Recent advancements in cancer research have led to major breakthroughs; however, the impact on overall cancer-related death rate remains unacceptable. Thus, further insights into tumor markers and subsequent development of targeted therapies are urgently needed. For decades the urokinase plasminogen activator (uPA) system has been thought to drive tumor progression by mediating directed extracellular proteolysis on the surface of migrating or invading cells. Intervention with this proteolysis by targeting of uPA receptor (uPAR) has been proposed to represent a novel approach for inhibiting tumor progression. Recent data have provided new insights into the role of uPAR in gastric cancer progression. In addition to mediating proteolysis, this receptor also appears to mediate cell signaling, proliferation, and survival, and these observations have revealed novel ways to target uPAR. In this review, we discuss uPAR expression in gastric cancer, the relationship between uPAR and Helicobacter pylori, and recent insights into uPAR-signaling mechanisms. The role of uPAR as a cancer target in gastric cancer is also summarized.
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References
1.
FerlayJ, ShinHR, BrayFet al.Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 2010; 127:2893.
2.
JonesPA, De ClerckYA. Extracellular matrix destruction by invasive tumor cells. Cancer Metastasis Rev, 1982; 1:289.
3.
DanoK, AndreasenPA, Grondahl-HansenJet al.Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res, 1985; 44:139.
4.
MignattiP, RifkinDB. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev, 1993; 73:161.
5.
Van RoyF, MareelM. Tumour invasion: Effects of cell adhesion and motility. Trends Cell Biol, 1992; 2:163.
6.
BinderBR, MihalyJ, PragerGW. uPAR-uPA-PAI-1 interactions and signaling: A vascular biologist's view. Thromb Haemost, 2007; 97:336.
7.
HildenbrandR, GandhariM, StroebelPet al.The urokinase-system—role of cell proliferation and apoptosis. Histol Histopathol, 2008; 23:227.
8.
SideniusN, BlasiF. The urokinase plasminogen activator system in cancer: Recent advances and implication for prognosis and therapy. Cancer Metastasis Rev, 2003; 22:205.
9.
PetersenLC, LundLR, NielsenLSet al.One-chain urokinase-type plasminogen activator from human sarcoma cells is a proenzyme with little or no intrinsic activity. J Biol Chem, 1988; 263:11189.
10.
WaltzDA, FujitaRM, YangXet al.Nonproteolytic role for the urokinase receptor in cellular migration in vivo. Am J Respir Cell Mol Biol, 2000; 22:316.
11.
TestaJE, QuigleyJP. The role of urokinase-type plasminogen activator in aggressive tumor cell behavior. Cancer Metastasis Rev, 1990; 9:353.
12.
DassK, AhmadA, AzmiASet al.Evolving role of uPA/uPAR system in human cancers. Cancer Treatment Rev, 2008; 34:122.
13.
IllemannM, BirdN, MajeedAet al.Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases. Int J Cancer, 2009; 124:1860.
14.
LindbergP, LarssonA, NielsenBS. Expression of plasminogen activator inhibitor-1, urokinase receptor and laminin gamma-2 chain is an early coordinated event in incipient oral squamous cell carcinoma. Int J Cancer, 2006; 118:2948.
15.
MigitaT, SatoE, SaitoKet al.Differing expression of MMPs-1 and −9 and urokinase receptor between diffuse- and intestinal-type gastric carcinoma. Int J Cancer, 1999; 84:74.
16.
NielsenBS, RankF, IllemannMet al.Stromal cells associated with early invasive foci in human mammary ductal carcinoma in situ coexpress urokinase and urokinase receptor. Int J Cancer, 2007; 120:2086.
17.
RomerJ, NielsenBS, PlougM. The urokinase receptor as a potential target in cancer therapy. Curr Pharmaceut Des, 2004; 10:2359.
18.
ZhangL, ZhaoZS, RuGQet al.Correlative studies on uPA mRNA and uPAR mRNA expression with vascular endothelial growth factor, microvessel density, progression and survival time of patients with gastric cancer. World J Gastroenterol, 2006; 12:3970.
19.
CarrieroMV, FrancoP, Del VecchioSet al.Tissue distribution of soluble and receptor-bound urokinase in human breast cancer using a panel of monoclonal antibodies. Cancer Res, 1994; 54:5445.
ChoiYK, YoonBI, KookYHet al.Overexpression of urokinase-type plasminogen activator in human gastric cancer cell line (AGS) induces tumorigenicity in severe combined immunodeficient mice. Jpn J Cancer Res, 2002; 93:151.
22.
