1. | Hong L, Han Y, Liu J, Brain L. Fibroblast growth factor receptor 2: a therapeutic target in gastric cancer. Expert Rev Gastroenterol Hepatol. 2013;7:759-765. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 14] [Cited by in F6Publishing: 14] [Article Influence: 1.3] [Reference Citation Analysis (0)] |
2. | Giordano A, Cito L. Advances in gastric cancer prevention. World J Clin Oncol. 2012;3:128-136. [PubMed] [DOI] [Cited in This Article: ] [Cited by in CrossRef: 12] [Cited by in F6Publishing: 16] [Article Influence: 1.3] [Reference Citation Analysis (0)] |
3. | Jakszyn P, Gonzalez CA. Nitrosamine and related food intake and gastric and oesophageal cancer risk: a systematic review of the epidemiological evidence. World J Gastroenterol. 2006;12:4296-4303. [PubMed] [Cited in This Article: ] |
4. | Zagari RM, Bazzoli F. Gastric cancer: who is at risk? Dig Dis. 2004;22:302-305. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 10] [Cited by in F6Publishing: 13] [Article Influence: 0.7] [Reference Citation Analysis (0)] |
5. | Zhang L, Yang J, Cai J, Song X, Deng J, Huang X, Chen D, Yang M, Wery JP, Li S. A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy. Sci Rep. 2013;3:2992. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 64] [Cited by in F6Publishing: 69] [Article Influence: 6.3] [Reference Citation Analysis (0)] |
6. | Teng L, Lu J. cMET as a potential therapeutic target in gastric cancer (Review). Int J Mol Med. 2013;32:1247-1254. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 19] [Cited by in F6Publishing: 23] [Article Influence: 2.1] [Reference Citation Analysis (0)] |
7. | Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392:402-405. [PubMed] [Cited in This Article: ] |
8. | Gabbert HE, Mueller W, Schneiders A, Meier S, Moll R, Birchmeier W, Hommel G. Prognostic value of E-cadherin expression in 413 gastric carcinomas. Int J Cancer. 1996;69:184-189. [PubMed] [Cited in This Article: ] |
9. | Wei D, Gong W, Oh SC, Li Q, Kim WD, Wang L, Le X, Yao J, Wu TT, Huang S. Loss of RUNX3 expression significantly affects the clinical outcome of gastric cancer patients and its restoration causes drastic suppression of tumor growth and metastasis. Cancer Res. 2005;65:4809-4816. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 77] [Cited by in F6Publishing: 84] [Article Influence: 4.4] [Reference Citation Analysis (0)] |
10. | Sugimoto S, Yamada H, Takahashi M, Morohoshi Y, Yamaguchi N, Tsunoda Y, Hayashi H, Sugimura H, Komatsu H. Early-onset diffuse gastric cancer associated with a de novo large genomic deletion of CDH1 gene. Gastric Cancer. 2013;Epub ahead of print. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 24] [Cited by in F6Publishing: 31] [Article Influence: 3.1] [Reference Citation Analysis (0)] |
11. | Biffi R, Pozzi S, Feroce I, Serrano D, Trovato C, Sonzogni A, Sabbatini A R, Didier F, Galimberti V, Corso G. Total prophylactic gastrectomy for HDGC (Hereditary Diffuse Gastric Cancer) syndrome caused by a mutation in the E-cadherin (CDH1) gene: the first Italian case. Available from: http://www.10igcc.com. [Cited in This Article: ] |
12. | Li J, McBean E, Li X, Berho M, Szomstein S, Rosenthal RJ. Laparoscopic prophylactic total gastrectomy with linear stapler side-to-side esophagojejunal anastomosis for hereditary diffuse gastric cancer syndrome in 2 siblings. Surg Laparosc Endosc Percutan Tech. 2013;23:e124-e126. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 5] [Cited by in F6Publishing: 8] [Article Influence: 0.8] [Reference Citation Analysis (0)] |
13. | Hebbard PC, Macmillan A, Huntsman D, Kaurah P, Carneiro F, Wen X, Kwan A, Boone D, Bursey F, Green J. Prophylactic total gastrectomy (PTG) for hereditary diffuse gastric cancer (HDGC): the Newfoundland experience with 23 patients. Ann Surg Oncol. 2009;16:1890-1895. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 78] [Cited by in F6Publishing: 75] [Article Influence: 5.0] [Reference Citation Analysis (0)] |
