Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2001 May;92(5):516–523. doi: 10.1111/j.1349-7006.2001.tb01124.x

Urokinase Receptor and Vascular Endothelial Growth Factor Are Synergistically Associated with the Liver Metastasis of Colorectal Cancer

Hiroyuki Konno 1,✉, Jinro Abe 1, Takeshi Kaneko 1, Megumi Baba 1, Atsushi Shoji 1, Kenichi Sunayama 1, Kinji Kamiya 1, Tatsuo Tanaka 1, Shohachi Suzuki 1, Satoshi Nakamura 1, Tetsumei Urano 2
PMCID: PMC5926736  PMID: 11376560

Abstract

Considering recent findings that the urokinase plasniinogen activation (PA) system is involved in invasion and vascular endothelial growth factor (VEGF) is involved in angiogenesis of colorectal cancer, we evaluated these factors in the liver metastasis of primary colorectal cancer. Cancer tissues from 71 colorectal cancer patients were assayed quantitatively for antigen levels of urokinase type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor‐1 and ‐2 (PAI‐1, PAI‐2), and were also assayed immunohistochemically for expression of VEGF protein. Among the PA system factors, both the levels of uPAR and PAI‐1 were significantly higher in larger tumors than in smaller ones, and were also significantly higher in tumors that invaded subserosa, serosa or adjacent organs than in mucosal, submucosal tumors or in tumors that invaded the muscle layer. The uPAR levels were significantly higher in tumors with liver metastasis than in those without. VEGF overexpression was significantly more frequent in tumors with lymph node involvement or liver metastasis than in those without. Among the PA system factors, the uPAR levels were significantly higher in tumors with VEGF overexpression and a multivariate analysis revealed that high uPA level and VEGF overexpression were independent risk factors for liver metastasis. The combination of high uPAR level and overexpression of VEGF was associated with the worst prognosis in patients with colorectal cancer. These results suggest that uPAR and VEGF might contribute Synergistically to the liver metastasis of colorectal cancer.

Keywords: Urokinase‐type plasminogen activator (uPA), uPA receptor (uPAR), Plasminogen activator inhibitor type 1 (PAI‐1), Vascular endothelial growth factor (VEGF), Microvessel density (MVD)

