Abstract
The events that mediate tumor progression in ovarian carcinoma are poorly understood to date. This review summarizes our results studying metastasis-associated molecules in advanced-stage ovarian carcinomas, details the co-expression of mRNA of these genes, and discusses their prognostic role. Fifty-five primary and metastatic FIGO stage III–IV ovarian carcinomas were analyzed for the expression of αv and β1 integrin subunits, the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP, the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), PEA3 and Ets-1 using mRNA in situ hybridization. Tumor and adjacent stromal cell expression was scored. The association between integrin subunit expression and the expression of MMP, TIMP-2, angiogenic genes, PEA3 and Ets-1 was statistically analyzed. αv integrin subunit mRNA expression in carcinoma cells showed significant association with that of MMP-2 and IL-8 in this cellular compartment, while the presence of β1 integrin subunit mRNA showed similar association with that of PEA3, Ets-1, IL-8, bFGF and MMP-2. Expression of β1 integrin subunit mRNA in stromal cells was associated with that of TIMP-2 and Ets-1 in this compartment. In addition, significant intercellular associations were found between αv integrin subunit mRNA expression in carcinoma cells and stromal cell expression of Ets-1, as well as between stromal cell expression of αv integrin subunit and labeling for IL-8 in carcinoma cells. The presence of β1 integrin subunit mRNA in carcinoma cells showed a significant association with that of Ets-1, IL-8 and bFGF in stromal cells, while the presence of β1 integrin subunit mRNA in stromal cells was associated with tumor PEA3 mRNA expression. To the best of our knowledge, this is the first evidence for coordinated autocrine and paracrine expression of members of these four families of metastasis-associated genes in human cancer. The results of this analysis support experimental data regarding cross-talk between carcinoma cells and peritumoral fibroblasts. They also suggest the existence of a putative activation sequence of metastatic genes, involving the β1 (and possibly αv) integrin subunits, IL-8, PEA3, Ets-1 and MMP in ovarian carcinoma.
Similar content being viewed by others
References
Liotta LA,Rao CN,Barsky SH: Tumor invasion and the extracellular matrix. Lab Invest 49: 636-649, 1983
Folkman J: Tumor angiogenesis. Adv Cancer Res 43: 175-203, 1985
Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82: 4-6, 1990
Fidler IJ,Ellis LM: The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79: 185-188, 1994
Werb Z: ECM and cell surface proteolysis: Regulating cellular ecology. Cell 91: 439-442, 1997
Ruoslahti E: Integrins. J Clin Invest 87: 1-5, 1991
Hood JD,Cheresh DA: Role of integrins in cell invasion and migration. Nature Rev 2: 91-100, 2002
Sanders RJ,Mainiero F,Giancotti FP: The role of integrins in tumorigenesis and metastasis. Cancer Invest 16: 329-344, 1998
Albelda SM: Role of integrins and other cell adhesion molecules in tumor progression and metastasis. Lab Invest 68: 4-17, 1993
Clezardin P: Recent insights into the role of integrins in cancer metastasis. Cell Mol Life Sci 54: 541-548, 1998
Varner JA,Cheresh DA: Integrins and cancer. Curr Opin Cell. Biol 8: 724-730, 1996
Liotta LA,Stetler-Stevenson WG: Tumor invasion and metastasis: An imbalance of positive and negative regulation. Cancer Res 51: 5054s-5059s (suppl), 1991
Chambers AF,Matrisian LM: Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89: 1260-1270, 1997
Folkman J,Klagsbrun M: Angiogenic factors. Science 235: 442-447, 1987
Tischer E,Mitchell R,Hartman T,Silva M,Gospodarowicz D,Fiddes JC,Abraham JA: The human gene for vascular endothelial growth factor. J Biol Chem 226: 11947-11954, 1991
Keck PJ,Hauser SD,Krivi G,Sanzo K,Warren T,Feder J,Connolly DT: Vascular permeability factor: An endothelial cell mitogen related to PDGF. Science 246: 1309-1312, 1989
Goldfarb M: The fibroblast growth factor family. Cell Growth Diff 1: 439-445, 1990
Gospodarowicz D,Neufeld G,Schweigerer L: Molecular and biological characterization of fibroblast growth factor: An angiogenic growth factor which also controls the proliferation and differentiation of mesoderm and neuroectoderm derived cells. Cell Diff 19: 1-17, 1986
