• Drug target
• Fibrinolytic system
• Plasminogen activator inhibitor 1
• Prognostic value
• Regulatory mechanism

• Humans
• Plasminogen Activator Inhibitor 1/genetics
• Plasminogen Activator Inhibitor 1/metabolism
• Urokinase-Type Plasminogen Activator/chemistry
• Urokinase-Type Plasminogen Activator/genetics
• Urokinase-Type Plasminogen Activator/metabolism
• Gastrointestinal Neoplasms
• Digestive System Neoplasms/genetics
• Inflammation

Gastric cancer (GC) is the most common gastrointestinal malignant tumor, and distant metastasis is a critical factor in the prognosis of patients with GC. Understanding the mechanism of GC metastasis will help improve patient prognosis. Studies have confirmed that urokinase-type plasminogen activator receptor (PLAUR) promotes GC metastasis; however, its relationship with anoikis resistance and associated mechanisms remains unclear. In this study, we demonstrated that PLAUR promotes the anoikis resistance and metastasis of GC cells and identified transcription Factor 7 Like 2 (TCF7L2) as an important transcriptional regulator of PLAUR. We also revealed that TCF7L2 is highly expressed in GC and promotes the anoikis resistance and metastasis of GC cells. Moreover, we found that TCF7L2 transcription activates PLAUR. Finally, we confirmed that TCF7L2 is an independent risk factor for poor prognosis of patients with GC. Our results show that TCF7L2 and PLAUR are candidate targets for developing therapeutic strategies for GC metastasis.

• anoikis
• gastric cancer
• transcription
• transcription Factor 7 Like 2
• urokinase-type plasminogen activator receptor

• Gene therapy technologies
• Monoclonal antibody therapy
• Nanoparticles (NPs)
• Oncolytic virotherapy
• Photodynamic therapy (PDT)/photothermal therapy (PTT)
• Tumour immunotherapy
• Urokinase-type plasminogen activator receptor (uPAR)

Patients with gastric and oesophageal adenocarcinomas (GOCs) have short life expectancies as their tumours spread to other sites early. This is facilitated by the increased expression of the urokinase plasminogen activation system (uPAS); a feature of the majority of GOCs. There is increasing appreciation of the importance of uPAS expression in a range of cell types within the tumour microenvironment. Abundant clinical evidence indicates that altered expression of uPAS proteins is associated with worse outcomes, including time to tumour recurrence and patient survival. Emerging technologies, including liquid biopsy, suggest a role of uPAS for the detection of circulating tumour cells, which are responsible for the dissemination of cancers. We review and summarise pre-clinical and clinical data that supports the use of uPAS as a biomarker in GOC.

Gastric and oesophageal cancers (GOCs) are lethal cancers which metastasise early and recur frequently, even after definitive surgery. The urokinase plasminogen activator system (uPAS) is strongly implicated in the invasion and metastasis of many aggressive tumours including GOCs. Urokinase plasminogen activator (uPA) interaction with its receptor, urokinase plasminogen activator receptor (uPAR), leads to proteolytic activation of plasminogen to plasmin, a broad-spectrum protease which enables tumour cell invasion and dissemination to distant sites. uPA, uPAR and the plasminogen activator inhibitor type 1 (PAI-1) are overexpressed in some GOCs. Accumulating evidence points to a causal role of activated receptor tyrosine kinase pathways enhancing uPAS expression in GOCs. Expression of these components are associated with poorer clinicopathological features and patient survival. Stromal cells, including tumour-associated macrophages and myofibroblasts, also express the key uPAS proteins, supporting the argument of stromal involvement in GOC progression and adverse effect on patient survival. uPAS proteins can be detected on circulating leucocytes, circulating tumour cells and within the serum; all have the potential to be developed into circulating biomarkers of GOC. Herein, we review the experimental and clinical evidence supporting uPAS expression as clinical biomarker in GOC, with the goal of developing targeted therapeutics against the uPAS.