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Reference

  • 1.Dano , K. , Andreasen , P. A. , Grondahl , H. J. , Kristensen , P. , Nielsen , L. S. and Skriver , L.Plasminogen activators, tissue degradation, and cancer . Adv. Cancer Res. , 44 , 139 – 266 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 2.Blasi , F. , Vassalli , J. D. and Dano , K.Urokinase‐type plasminogen activator: proenzyme, receptor, and inhibitors . J. Cell Biol , 104 , 801 – 804 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Andreasen , P. A. , Kjoller , L. , Christensen , L. and Duffy , M. J.The urokinase‐type plasminogen activator system in cancer metastasis: a review . Int. J. Cancer , 72 , 1 – 22 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 4.Folkman , J.Anti‐angiogenesis: new concept for therapy of solid tumor . Ann. Surg. , 175 , 409 – 416 ( 1972. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Folkman , J.Tumor angiogenesis . Adv. Cancer Res. , 43 , 175 – 203 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 6.Keck , P. J. , Hauser , S. D. , Krivi , G. , Sanzo , K. , Warren , T. , Feder , J. and Connolly , D. T.Vascular permeability factor, an endothelial cell mitogen related to PDGF . Science , 246 , 1309 – 1312 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 7.Leung , D. W. , Cachianes , G. , Kuang , W. J. , Goeddel , D. V. and Ferrara , N.Vascular endothelial growth factor is a secreted angiogenic mitogen . Science , 246 , 1306 – 1309 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 8.Liotta , L. A. , Steeg , P. S. and Stetler‐Stevenson , W. G.Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation . Cell , 64 , 327 – 336 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 9.Duffy , M. J.The role of proteolytic enzymes in cancer invasion and metastasis . Clin. Exp. Metastasis , 10 , 145 – 155 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 10.Dano , K. , Behrendt , N. , Brunner , N. , Eliis , V. , Ploug , M. and Pyke , C.The urokinase receptor. Protein structure and role in plasminogen activation and cancer invasion . Fibrinolysis , 8 ( Suppl.l ), 189 – 203 ( 1994. ). [Google Scholar]
  • 11.Duffy , M. J. , Reilly , D. , O'Sullivan , C. , O'Higgins , N. , Fennelly , J. J. and Andreasen , P.Urokinase‐plasminogen activator, a new and independent prognostic marker in breast cancer . Cancer Res. , 50 , 6827 – 6829 ( 1990. ). [PubMed] [Google Scholar]
  • 12.Hasui , Y. , Marutsuka , K. , Suzumiya , J. , Kitada , S. , Osada , Y. and Sumiyoshi , A.The content of urokinase‐type plasminogen activator antigen as a prognostic factor in urinary bladder cancer . Int. J. Cancer , 50 , 871 – 874 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 13.Duffy , M. J. , Reilly , D. , McDermott , E. , O'Higgins , N. , Fennelly , J. J. and Andreasen , P. A.Urokinase plasminogen activator as a prognostic marker in different subgroups of patients with breast cancer . Cancer , 74 , 2276 – 2280 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 14.Mulcahy , H. E. , Duffy , M. J. , Gibbons , D. , McCarthy , P. , Parfrey , N. A. , O'Donoghue , D. P. and Sheahan , K.Urokinase‐type plasminogen activator and outcome in Dukes' B colorectal cancer . Lancet , 344 , 583 – 584 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 15.Pedersen , H. , Brunner , N. , Francis , D. , Osterlind , K. , Ronne , E. , Hansen , H. H. , Dano , K. and Grondahl‐Hansen , J.Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue . Cancer Res. , 54 , 4671 – 4675 ( 1994. ). [PubMed] [Google Scholar]
  • 16.Sprengers , E. D. and Kluft , C.Plasminogen activator inhibitors . Blood , 69 , 381 – 387 ( 1987. ). [PubMed] [Google Scholar]