BeyerBC, HeissMM, SimonEHet al.Urokinase system expression in gastric carcinoma: Prognostic impact in an independent patient series and first evidence of predictive value in preoperative biopsy and intestinal metaplasia specimens. Cancer, 2006; 106:1026.
23.
KanekoT, KonnoH, BabaMet al.Urokinase-type plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer. Cancer Sci, 2003; 94:43.
24.
ZhaoW, WangX, QuBet al.Clinical significance of plasma tissue factor pathway and urokinase-type plasminogen activator system in cancer patients. Chin Med J (Engl), 2002; 115:702.
25.
KitaY, FukagawaT, MimoriKet al.Expression of uPAR mRNA in peripheral blood is a favourite marker for metastasis in gastric cancer cases. Br J Cancer, 2009; 100:153.
26.
AsakaM, KatoM, GrahamDY. Prevention of gastric cancer by Helicobacter pylori eradication. Int Med, 2009; 49:633.
27.
GrahamDY, ShiotaniA. The time to eradicate gastric cancer is now. Gut, 2005; 54:735.
28.
RuggeM, CassaroM, LeoGet al.Helicobacter pylori and gastric cancer: Both primary and secondary preventive measures are required. Arch Int Med, 1999; 159:2483.
29.
SipponenP, GrahamDY. Importance of atrophic gastritis in diagnostics and prevention of gastric cancer: Application of plasma biomarkers. Scand J Gastroenterol, 2007; 42:2.
IwamotoJ, MizokamiY, TakahashiKet al.Expressions of urokinase-type plasminogen activator, its receptor and plasminogen activator inhibitor-1 in gastric cancer cells and effects of Helicobacter pylori. Scand J Gastroenterol, 2005; 40:783.
32.
KimMH, YooHS, ChangHJet al.Urokinase plasminogen activator receptor is upregulated by Helicobacter pylori in human gastric cancer AGS cells via ERK, JNK, and AP-1. Biochem Biophys Res Commun, 2005; 333:874.
33.
YamaokaY, KatoM, AsakaM. Geographic differences in gastric cancer incidence can be explained by differences between Helicobacter pylori strains. Int Med, 2008; 47:1077.
34.
HoughtonJ, WangTC. Helicobacter pylori and gastric cancer: A new paradigm for inflammation-associated epithelial cancers. Gastroenterology, 2005; 128:1567.
35.
FutagamiS, HiratsukaT, TatsuguchiAet al.Monocyte chemoattractant protein 1 (MCP-1) released from Helicobacter pylori stimulated gastric epithelial cells induces cyclooxygenase 2 expression and activation in T cells. Gut, 2003; 52:1257.
36.
KitadaiY, SasakiA, ItoMet al.Helicobacter pylori infection influences expression of genes related to angiogenesis and invasion in human gastric carcinoma cells. Biochem Biophys Res Commun, 2003; 311:809.
37.
GoozM, GoozP, SmolkaAJ. Epithelial and bacterial metalloproteinases and their inhibitors in H. pylori infection of human gastric cells. Am J Physiol Gastrointest Liver Physiol, 2001; 281:G823.
38.
Alpizar-AlpizarW, NielsenBS, SierraRet al.Urokinase plasminogen activator receptor is expressed in invasive cells in gastric carcinomas from high- and low-risk countries. Int J Cancer, 2010; 126:405.
39.
KennyS, DuvalC, SammutSJet al.Increased expression of the urokinase plasminogen activator system by Helicobacter pylori in gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol, 2008; 295:G431.
40.
KimMH, YooHS, KimMYet al.Helicobacter pylori stimulates urokinase plasminogen activator receptor expression and cell invasiveness through reactive oxygen species and NF-kappaB signaling in human gastric carcinoma cells. Int J Mol Med, 2007; 19:689.
41.
IwamotoJ, MizokamiY, TakahashiKet al.The effects of cyclooxygenase2-prostaglandinE2 pathway on Helicobacter pylori-induced urokinase-type plasminogen activator system in the gastric cancer cells. Helicobacter, 2008; 13:174.
42.
BeneMC, CastoldiG, KnappWet al.CD87 (urokinase-type plasminogen activator receptor), function and pathology in hematological disorders: A review. Leukemia, 2004; 18:394.
43.
JacobsenB, PlougM. The urokinase receptor and its structural homologue C4.4A in human cancer: Expression, prognosis and pharmacological inhibition. Curr Med Chem, 2008; 15:2559.
44.
RaschMG, LundIK, AlmasiCEet al.Intact and cleaved uPAR forms: Diagnostic and prognostic value in cancer. Front Biosci, 2008; 13:6752.
45.
MazarAP. Urokinase plasminogen activator receptor choreographs multiple ligand interactions: Implications for tumor progression and therapy. Clin Cancer Res, 2008; 14:5649.
46.
YamadaA, SaitoN, KameokaSet al.Clinical significance of epidermal growth factor (EGF) expression in gastric cancer. Hepatogastroenterology, 2007; 54:1049.
47.
BaekMK, KimMH, JangHJet al.EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-kappaB signaling in human gastric carcinoma cells. Oncol Rep, 2008; 20:1569.
48.
WangY, DangJ, JohnsonLKet al.Structure of the human urokinase receptor gene and its similarity to CD59 and the Ly-6 family. Eur J Biochem, 1995; 227:116.
49.
CampER, YangA, GrayMJet al.Tyrosine kinase receptor RON in human pancreatic cancer: Expression, function, and validation as a target. Cancer, 2007; 109:1030.
50.
ThangasamyA, RoggeJ, AmmanamanchiS. Recepteur d'origine nantais tyrosine kinase is a direct target of hypoxia-inducible factor-1alpha-mediated invasion of breast carcinoma cells. J Biol Chem, 2009; 284:14001.
51.
ZhangK, ZhouYQ, YaoHPet al.Alterations in a defined extracellular region of the RON receptor tyrosine kinase promote RON-mediated motile and invasive phenotypes in epithelial cells. Int J Oncol, 2010; 36:255.
52.
ZhouD, PanG, ZhengCet al.Expression of the RON receptor tyrosine kinase and its association with gastric carcinoma versus normal gastric tissues. BMC Cancer, 2008; 8:353.
53.
ParkJS, ParkJH, KhoiPNet al.MSP-induced RON activation upregulates uPAR expression and cell invasiveness via MAPK, AP-1 and NF-kappaB signals in gastric cancer cells. Carcinogenesis, 2011; 32:175.
54.
BootcovMR, BauskinAR, ValenzuelaSMet al.MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A, 1997; 94:11514.
55.
FairlieWD, MooreAG, BauskinARet al.MIC-1 is a novel TGF-beta superfamily cytokine associated with macrophage activation. J Leuk Biol, 1999; 65:2.
56.
BuckhaultsP, RagoC, St CroixBet al.Secreted and cell surface genes expressed in benign and malignant colorectal tumors. Cancer Res, 2001; 61:6996.
57.
KaranD, KellyDL, RizzinoAet al.Expression profile of differentially-regulated genes during progression of androgen-independent growth in human prostate cancer cells. Carcinogenesis, 2002; 23:967.
58.
WelshJB, SapinosoLM, SuAIet al.Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res, 2001; 61:5974.
59.
LeeDH, YangY, LeeSJet al.Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system. Cancer Res, 2003; 63:4648.
60.
LeeKH, ChoiEY, HyunMSet al.Hepatocyte growth factor/c-met signaling in regulating urokinase plasminogen activator in human stomach cancer: A potential therapeutic target for human stomach cancer. Korean J Intern Med, 2006; 21:20.
61.
AokiJ, TairaA, TakanezawaYet al.Serum lysophosphatidic acid is produced through diverse phospholipase pathways. J Biol Chem, 2002; 277:48737.
62.
van LeeuwenFN, GiepmansBN, van MeeterenLAet al.Lysophosphatidic acid: Mitogen and motility factor. Biochem Soc Transact, 2003; 31:1209.
63.
KimMH, ParkJS, ChangHJet al.Lysophosphatidic acid promotes cell invasion by up-regulating the urokinase-type plasminogen activator receptor in human gastric cancer cells. J Cell Biochem, 2008; 104:1102.
64.
KunigalS, LakkaSS, GondiCSet al.RNAi-mediated downregulation of urokinase plasminogen activator receptor and matrix metalloprotease-9 in human breast cancer cells results in decreased tumor invasion, angiogenesis and growth. Int J Cancer, 2007; 121:2307.
65.
LeakeD, DoerrTD, ScottG. Expression of urokinase-type plasminogen activator and its receptor in keloids. Arch Otolaryngol Head Neck Surg, 2003; 129:1334.
66.
ShushakovaN, TkachukN, DangersMet al.Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor. J Cell Sci, 2005; 118:2743.
67.
ZhangG, KimH, CaiXet al.Urokinase receptor deficiency accelerates renal fibrosis in obstructive nephropathy. J Am Soc Nephrol, 2003; 14:1254.