14. | Pandalai PK, Lauwers GY, Chung DC, Patel D, Yoon SS. Prophylactic total gastrectomy for individuals with germline CDH1 mutation. Surgery. 2011;149:347-355. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 46] [Cited by in F6Publishing: 51] [Article Influence: 3.6] [Reference Citation Analysis (0)] |
15. | Newman EA, Mulholland MW. Prophylactic gastrectomy for hereditary diffuse gastric cancer syndrome. J Am Coll Surg. 2006;202:612-617. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 33] [Cited by in F6Publishing: 35] [Article Influence: 1.9] [Reference Citation Analysis (0)] |
16. | Santos-Sousa H, Marcos-Silva L, Costa-Maia J, Pinto-De-Sousa J, David L. Mesothelin expression and its clinicopathological and prognostic significance in gastric and gastroesophageal junction cancer. Available from: http://www.10igcc.com. [Cited in This Article: ] |
17. | Luo L, Shi HZ, Liang QL, Jiang J, Qin SM, Deng JM. Diagnostic value of soluble mesothelin-related peptides for malignant mesothelioma: a meta-analysis. Respir Med. 2010;104:149-156. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 40] [Cited by in F6Publishing: 40] [Article Influence: 2.7] [Reference Citation Analysis (0)] |
18. | Ho M, Hassan R, Zhang J, Wang QC, Onda M, Bera T, Pastan I. Humoral immune response to mesothelin in mesothelioma and ovarian cancer patients. Clin Cancer Res. 2005;11:3814-3820. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 112] [Cited by in F6Publishing: 123] [Article Influence: 6.5] [Reference Citation Analysis (0)] |
19. | Hassan R, Bera T, Pastan I. Mesothelin: a new target for immunotherapy. Clin Cancer Res. 2004;10:3937-3942. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 320] [Cited by in F6Publishing: 325] [Article Influence: 17.1] [Reference Citation Analysis (0)] |
20. | Chang MC, Chen CA, Chen PJ, Chiang YC, Chen YL, Mao TL, Lin HW, Lin Chiang WH, Cheng WF. Mesothelin enhances invasion of ovarian cancer by inducing MMP-7 through MAPK/ERK and JNK pathways. Biochem J. 2012;442:293-302. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 97] [Cited by in F6Publishing: 113] [Article Influence: 9.4] [Reference Citation Analysis (0)] |
21. | Baba K, Ishigami S, Arigami T, Uenosono Y, Okumura H, Matsumoto M, Kurahara H, Uchikado Y, Kita Y, Kijima Y. Mesothelin expression correlates with prolonged patient survival in gastric cancer. J Surg Oncol. 2012;105:195-199. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 44] [Cited by in F6Publishing: 47] [Article Influence: 3.6] [Reference Citation Analysis (0)] |
22. | Kim J, Cho S, Jang Y, Park S, Park S, Kim S, Mok Y, Kim C. The prognostic significance of p16 gene protein loss in intestinal type gastric cancer. Available from: http://www.10igcc.com. [Cited in This Article: ] |
23. | Tam KW, Zhang W, Soh J, Stastny V, Chen M, Sun H, Thu K, Rios JJ, Yang C, Marconett CN. CDKN2A/p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small-cell lung cancer. J Thorac Oncol. 2013;8:1378-1388. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 49] [Cited by in F6Publishing: 60] [Article Influence: 6.0] [Reference Citation Analysis (0)] |
24. | Matsuda Y, Ichida T, Matsuzawa J, Sugimura K, Asakura H. p16(INK4) is inactivated by extensive CpG methylation in human hepatocellular carcinoma. Gastroenterology. 1999;116:394-400. [PubMed] [Cited in This Article: ] |
25. | Emig R, Magener A, Ehemann V, Meyer A, Stilgenbauer F, Volkmann M, Wallwiener D, Sinn HP. Aberrant cytoplasmic expression of the p16 protein in breast cancer is associated with accelerated tumour proliferation. Br J Cancer. 1998;78:1661-1668. [PubMed] [Cited in This Article: ] |
26. | Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet. 1994;8:27-32. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 785] [Cited by in F6Publishing: 742] [Article Influence: 24.7] [Reference Citation Analysis (0)] |
27. | Cao W, Zhang B, Ding F, Zhang W, Sun B, Liu Z. Expression of SLP-2 was associated with invasion of esophageal squamous cell carcinoma. PLoS One. 2013;8:e63890. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 10] [Cited by in F6Publishing: 12] [Article Influence: 1.1] [Reference Citation Analysis (0)] |
28. | Wang WX, Lin QF, Shen D, Liu SP, Mao WD, Ma G, Qi WD. Clinicopathological significance of SLP-2 overexpression in human gallbladder cancer. Tumour Biol. 2014;35:419-423. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 7] [Cited by in F6Publishing: 10] [Article Influence: 0.9] [Reference Citation Analysis (0)] |
29. | Cao W, Zhang B, Li J, Liu Y, Liu Z, Sun B. SLP-2 overexpression could serve as a prognostic factor in node positive and HER2 negative breast cancer. Pathology. 2011;43:713-718. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 8] [Cited by in F6Publishing: 11] [Article Influence: 0.9] [Reference Citation Analysis (0)] |
30. | Liu D, Zhang L, Shen Z, Tan F, Hu Y, Yu J, Li G. Increased levels of SLP-2 correlate with poor prognosis in gastric cancer. Gastric Cancer. 2013;16:498-504. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 17] [Cited by in F6Publishing: 23] [Article Influence: 2.1] [Reference Citation Analysis (0)] |
31. | Chu D, Chu D, Wang W. Notch1 expression, which is related to p65 status, is an independent predictor of prognosis in gastric cancer. Available from: http://www.10igcc.com. [Cited in This Article: ] |
32. | Ahn S, Hyeon J, Park CK. Notch1 and Notch4 are markers for poor prognosis of hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2013;12:286-294. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 38] [Cited by in F6Publishing: 41] [Article Influence: 3.7] [Reference Citation Analysis (0)] |
33. | Willander K, Dutta RK, Ungerbäck J, Gunnarsson R, Juliusson G, Fredrikson M, Linderholm M, Söderkvist P. NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients. BMC Cancer. 2013;13:274. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 25] [Cited by in F6Publishing: 26] [Article Influence: 2.4] [Reference Citation Analysis (0)] |
34. | Chen X, Wen L, Wang F, Yang K, Zhang B, Chen Z, Chen J, Mo X, Zhou Z, Hu J. Protein, mRNA expressions and prognostic significance of CD44 in human gastric adenocarcinoma. Available from: http://www.10igcc.com. [Cited in This Article: ] |
35. | Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, Goulet R, Badve S, Nakshatri H. CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res. 2006;8:R59. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 702] [Cited by in F6Publishing: 727] [Article Influence: 42.8] [Reference Citation Analysis (0)] |
36. | Misra S, Hascall VC, Berger FG, Markwald RR, Ghatak S. Hyaluronan, CD44, and cyclooxygenase-2 in colon cancer. Connect Tissue Res. 2008;49:219-224. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 42] [Cited by in F6Publishing: 46] [Article Influence: 2.9] [Reference Citation Analysis (0)] |
37. | Mărgăritescu C, Pirici D, Simionescu C, Stepan A. The utility of CD44, CD117 and CD133 in identification of cancer stem cells (CSC) in oral squamous cell carcinomas (OSCC). Rom J Morphol Embryol. 2011;52:985-993. [PubMed] [Cited in This Article: ] |
38. | Hirata K, Suzuki H, Imaeda H, Matsuzaki J, Tsugawa H, Nagano O, Asakura K, Saya H, Hibi T. CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence. Br J Cancer. 2013;109:379-386. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 88] [Cited by in F6Publishing: 98] [Article Influence: 8.9] [Reference Citation Analysis (0)] |
39. | Bosviel R, Garcia S, Lavediaux G, Michard E, Dravers M, Kwiatkowski F, Bignon YJ, Bernard-Gallon DJ. BRCA1 promoter methylation in peripheral blood DNA was identified in sporadic breast cancer and controls. Cancer Epidemiol. 2012;36:e177-e182. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 43] [Cited by in F6Publishing: 40] [Article Influence: 3.3] [Reference Citation Analysis (0)] |
40. | Tommasi S, Pinto R, Petriella D, Pilato B, Lacalamita R, Santini D, Zito F, Colucci G, Paradiso A, Silvestris N. Oncosuppressor methylation: a possible key role in colon metastatic progression. J Cell Physiol. 2011;226:1934-1939. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 16] [Cited by in F6Publishing: 17] [Article Influence: 1.3] [Reference Citation Analysis (0)] |
41. | Li L, Shen Y, Wang M, Tang D, Luo Y, Jiao W, Wang Z, Yang R, Tian K. Identification of the methylation of p14ARF promoter as a novel non-invasive biomarker for early detection of lung cancer. Clin Transl Oncol. 2014;16:581-589. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 6] [Cited by in F6Publishing: 8] [Article Influence: 0.7] [Reference Citation Analysis (0)] |
42. | Calcagno D, Calcagno D, Wisnieski F, Chen ES, Gigek CO, Santos L, Leal MF, Pontes TB, Demachki S, Assumpção PP. Clinical significance of the DNA methyltranferase mRNA expression in gastric adenocarcinoma. Available from: http://www.10igcc.com. [Cited in This Article: ] |
43. | Calcagno D, Calcagno DQ, Wisnieski F, Chen ES, Gigek CO, Leal MF, Pontes TB, Demachki S, Ricardo A, Assumpção PP. Identification of genes epigenetically silenced in human gastric adenicarcinoma cells. Available from: http://www.10igcc.com. [Cited in This Article: ] |
44. | Liu D, Zhang L, Shen Z, Tan F, Hu Y, Yu J, Li G. Clinicopathological significance of NMIIA Overexpression in Human Gastric Cancer. Int J Mol Sci. 2012;13:15291-15304. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 21] [Cited by in F6Publishing: 27] [Article Influence: 2.3] [Reference Citation Analysis (0)] |
45. | Choi W. The significance of the number of LOH in major tumor suppressor genes as a prognostic factor. Available from: http://www.10igcc.com. [Cited in This Article: ] |
46. | Linē A, Zayakin P, Ancāns G, Siliņa K, Meistere I, Kalniņa Z, Andrejeva D, Endzeliņš E, Ivanova L, Pismennaja A. Identification of tumor-associated autoantibody signature for the early detection of gastric cancer. Available from: http://www.10igcc.com. [Cited in This Article: ] |
47. | Ali Z, Deng Y, Ma C. Progress of research in gastric cancer. J Nanosci Nanotechnol. 2012;12:8241-8248. [PubMed] [Cited in This Article: ] |
48. | Chen D, Zhang YJ, Zhu KW, Wang WC. A systematic review of vascular endothelial growth factor expression as a biomarker of prognosis in patients with osteosarcoma. Tumour Biol. 2013;34:1895-1899. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 42] [Cited by in F6Publishing: 40] [Article Influence: 3.6] [Reference Citation Analysis (0)] |
49. | Fontanini G, Vignati S, Boldrini L, Chinè S, Silvestri V, Lucchi M, Mussi A, Angeletti CA, Bevilacqua G. Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma. Clin Cancer Res. 1997;3:861-865. [PubMed] [Cited in This Article: ] |
50. | Claffey KP, Brown LF, 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 Res. 1996;56:172-181. [PubMed] [Cited in This Article: ] |
51. | Kruszyna L, Murawa D, Murawa P, Jacodzinski P, Oszkinis G. Expression and clinical significance of genes responsible for angiogenesis and progression in gastric cancer. Available from: http://www.10igcc.com. [Cited in This Article: ] |
52. | Partika R, Donocik J, Kokocinska D, Jalowiecki P. Evaluation of concentration of VEGF and EGF on biological properties of gastric cancer cells. Available from: http://www.10igcc.com. [Cited in This Article: ] |
53. | Yingwei P, Chunfeng L. Experimental study on the effects of VEGF and EGF on biological properties of gastric cancer cells. Available from: http://www.10igcc.com. [Cited in This Article: ] |
54. | Donizy P, Donizy P, Matkowski R, Rudno-Rudzinska J, Frejlinch E, Kabarowski J, Kelan W, Halon A. Clinical significance of gastric cancer immunoprofile related to angiogenesis (VEGF-C, VEGF-D, VEGFR3) and enzymatic degradation of extracellular matrix (MMP-2,9/TIMP-1,2). Available from: http://www.10igcc.com. [Cited in This Article: ] |
55. | Pascale V, Marrelli D, Garosi L, Corso G, Flauti G, Caputo E, Roviello F. Different frequency of microsatellite instability (MSI) in patients coming from high-risk and low-risk areas of Italy: clinico-pathological implications. Available from: http://www.10igcc.com. [Cited in This Article: ] |
56. | Kim SY, Choi YY, An JY, Kwon IG, Cho I, Kim H, Cheong J, Hyung WJ, Noh SH. MSI-H related to worse prognosis in T4N0 gastric cancer patients. Available from: http://www.10igcc.com. [Cited in This Article: ] |
57. | Lee HS, Choi SI, Lee HK, Kim HS, Yang HK, Kang GH, Kim YI, Lee BL, Kim WH. Distinct clinical features and outcomes of gastric cancers with microsatellite instability. Mod Pathol. 2002;15:632-640. [PubMed] [Cited in This Article: ] |
58. | Beghelli S, de Manzoni G, Barbi S, Tomezzoli A, Roviello F, Di Gregorio C, Vindigni C, Bortesi L, Parisi A, Saragoni L. Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers. Surgery. 2006;139:347-356. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 101] [Cited by in F6Publishing: 111] [Article Influence: 6.2] [Reference Citation Analysis (0)] |
59. | Falchetti M, Saieva C, Lupi R, Masala G, Rizzolo P, Zanna I, Ceccarelli K, Sera F, Mariani-Costantini R, Nesi G. Gastric cancer with high-level microsatellite instability: target gene mutations, clinicopathologic features, and long-term survival. Hum Pathol. 2008;39:925-932. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 86] [Cited by in F6Publishing: 103] [Article Influence: 6.4] [Reference Citation Analysis (0)] |
60. | Oki E, Kakeji Y, Zhao Y, Yoshida R, Ando K, Masuda T, Ohgaki K, Morita M, Maehara Y. Chemosensitivity and survival in gastric cancer patients with microsatellite instability. Ann Surg Oncol. 2009;16:2510-2515. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 54] [Cited by in F6Publishing: 60] [Article Influence: 4.0] [Reference Citation Analysis (0)] |
61. | An JY, Kim H, Cheong JH, Hyung WJ, Kim H, Noh SH. Microsatellite instability in sporadic gastric cancer: its prognostic role and guidance for 5-FU based chemotherapy after R0 resection. Int J Cancer. 2012;131:505-511. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 91] [Cited by in F6Publishing: 115] [Article Influence: 8.8] [Reference Citation Analysis (0)] |
62. | Hudler P. Genetic aspects of gastric cancer instability. ScientificWorldJournal. 2012;2012:761909. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 67] [Cited by in F6Publishing: 74] [Article Influence: 6.2] [Reference Citation Analysis (0)] |
63. | Liu B, Gao J, Chen X, Li J, Lu M, Qu Y, Zhu Z. Inhibition gastric cancer cell migration and invasion by monoclonal antibody MS57-2.1. Available from: http://www.10igcc.com. [Cited in This Article: ] |
64. | Gao J, Qu Y, Li M, Zhou Y, Wang L, Lu M, Tao S, Liu B, Zhu Z. Cell membrane protein MS57A and MS57B are novel markers on gastric cancer cell lines and potential therapeutic targets of gastric cancer: Expressed on the gastric cancer cell surface defined by MS57-2.1 mAb. Transl Gastrointest Cancer. 2012;1 (Suppl 1). [Cited in This Article: ] |
65. | Calcagno D, Soares BM, Barreto LDH, Ramos JAB, De Almeida SB, Pinto LC, Ferreira VF, Nogueira AF, Azevedo EC, Calcagno DQ. Cytotoxic and genotoxic potential of E-2-Benzo [D] Thiazol in normal and gstric tumor cells. Available from: http://www.10igcc.com. [Cited in This Article: ] |
66. | Tsuboi K, Matsuo Y, Shamoto T, Shibata T, Wakasugi T, Funahashi H, Kimura M, Takeyama H. PKD regulates VEGF secretion in gastric cancer. Available from: http://www.10igcc.com. [Cited in This Article: ] |
67. | Ellwanger K, Hausser A. Physiological functions of protein kinase D in vivo. IUBMB Life. 2013;65:98-107. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 29] [Cited by in F6Publishing: 31] [Article Influence: 2.8] [Reference Citation Analysis (0)] |
68. | Rozengurt E. Protein kinase D signaling: multiple biological functions in health and disease. Physiology (Bethesda). 2011;26:23-33. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 147] [Cited by in F6Publishing: 176] [Article Influence: 13.5] [Reference Citation Analysis (0)] |
69. | Ilson DH. Angiogenesis in gastric cancer: hitting the target? Lancet. 2014;383:4-6. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 22] [Cited by in F6Publishing: 24] [Article Influence: 2.4] [Reference Citation Analysis (0)] |
70. | Scartozzi M, Giampieri R, Loretelli C, Bittoni A, Mandolesi A, Faloppi L, Bianconi M, Del Prete M, Andrikou K, Bearzi I. Tumor angiogenesis genotyping and efficacy of first-line chemotherapy in metastatic gastric cancer patients. Pharmacogenomics. 2013;14:1991-1998. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 14] [Cited by in F6Publishing: 16] [Article Influence: 1.5] [Reference Citation Analysis (0)] |
71. | Graziosi L, Marino E, Renga B, Santorelli C, Cavazzoni E, Fiorucci S, Donini A. Effect of the CCR5 antagonist maraviroc in reducing gastric cancer dissemination in rodent models of peritoneal metastasis. Available from: http://www.10igcc.com. [Cited in This Article: ] |
72. | Lieberman-Blum SS, Fung HB, Bandres JC. Maraviroc: a CCR5-receptor antagonist for the treatment of HIV-1 infection. Clin Ther. 2008;30:1228-1250. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 110] [Cited by in F6Publishing: 107] [Article Influence: 6.7] [Reference Citation Analysis (0)] |
73. | Sayana S, Khanlou H. Maraviroc: a new CCR5 antagonist. Expert Rev Anti Infect Ther. 2009;7:9-19. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 41] [Cited by in F6Publishing: 41] [Article Influence: 2.7] [Reference Citation Analysis (0)] |
74. | Brown KC, Paul S, Kashuba AD. Drug interactions with new and investigational antiretrovirals. Clin Pharmacokinet. 2009;48:211-241. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 68] [Cited by in F6Publishing: 69] [Article Influence: 4.6] [Reference Citation Analysis (0)] |
75. | Ochoa-Callejero L, Pérez-Martínez L, Rubio-Mediavilla S, Oteo JA, Martínez A, Blanco JR. Maraviroc, a CCR5 antagonist, prevents development of hepatocellular carcinoma in a mouse model. PLoS One. 2013;8:e53992. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 65] [Cited by in F6Publishing: 69] [Article Influence: 6.3] [Reference Citation Analysis (0)] |
76. | Velasco-Velázquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP, Pestell RG. CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res. 2012;72:3839-3850. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 187] [Cited by in F6Publishing: 208] [Article Influence: 17.3] [Reference Citation Analysis (0)] |
77. | Velasco-Velázquez M, Pestell RG. The CCL5/CCR5 axis promotes metastasis in basal breast cancer. Oncoimmunology. 2013;2:e23660. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 51] [Cited by in F6Publishing: 57] [Article Influence: 5.7] [Reference Citation Analysis (0)] |
78. | Calcagno D, Barbosa GS, Ralph ACL, Gregòrio L, Lemos TLG, Burbano RR, Calcagno DQ, Smith MDAC, Montenegro RC, Vasconcellos MC. Anticancer activity of biflorin on gastric cancer cell line. Available from: http://www.10igcc.com. [Cited in This Article: ] |
79. | Vasconcellos MC, Bezerra DP, Fonseca AM, Araújo AJ, Pessoa C, Lemos TL, Costa-Lotufo LV, de Moraes MO, Montenegro RC. The in-vitro and in-vivo inhibitory activity of biflorin in melanoma. Melanoma Res. 2011;21:106-114. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 13] [Cited by in F6Publishing: 12] [Article Influence: 0.9] [Reference Citation Analysis (0)] |
80. | Vasconcellos MC, Bezerra DP, Fonseca AM, Pereira MR, Lemos TL, Pessoa OD, Pessoa C, Moraes MO, Alves AP, Costa-Lotufo LV. Antitumor activity of biflorin, an o-naphthoquinone isolated from Capraria biflora. Biol Pharm Bull. 2007;30:1416-1421. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 20] [Cited by in F6Publishing: 20] [Article Influence: 1.2] [Reference Citation Analysis (0)] |