  • 17.Chambers , S. K. , Ivins , C. M. and Carcangiu , M. L.Plasminogen activator inhibitor‐1 is an independent poor prognostic factor for survival in advanced stage epithelial ovarian cancer patients . Int. J. Cancer , 79 , 449 – 454 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 18.Deng , G. , Curriden , S. A. , Wang , S. , Rosenberg , S. and Loskutoff , D. J.Is plasminogen activator inhibitor‐1 the molecular switch that governs urokinase receptor‐mediated cell adhesion and release ? J. Cell Biol , 134 , 1563 – 1571 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Stefansson , S. and Lawrence , D. A.The serpin PAI‐1 inhibits cell migration by blocking integrin αVβ3 binding to vitronectin . Nature , 383 , 441 – 443 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 20.Berkman , R. A. , Merrill , M. J. and Reinhold , W. C.Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms . J. Clin. Invest. , 91 , 153 – 159 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Plate , K. H. , Breier , G. , Weich , H. A. and Risau , W.Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo . Nature (Lond.) , 359 , 845 – 848 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 22.Brown , L. F. , Berse , B. , Jackman , R. W. , Tognazzi , K. , Manseau , E. J. and Dvorak , H. F.Increased expression of vascular permeability factor and its receptors in kidney and bladder carcinoma . Am. J. Pathol. , 143 , 1255 – 1262 ( 1993. ). [PMC free article] [PubMed] [Google Scholar]
  • 23.Brown , L. F. , Berse , B. , Jackman , R. W. , Tognazzi , K. , Manseau , E. J. , Senger , D. R. and Dvorak , H. F.Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract . Cancer Res. , 53 , 4727 – 4735 ( 1993. ). [PubMed] [Google Scholar]
  • 24.Maeda , K. , Chung , Y. S. , Ogawa , Y. , Takatsuka , S. , Kang , S. M. , Ogawa , M. , Sawada , T. and Sowa , M.Prognostic value of vascular endothelial growth factor expression in gastric carcinoma . Cancer , 77 , 858 – 863 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 25.Chen , Z.‐Q. , Fisher , R. J. , Riggs , C. W. , Rhim , J. S. and Lautenberger , J. A.Inhibition of vascular endothelial growth factor‐induced endothelial cell migration by ETS1 antisense oligonucleotides . Cancer Res. , 57 , 2013 – 2019 ( 1997. ). [PubMed] [Google Scholar]
  • 26.de Vries , C. , Escobedo , J. A. , Ueno , H. , Houck , K. , Ferrara , N. and Williams , L. T.The fms‐like tyrosine kinase, a receptor for vascular endothelial growth factor . Science , 255 , 989 – 991 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 27.Terman , B. I. , Dougher‐Vermazen , M. , Carrion , M. E. , Dimitrov , D. , Armellino , D. C. , Gospodarowicz , D. and Bohlen , P.Identification of the KDR tyrosine kinase as a receptor for vascular endothelial growth factor . Biochem. Biophys. Res. Commum. , 187 , 1579 – 1586 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 28.Senger , D. R. , Galli , S. J. , Dvorak , A. M. , Perruzzi , C. A. , Harvey , V. S. and Dvorak , H. F.Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid . Science , 219 , 983 – 985 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 29.Gerber , H. P. , Dixit , V. and Ferrara , N.Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl‐2 and A1 in vascular endothelial cells . J. Biol. Chem. , 273 , 13313 – 13316 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 30.Gupta , K. , Kshirsagar , S. , Li , W. , Gui , L. , Ramakrishnan , S. , Gupta , P. , Law , P. Y. and Hebbel , R. P.VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling . Exp. Cell Res. , 247 , 495 – 504 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 31.Gabrilovich , B. D. , Ishida , T. , Oyama , T. , Ran , S. , Kravtsov , V. , Nadaf , S. and Carbone , D. P.Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo . Blood , 92 , 4150 – 4166 ( 1998. ). [PubMed] [Google Scholar]
  • 32.Min , H. Y. , Doyle , L. V. , Vitt , C. R. , Zandonella , C. L. , Stratton‐Thomas , J. R. , Shuman , M. A. and Rosenberg , S.Urokinase receptor antagonists inhibit angiogenesis and primary tumor growth in syngeneic mice . Cancer Res. , 56 , 2428 – 2433 ( 1996. ). [PubMed] [Google Scholar]