Koch AE,Polverini PJ,Kunkel SL,Harlow LA,DiPietro LA,Elner VM,Elner SG,Strieter RM: Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258: 1798-1801, 1992
Nunn MF,Seeburg PM,Moscovici C,Duesberg PH: Tripartite structure of the avian erythroblastosis virus E26 transforming gene. Nature 306: 391-395, 1983
Wasylyk B,Hahn SL,Giovane A: The Ets family of transcription factors. Eur J Biochem 211: 7-18, 1993
Vandenbunder B,Queva C,Desbiens X,Wernert N,Stehelin D: Expression of the transcription factor c-ets-1 correlates with the occurrence of invasive processes during normal and pathological development. Invasion Metastas 14: 198-209, 1994-5
Davidson B,Reich R,Goldberg I,Gotlieb WH,Kopolovic J,Berner A,Ben-Baruch G,Bryne M,Nesland JM: Ets-1 mRNA expression is a novel marker of poor survival in ovarian carcinoma. Clin Cancer Res 7: 551-557, 2001
Calmels TPG,Mattot V,Wernert N,Vandenbunder B,Stehelin D: Invasive tumors induce c-ets-1 transcription Coordinated expression of integrin subunits and others 113 factor expression in adjacent stroma. Biol Cell 84: 53-61, 1995
Iwasaka C,Tanaka K,Abe M,Sato Y: Ets-1 regulates angiogenesis by inducing the expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of vascular endothelial cells. J Cell Physiol 169: 522-531, 1996
Oda N,Abe M,Sato Y: Ets-1 converts endothelial cells to the angiogenic phenotype by inducing the expression of matrix metalloproteinases and integrin β3. J Cell Physiol 178: 121-132, 1999
Himelstein BP,Lee EJ,Sato H,Seiki M,Muschel RJ: Tumor cell contact mediated transcriptional activation of the fibroblast matrix metalloproteinase-9 gene: Involvement of multiple transcription factors including Ets and an alternating purine-pyrimidine repeat. Clin Exp Metastas 16: 169-177, 1998
Donahue JP,Sugg N,Hawiger J: The integrin av gene: Identification and characterization of the promoter region. Biochym Biophys Acta 1219: 228-232, 1994
Takaoka AS,Yamada T,Gotoh M,Kanai Y,Imai K,Hirohashi S: Cloning and characterization of the β4-integrin gene promoter and enhancers. J Biol Chem 273: 33848-33855, 1998
Seftor REB,Seftor EA,Gehlsen KR,Stetler-Stevenson WG,Brown PD,Ruoslahti E,Hendrix MJ: Role of the ανβ3 integrin in human melanoma cell invasion. Proc Natl Acad Sci USA 89: 1557-1561, 1992
Seftor REB,Seftor EA,Stetler-Stevenson WG,Hendrix MJC: The 72 kDa type IV collagenase is modulated via differential expression of αvβ 3 and α5 β 1 integrins during human melanoma cell invasion. Cancer Res 53: 3411-3415, 1993
Shibata K,Kikkawa F,Nawa A,Suganuma N,Hamaguchi M: Fibronectin secretion from human peritoneal tissue induces Mr 92,000 type IV collagenase expression and invasion in ovarian cancer cell lines. Cancer Res 57: 5416-5420, 1997
Segain JP,Harb J,Gregoire M,Meflah K,Menanteau J: Induction of fibroblast gelatinase B expression by direct contact with cell lines derived from primary tumor but not from metastases. Cancer Res 56: 5 506-5512, 1996
Ellerbroek SM,Fishman DA,Kearns AS,Bafetti LM,Stack MS: Ovarian carcinoma regulation of matrix metalloproteinase-2 and membrane-type 1 matrix metalloproteinase through β1 integrin. Cancer Res 59: 1635-1641, 1999
Deryugina EI,Bourdon MA,Jungwirth K,Smith JW,Strongin AY: Functional activation of integrin αvβ3 in tumor cells expressing membrane type 1 matrix metalloproteinase. Int J Cancer 86: 15-23, 2000
Morini M,Mottolese M,Ferrari N,Ghiorzo F,Buglioni S,Mortarini R,Noonan DM,Natali PG,Albini A: The α3β1 integrin is associated with mammary carcinoma cell metastasis, invasion, and Gelatinase B (MMP-9) activity. Int J Cancer 87: 336-342, 2000
Deryugina EI,Ratnikov B,Monosov E,Postnova TI,DiScipio R,Smith JW,Strongyn AY: MT1-MMP initiates activation of pro-MMP-2 and integrin αvβ promotes maturation of MMP-2 in breast carcinoma cells. ExpCell Res 263: 209-223, 2001
Daemi N,Thomasset N,Lissitzky JC,Dumortier J,Jacquier MF,Pourreyron C,Rousselle P,Chayvialle JA,Remy L: Anti-βintegrin antibodies enhance migratory and invasive abilities of human colon adenocarcinoma cells and their MMP-2 expression. Int J Cancer 85: 850-856, 2000
Werb Z,Tremble PM,Behrendtsen O,Crowley E,Damsky CH: Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. J Cell Biol 109: 877-889, 1989
Demeure MJ,Damsky CH,Elfman F,Goretzki PE,Wong MG,Clark OH: Invasion by cultured human follicular thyroid cancer correlates with increased β1 integrins and production of proteases. World J Surg 16: 770-776, 1992
Vo HP,Lee MK,Crowe DL: α2β1 integrin signaling via the mitogen activated protein kinase pathway modulates retinoic acid-dependent tumor cell invasion and transcriptional downregulation of matrix metalloproteinase 9 activity. Int J Oncol 13: 1127-1134, 1998
Hofmann UB,Westphal JR,Waas ET,Becker JC,Ruiter DJ,van Muijen GNP: Coexpression of integrin αvβ3 and matrix metalloproteinase-2 (MMP-2) coincides with MMP-2 activation. Correlation with melanoma progression. J Invest Dermatol 115: 625-632, 2000
Heino J: Biology of tumor cell invasion: Interplay of cell adhesion and matrix degradation. Int J Cancer 65: 717-722, 1996
Brooks PC,Clark RAF,Cheresh DA: Requirement of vascular integrin αvβ3 for angiogenesis. Science 264: 569-571, 1994
Brooks PC,Strömblad S,Sanders LC,von Schalscha TL,Aimes RT,Stetler-Stevenson WG,Quigley JP,Cheresh DA: Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin αvβ3. Cell 85: 683-693, 1996
Reed JA,Manahan LJ,Parks CS,Brigati DJ: Complete one-hour immunocytochemistry based on capillary action. Biotechniques 13: 434-443, 1992
Davidson B,Goldberg I,Kopolovic J,Lerner-Geva L,Gotlieb WH,Ben-Baruch G,Reich R: MMP-2 and TIMP-2 expression correlates with poor prognosis in cervical carcinoma-A clinicopathologic study using immunohistochemistry and mRNA in situ hybridization. Gynecol Oncol 73: 372-382, 1999
Davidson B,Goldberg I,Gotlieb WH,Kopolovic J,Ben-Baruch G,Nesland JM,Berner A,Bryne M,Reich R: High levels of MMP-2, MMP-9, MT1-MMP and TIMP-2 mRNA correlate with poor survival in ovarian carcinoma. Clin ExpMetasta s 17: 7 99-808, 1999
Goldberg I,Davidson B,Reich R,Gotlieb WH,Ben-Baruch G,Bryne M,Berner A,Nesland JM,Kopolovic J: aV integrin is a novel marker of poor prognosis in advanced-stage ovarian carcinoma. Clin Cancer Res 7: 4073-4079, 2001
Lupetti R,Mortarini R,Panceri P,Sensi M,Anichini A: Interaction with fibronectin regulates cytokine gene expres-sion in human melanoma cells. Int J Cancer 66: 110-116, 1996
Garcia-Velasco JA,Arici A: Interleukin-8 expression in endometrial stromal cells is regulated by integrin-dependent cell adhesion. Hum Mol Reprod 5: 1135-1140, 1999
Kanda S,Tomasini-Johansson B,Klint P,Dixelius J,Rubin K,Claesson-Welsh L: Signaling via fibroblast growth factor receptor-1 is dependent on extracellular matrix in capillary endothelial cell differentiation. Exp Cell Res 248: 203-213, 1999
Collo G,Pepper MS: Endothelial cell integrin α5β1 expression is modulated by cytokines and during migration in vitro. J Cell Sci 112: 569-578, 1999
Davidson B,Risberg B,Goldberg I,Nesland JM,Berner A,Trope' CG,Kristensen GB,Bryne M,Reich R: Ets-1 mRNA expression in effusions of serous ovarian carcinoma patients is a marker of poor outcome. Am J Surg Pathol 25: 1493-1500, 2001
Elenbaas B,Weinberg RA: Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. ExpCell Res 264: 169-184, 2001
Greene GF,Kitadai Y,Pettaway CA,von Eschenbach AC,Bucana CD,Fidler IJ: Correlation of metastasis-related gene expression with metastatic potential in human prostate carcinoma cells implanted in nude mice using an in situ messenger RNA hybridization technique. Am J Pathol 150: 1571-1582, 1997
Nakayama T,Ito M,Ohtsuru A,Naito S,Nakashima M,Fagin JA,Yamashita S,Sekine I: Expression of the Ets-1 proto-oncogene in human gastric carcinoma. Correlation with tumor invasion. Am J Pathol 149: 1931-1939, 1996
Xing X,Wang SC,Xia W,Zou Y,Shao R,Kwong KY,Yu Z,Zhang S,Miller S,Huang L,Hung MC: The Ets protein PEA3 suppresses HER-2/neu overexpression and inhibits tumorigenesis. Nature Med 6: 189-195, 2000
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Davidson, B., Goldberg, I., Gotlieb, W.H. et al. Coordinated expression of integrin subunits, matrix metalloproteinases (MMP), angiogenic genes and Ets transcription factors in advanced-stage ovarian carcinoma: A possible activation pathway?. Cancer Metastasis Rev 22, 103–115 (2003). https://doi.org/10.1023/A:1022272204045
Issue Date:
DOI: https://doi.org/10.1023/A:1022272204045