• biomarkers
• circulating tumour cell (CTC)
• gastric cancer
• oesophageal cancer
• plasminogen activator inhibitor type 1 (PAI-1)
• serine proteases
• serpins
• tumour microenvironment
• urokinase plasminogen activator (uPA)
• urokinase plasminogen activator receptor (uPAR)

• Angiogenesis
• Gastric cancer
• Gene
• Prognostic

Helicobacter pylori (H. pylori) infection is a well-established risk factor for the development of gastric cancer (GC), one of the most common and deadliest neoplasms worldwide. H. pylori infection induces chronic inflammation in the gastric mucosa that, in the absence of treatment, may progress through a series of steps to GC. GC is only one of several clinical outcomes associated with this bacterial infection, which may be at least partially attributed to the high genetic variability of H. pylori. The biological mechanisms underlying how and under what circumstances H. pylori alters normal physiological processes remain enigmatic. A key aspect of carcinogenesis is the acquisition of traits that equip preneoplastic cells with the ability to invade. Accumulating evidence implicates H. pylori in the manipulation of cellular and molecular programs that are crucial for conferring cells with invasive capabilities. We present here an overview of the main findings about the involvement of H. pylori in the acquisition of cell invasive behavior, specifically focusing on the epithelial-to-mesenchymal transition, changes in cell polarity, and deregulation of molecules that control extracellular matrix remodeling.

• Helicobacter pylori
• Plasminogen activation system
• Invasion
• Epithelial-to-mesenchymal transition
• Cell polarity
• Gastric carcinogenesis

• ATN-658
• PAI-2
• cancer imaging
• metastasis
• plasminogen activator inhibitor-1
• plasminogen activator system
• uPA
• urokinase-type plasminogen activator receptor

The urokinase plasminogen activation (uPA) system is a crucial pathway for tumour invasion and establishment of metastasis. Although there is good evidence that uPA system expression is a clinically relevant biomarker in some solid tumours, its role in gastroesophageal cancer is uncertain.

We identified 22 studies encompassing 1966 patients which fulfilled the inclusion criteria. uPA, uPAR, or PAI-1 expression is significantly associated with high risk clinicopathological features. High uPA expression is associated with a shorter RFS (HR 1.90 95% 1.16–3.11, p = 0.01) and OS (HR 2.21 95% CI 1.74–2.80, p < 0.0001). High uPAR expression is associated with poorer OS (HR 2.21 95%CI 1.82–2.69, p < 0.0001). High PAI-1 expression is associated with shorter RFS (HR 1.96 96% CI 1.07–3.58, p = 0.03) and OS (HR 1.84 95%CI 1.28–2.64, p < 0.0001). There was no significant association between PAI-2 expression and OS (HR 0.97 95%CI 0.48–1.94, p < 0.92) although data was limited.

We undertook a systematic review evaluating expression of uPA, urokinase plasminogen activator receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1/SerpinE1) and plasminogen activator inhibitor-2 (PAI-2/SerpinB2) on primary oesophageal, gastro-oesophageal junction, and gastric adenocarcinomas. We performed a meta-analysis of clinicopathological associations, overall survival (OS) and recurrence free survival (RFS).

We conclude that the uPA system is a clinically relevant biomarker in primary gastroesophageal cancer, with higher expression of uPA, uPAR and PAI-1 associated with higher risk disease and poorer prognosis. This also highlights the potential utility of the uPA system as a therapeutic target for improved treatment strategies.

• gastrointestinal neoplasms
• stomach neoplasms
• urokinase plasminogen activator
• urokinase-type plasminogen activator

• Gastric mucosa
• Gastric proton pump
• Gastrin
• Plasminogen activator inhibitor-1

• Animals
• Enterochromaffin-like Cells/enzymology
• Enterochromaffin-like Cells/pathology
• Female
• Gastric Mucosa/enzymology
• Gastric Mucosa/pathology
• Gastrins/blood
• H(+)-K(+)-Exchanging ATPase/genetics
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Pyloric Antrum/enzymology
• Pyloric Antrum/pathology
• Serpin E2/genetics
• Serpin E2/metabolism

Cell surface-associated proteolysis mediated by plasmin (PLA) is an essential feature of wound healing, angiogenesis and cell invasion, processes that are dysregulated in cancer development, progression and systemic spread. The generation of PLA, initiated by the binding of its precursor plasminogen (PLG) to the cell surface, is regulated by an array of activators, inhibitors and receptors. In this review, we will highlight the importance of the best-characterized components of the PLG/PLA cascade in the pathogenesis of cancer focusing on the role of the cell surface-PLG receptors (PLG-R). PLG-R overexpression has been associated with poor prognosis of cancer patients and resistance to chemotherapy. We will also discuss recent findings on the molecular mechanisms regulating cell surface expression and distribution of PLG-R.

Tumor invasion and metastasis is a highly complicated, multi-step phenomenon. In the complex event of tumor progression, tumor cells interact with basement membrane and extracellular matrix components. Proteolytic enzymes (proteinases) are involved in the degradation of extracellular matrix, but also in cancer invasion and metastasis. The four categories of proteinases (cysteine-, serine-, aspartic-, and metalloproteinases) are named and classified according to the essential catalytic component in their active site. We and others have shown that proteolytic enzymes play a major role not only in colorectal cancer (CRC) invasion and metastasis, but also in malignant transformation of precancerous lesions into cancer. Tissue and serum-plasma antigen concentrations of proteinases might be of great value in identifying patients with poor prognosis in CRC. Our results, in concordance with others indicate the potential tumor marker impact of proteinases for the early diagnosis of CRC. In addition, proteinases may also serve as potential target molecules for therapeutic agents.

• Proteinase
• Cathepsin
• Plasminogen activator
• Matrix metalloproteinase
• Colorectal cancer
• Adenoma
• Invasion
• Metastasis
• Biomarker
• Prognosis

• Animals
• Antineoplastic Agents/therapeutic use
• Basement Membrane/metabolism
• Biomarkers, Tumor/metabolism
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/enzymology
• Colorectal Neoplasms/pathology
• Disease Progression
• Drug Design
• Extracellular Matrix/metabolism
• Humans
• Molecular Targeted Therapy
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Peptide Hydrolases/metabolism
• Protease Inhibitors/therapeutic use

• pancreatic cancer
• reverse-phase protein arrays
• proteomic profiling
• biomarkers

• cancer
• invasion
• metastasis
• prognosis
• urokinase

• Disease Progression
• Humans
• Neoplasms/classification
• Neoplasms/enzymology
• Neoplasms/physiopathology
• Urokinase-Type Plasminogen Activator/chemistry
• Urokinase-Type Plasminogen Activator/metabolism

• Gastric adenocarcinoma
• Krűppel-like factor 8
• survival

Elevated level of urokinase receptor (uPAR) is detected in various aggressive cancer types and is closely associated with poor prognosis of cancers. Binding of uPA to uPAR triggers the conversion of plasminogen to plasmin and the subsequent activation of metalloproteinases. These events confer tumor cells with the capability to degrade the components of the surrounding extracellular matrix, thus contributing to tumor cell invasion and metastasis. uPA-uPAR interaction also elicits signals that stimulate cell proliferation/survival and the expression of tumor-promoting genes, thus assisting tumor development. In addition to its interaction with uPA, uPAR also interacts with vitronectin and this interaction promotes cancer metastasis by activating Rac and stimulating cell migration. Although underlying mechanisms are yet to be fully elucidated, uPAR has been shown to facilitate epithelial-mesenchymal transition (EMT) and induce cancer stem cell-like properties in breast cancer cells. The fact that uPAR lacks intracellular domain suggests that its signaling must be mediated through its co-receptors. Indeed, uPAR interacts with diverse transmembrane proteins including integrins, ENDO180, G protein-coupled receptors and growth factor receptors in cancer cells and these interactions are proven to be critical for the role of uPAR in tumorigenesis. Inhibitory peptide that prevents uPA-uPAR interaction has shown the promise to prolong patients' survival in the early stage of clinical trial. The importance of uPAR's co-receptor in uPAR's tumor-promoting effects implicate that anti-cancer therapeutic agents may also be developed by disrupting the interactions between uPAR and its functional partners.

• uPA
• uPAR
• urokinase receptor

• aspirin
• gastric lesion
• hemostasis
• nonsteroidal anti-inflammatory drugs
• stomach

• ARNTL Transcription Factors/analysis
• ARNTL Transcription Factors/genetics
• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor/analysis
• Cell Line, Tumor
• Colorectal Neoplasms/chemistry
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/mortality
• Colorectal Neoplasms/pathology
• Female
• Humans
• Lymphatic Metastasis
• Male
• Microsatellite Instability
• Middle Aged
• Neoplasm Grading
• Neoplasm Invasiveness
• Neoplasm Staging
• Plasminogen Activator Inhibitor 1/analysis
• Plasminogen Activator Inhibitor 1/blood
• Plasminogen Activator Inhibitor 1/genetics
• Predictive Value of Tests
• RNA, Messenger/analysis
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Analysis

• urokinase plasminogen activator
• enterochromaffin-like cells
• gastric neuroendocrine tumor
• migration
• invasion

Gastric cancer is one of the leading causes of cancer-related deaths worldwide, although the incidence has gradually decreased in many Western countries. Two main gastric cancer histotypes, intestinal and diffuse, are recognised. Although most of the described genetic alterations have been observed in both types, different genetic pathways have been hypothesized. Genetic and epigenetic events, including 1q loss of heterozygosity (LOH), microsatellite instability and hypermethylation, have mostly been reported in intestinal-type gastric carcinoma and its precursor lesions, whereas 17p LOH, mutation or loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer. In this review, we summarize the sometimes contradictory findings regarding those markers which influence the progression of gastric adenocarcinoma.

• Gastric cancer
• Gene alterations
• Prognosis
• Molecular pathology

• enzastaurin
• u-par
• rassf1
• fhit
• invasion and metastasis

• Blotting, Western
• Carcinoma, Non-Small-Cell Lung/pathology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Electrophoretic Mobility Shift Assay
• Enzyme-Linked Immunosorbent Assay
• Gene Knockdown Techniques
• Humans
• Indoles/pharmacology
• Lung Neoplasms/pathology
• Neoplasm Invasiveness/prevention & control
• Neoplasm Metastasis/prevention & control
• Nucleic Acid Hybridization
• Reverse Transcriptase Polymerase Chain Reaction

• Animals
• Antibodies, Monoclonal/pharmacology
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents/pharmacology
• Biomarkers, Tumor/biosynthesis
• Biomarkers, Tumor/genetics
• Cadherins/biosynthesis
• Cadherins/genetics
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/pathology
• Cetuximab
• Chick Embryo
• Epidermal Growth Factor/antagonists & inhibitors
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/metabolism
• Gene Expression
• Humans
• JNK Mitogen-Activated Protein Kinases/metabolism
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• MAP Kinase Signaling System
• Neoplasm Metastasis
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-jun/metabolism
• Receptors, Urokinase Plasminogen Activator/biosynthesis
• Receptors, Urokinase Plasminogen Activator/genetics

• K08 CA118730 NCI NIH HHS
• K08 CA118730-04 NCI NIH HHS

• gastric cancer
• primary gastric epithelial cells
• cage
• hb-egf

• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Adenocarcinoma/surgery
• Adenoma/metabolism
• Adenoma/pathology
• Adenoma/surgery
• Apoptosis Regulatory Proteins/metabolism
• Biomarkers, Tumor/metabolism
• Colon/metabolism
• Colon/pathology
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/surgery
• Humans
• Neoplasm Recurrence, Local/metabolism
• Neoplasm Recurrence, Local/pathology
• Neoplasm Staging
• Phosphorylation
• Prognosis
• Prospective Studies
• Proto-Oncogene Proteins c-akt/metabolism
• RNA-Binding Proteins/metabolism
• Rectum/metabolism
• Rectum/pathology
• Survival Rate

The prognosis of pancreatic adenocarcinoma is affected by early metastases and local tumour invasion beyond surgical margins. Gene expression profiling in pancreatic cancer tissue is complicated due to the high amount of RNAses being present in human tissue and that of suitable models. In order to demonstrate early metastases, the models should take into account the anatomical environment of the tumour. Using the orthotopic transplantation of pancreatic tumour cells in SCID (severe combined immunodeficiency) mice, these interactions are taken into consideration. In order to identify genes associated with local tumour invasion and metastases in ductal pancreatic cancer, we investigated a human pancreatic tumour cell line derived from an orthopic pancreatic tumour model in SCID mice. Differential gene expression was performed on the basis of microarray technique. The human MiaPaca-2 cell line was implanted orthotopically in SCID mice. Transcriptional profiling was performed on fresh frozen tissue derived from the primary tumour, the tumour invasion front and the liver metastases. Differentially expressed genes were identified using statistical analyses, and were validated with external databases and with immunohistochemistry. A total of 1066 of 14 500 genes were significantly differentially expressed. Comparing the primary tumour with the tumour invasion front, there were 614 statistically significant up- and 348 downregulated genes. Twenty-five statistically significant up- and 181 downregulated genes were identified comparing the liver metastases with the primary tumour. Eight genes (PAI-1, BNIP3l, VEGF, NSE, RGS4, HSP27, GADD45A, PTPN14) were chosen and validated in a semi-quantitative immunohistochemical analysis, which revealed a positive correlation to the array data. Overrepresentation analyses revealed a total of 66 significantly regulated pathways associated with cell proliferation, cell stress, cell communication metabolic and cytokine function. In conclusion, model marker genes for local invasion and liver metastases can be identified using transcriptional profiling in the SCID mouse. Overrepresentation analysis secures a good and fast overview about the significantly regulated genes and can assign genes to certain pathways. These marker genes can be related to the apoptotic cascade, angiogenesis and cell interaction.

• Animals
• Apoptosis
• Biomarkers
• Biomarkers, Tumor
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoxia
• Hypoxia-Inducible Factor 1/metabolism
• Models, Biological
• Neoplasms/diagnosis
• Neoplasms/metabolism
• Neoplasms/pathology
• Neovascularization, Pathologic
• Prognosis
• Treatment Outcome

• CA40355 NCI NIH HHS
• CA42745 NCI NIH HHS

AIM: To investigate the expression of morphogene Sonic hedgehog (Shh), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) in gastric epithelium of mongolian gerbils after H pylori inoculation and their correlations with the pathologic changes of Helicobacter pylori related gastritis.

METHODS: A total of 50 male mongolian gerbils were inoculated with H pylori and another 50 gerbils served as controls. The levels of Shh, IL-1β and TNF-α mRNA expression were detected by reverse transcription-polymerase chain reaction (RT-PCR), and the level of Shh protein expression was examined by immunohistochemistry 4, 12, 24, 36 and 48 weeks after inoculation.

RESULTS: As compared with those in the controls, both the expression levels of Shh mRNA and protein were decreased significantly at the 36^th (t = 3.24, P < 0.05; Z = 4.84, P < 0.001) and 48^th week (t = 3.01, P < 0.05; Z = 4.65, P < 0.001) after H pylori inoculation. Furthermore, the level of Shh mRNA expression was negatively correlated with the expression of IL-1β mRNA, TNF-α mRNA and the grade of gastritis, respectively (r = -0.372, P < 0.01; r = -0.301, P < 0.05; r = -0.397, P < 0.001). Similarly, the level of Shh protein expression was negatively correlated with the expression of IL-1β mRNA, TNF-α mRNA and the grade of gastritis (r = -0.321, P < 0.05; r = -0.313, P < 0.05; r = -0.371, P < 0.001) respectively.

CONCLUSION: After H pylori infection, the expression of IL-1β and TNF-α is increased and positively correlated with the grade of gastritis, and while the expression of Shh is decreased and negatively correlated with the expression of IL-1β, TNF-α and gastritis grades.

• Helicobacter pylori
• Sonic hedgehog
• Interleukin-1β
• Tumor necrosis factor-a
• Atrophic gastritis

• Animals
• Helicobacter Infections/complications
• Helicobacter Infections/microbiology
• Helicobacter pylori/pathogenicity
• Humans
• Risk Factors
• Stomach Neoplasms/etiology

• Wellcome Trust