  • 33.Pepper , M. S. , Ferrara , N. , Orci , L. and Montesano , R.Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor‐1 in microvascular endothelial cells . Biochem. Biophys. Res. Commun. , 181 , 902 – 906 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 34.Mandriota , S. J. , Seghezzi , G. , Vassalli , J.‐D. , Ferrara , N. , Wasi , S. , Mazzieri , R. , Mignatti , P. and Pepper , M. S.Vascular endothelial growth factor increases urokinase receptor expression in vascular endothelial cells . J. Biol. Chem. , 270 , 9709 – 9716 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 35.Nakamura , S. , Suzuki , S. and Konno , H.Resection of hepatic metastasis of colorectal carcinoma: 20 year's experience . J. Hepatobiliary Panereat. Surg. , 6 , 16 – 22 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 36.Abe , J. , Urano , T. , Konno , H. , Erhan , Y. , Tanaka , T. , Nishino , N. , Takada , A. and Nakamura , S.Larger and more invasive colorectal carcinoma contains larger amounts of plasminogen activator inhibitor type 1 and its relative ratio over urokinase receptor correlates well with tumor size . Cancer , 86 , 2602 – 2611 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 37.Simon , D. L , Wei , Y. , Zhang , L. , Rao , N. K. , Xu , H. , Chen , Z. , Liu , Q. , Rosenberg , S. and Chapman , H. A.Identification of a urokinase receptor‐integrin interaction site. Promiscuous regulator of integrin function . J. Biol. Chem. , 275 , 10228 – 10234 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 38.Konno , H. , Baba , M. , Tanaka , T. , Kamiya , K. , Ota , M. , Oba , K. , Shoji , A. , Kaneko , T. and Nakamura , S.Overexpression of vascular endothelial growth factor is responsible for the hematogenous recurrence of early‐stage gastric carcinoma . Eur. Surg. Res. , 32 , 177 – 181 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 39.Takahashi , Y. , Kitadai , Y. , Bucana , C. D. , Cleary , K. R. and Ellis , L. M.Expression of vascular endothelial growth factor and its receptor (KDR) correlates with vascularity, metastasis, and proliferation of colon cancer . Cancer Res. , 55 , 3964 – 3968 ( 1995. ). [PubMed] [Google Scholar]
  • 40.Tomoda , M. , Maehara , Y. , Kakeji , Y. , Ohno , S. , Ichiyoshi , Y. and Sugimachi , K.Intratumoral neovascularization and growth pattern in early gastric carcinoma . Cancer , 85 , 2240 – 2246 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 41.Cascinu , S. , Staccioli , M. P. , Gasparini , G. , Giordani , G. , Catalano , V. , Ghiselli , R. , Rossi , C. , Baldelli , A. M. , Graziano , F. , Saba , V. , Muretto , P. and Catalano , G.Expression of vascular endothelial growth factor can predict event‐free survival in stage II colon cancer . Clin. Cancer Res. , 6 , 2803 – 2807 ( 2000. ). [PubMed] [Google Scholar]
  • 42.Nakata , S. , Ito , K. , Fujimori , M. , Shingu , K. , Kajikawa , S. , Adachi , W. , Matsuyama , I. , Tsuchiya , S. , Kuwano , M. and Amano , J.Involvement of vascular endothelial growth factor and urokinase‐type plasminogen activator receptor in microvessel invasion in human colorectal cancers . Int. J. Cancer , 79 , 179 – 186 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 43.Kursch , A. , Tkachuk , S. , Haller , H. , Dietz , R. , Gulba , D. C. , Lipp , M. and Dumler , I.Urokinase stimulates human vascular smooth muscle cell migration via phosphatidylinositol 3‐kinase‐tyk2 interaction . J. Biol. Chem. , 15 , 39466 – 39473 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 44.Toi , M. , Kondo , S. , Suzuki , H. , Yamamoto , Y. , Inada , K. , Imazawa , T. , Taniguchi , T. and Tominaga , T.Quantitative analysis of vascular endothelial growth factor in primary breast cancer . Cancer , 77 , 1101 – 1106 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 45.Shen , G. H. , Ghazizadeh , M. , Kawanami , O. , Shimizu , H. , Araki , T. and Sugisaki , Y.Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma . Br. J. Cancer , 82 , 196 – 203 ( 2000. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Kumar , S. , Ghellal , A. , Cheng , L. , Byrne , G. , Haboubi , N. , Wang , J. M. and Bundred , N.Breast carcinoma: vascular density determined using CD 105 antibody correlates with tumor prognosis . Cancer Res. , 59 , 856 – 861 ( 1999. ). [PubMed] [Google Scholar]
  • 47.Ohta , Y. , Shridhar , V. , Bright , R. K. , Kalemkerian , G. P. , Du , W. , Carbone , M. , Watanabe , Y. and Pass , H. I.VEGF and VEGF type C play an important role in angiogenesis and lymphangioma in human malignant mesothelioma tumours . Br. J. Cancer , 81 , 54 – 61 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES