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Horm Metab Res 2003; 35(11/12): 802-808
DOI: 10.1055/s-2004-814143
Review
© Georg Thieme Verlag Stuttgart · New York

The Role of the IGF-I Receptor in the Regulation of Matrix Metalloproteinases, Tumor Invasion and Metastasis

D.  Zhang1 , A.  A.  Samani1 , P.  Brodt1
  • 1Department of Surgery (D.Z, A.S., P.B.) and Medicine (P.B.), McGill University Health Center, the Royal Victoria Hospital, Montreal, Quebec, Canada
Supported by grant # mop-10505 from the Canadian Institute for Health Research and by a Terry Fox New Frontiers initiative grant (to P.B.).
Further Information

Publication History

Received 29 September 2003

Accepted without Revision 27 October 2003

Publication Date:
07 January 2004 (online)

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Abstract

The breakdown of the extracellular matrix (ECM) by proteinases is an essential step in the process of cancer invasion and metastasis. Malignant progression is frequently associated with upregulated production and/or activity of one or several ECM degrading proteinases. Prominent among them are the matrix metalloproteinases (MMPs). The MMPs constitute a family of structurally related, zinc-dependent endopeptidases collectively capable of degrading essentially all the components of the extracellular matrix. At present, 23 members of the human MMP gene family are known. The increased expression and/or activity of one or more members of this family have been documented in essentially all human malignancies and some have been implicated in the process of angiogenesis. Prominent among those are MMP-2 and MT1-MMP, two metalloproteinases that form a cell membrane-associated complex leading to MMP-2 activation and ECM proteolysis. Here, we review our data that identified the type 1 insulin-like growth factor receptor (IGF-IR) as a regulator of tumor invasion and the synthesis of MT1-MMP and MMP-2 and report on the signal transduction pathways that mediate this regulation. These findings are discussed in the context of a broader review of the role of the IGF-IR/IGF axis in the regulation of tumor invasion and metastasis.

Key words

IGF-I receptor - MT1-MMP - MMP-2 - Invasion - Metastasis

References

  • 1 Brinckerhoff C E, Matrisian L M. Matrix metalloproteinases: a tail of a frog that became a prince.  Nat Rev Mol Cell Biol. 2002;  3 207-214
    CrossrefPubMedGoogle Scholar
  • 2 Somerville R P, Oblander S A, Apte S S. Matrix metalloproteinases: old dogs with new tricks.  Genome Biol. 2003;  4 216
    CrossrefPubMedGoogle Scholar
  • 3 Baker E A, Leaper D J. Profiles of matrix metalloproteinases and their tissue inhibitors in intraperitoneal drainage fluid: relationship to wound healing.  Wound Repair Regen. 2003;  11 268-274
    CrossrefPubMedGoogle Scholar
  • 4 Zaidi M, Blair H C, Moonga B S, Abe E, Huang C L. Osteoclastogenesis, bone resorption, and osteoclast-based therapeutics.  J Bone Miner Res. 2003;  18 599- 609
    PubMedGoogle Scholar
  • 5 Murphy G, Knauper V, Atkinson S, Butler G, English W, Hutton M, Stracke J, Clark I. Matrix metalloproteinases in arthritic disease.  Arthritis Res. 2002;  4 S39-49
    CrossrefPubMedGoogle Scholar
  • 6 Ikeda U, Shimada K. Matrix metalloproteinases and coronary artery diseases.  Clin Cardiol. 2003;  26 55-59
    PubMedGoogle Scholar
  • 7 Vihinen P, Kahari V M. Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets.  Int J Cancer. 2002;  99 157-166
    CrossrefPubMedGoogle Scholar
  • 8 Giunciuglio D, Culty M, Fassina G, Masiello L, Melchiori A, Paglialunga G, Arand G, Ciardiello F, Basolo F, Thompson E W. et al . Invasive phenotype of MCF10A cells overexpressing c-Ha-ras and c-erbB-2 oncogenes.  Int J Cancer. 1995;  63 815-822
    PubMedGoogle Scholar
  • 9 Kaya M, Yoshida K, Higashino F, Mitaka T, Ishii S, Fujinaga K. A single ets-related transcription factor, E1AF, confers invasive phenotype on human cancer cells.  Oncogene. 1996;  12 221-227
    PubMedGoogle Scholar
  • 10 Stetle-Stevenenson W. Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention.  J Clin Invest. 1999;  103 1237-1241
    PubMedGoogle Scholar
  • 11 Pirila E, Sharabi A, Salo T, Quaranta V, Tu H, Heljasvaara R, Koshikawa N, Sorsa T, Maisi P. Matrix metalloproteinases process the laminin-5 gamma 2-chain and regulate epithelial cell migration.  Biochem Biophys Res Commun. 2003;  303 1012-1017
    CrossrefPubMedGoogle Scholar
  • 12 Levi E, Fridman R, Miao H Q, Ma Y S, Yayon A, Vlodavsky I. Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1.  Proc Natl Acad Sci USA. 1996;  93 7069-7074
    CrossrefPubMedGoogle Scholar
  • 13 Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H, Itohara S. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice.  Cancer Res. 1998;  58 1048-1051
    PubMedGoogle Scholar
  • 14 Llorens A, Vinyals A, Alia P, Lopez-Barcons L, Gonzalez-Garrigues M, Fabra A. Metastatic ability of MXT mouse mammary subpopulations correlates with clonal expression and/or membrane-association of gelatinase A.  Mol Carcinog. 1997;  19 54-66
    CrossrefPubMedGoogle Scholar
  • 15 Bashyam M D. Understanding cancer metastasis: an urgent need for using differential gene expression analysis.  Cancer. 2002;  94 1821-1829
    CrossrefPubMedGoogle Scholar
  • 16 Nagata M, Fujita H, Ida H, Hoshina H, Inoue T, Seki Y, Ohnishi M, Ohyama T, Shingaki S, Kaji M, Saku T, Takagi R. Identification of potential biomarkers of lymph node metastasis in oral squamous cell carcinoma by cDNA microarray analysis.  Int J Cancer. 2003;  106 683-689
    CrossrefPubMedGoogle Scholar
  • 17 Wasenius V M, Hemmer S, Kettunen E, Knuutila S, Franssila K, Joensuu H. Hepatocyte growth factor receptor, matrix metalloproteinase-11, tissue inhibitor of metalloproteinase-1, and fibronectin are up-regulated in papillary thyroid carcinoma: a cDNA and tissue microarray study.  Clin Cancer Res. 2003;  9 68-75
    PubMedGoogle Scholar
  • 18 Zhang X, Liu Y, Gilcrease M Z, Yuan X H, Clayman G L, Adler-Storthz K, Chen Z. A lymph node metastatic mouse model reveals alterations of metastasis-related gene expression in metastatic human oral carcinoma sublines selected from a poorly metastatic parental cell line.  Cancer. 2002;  95 1663-1672
    CrossrefPubMedGoogle Scholar
  • 19 Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M. A matrix metalloproteinase expressed on the surface of invasive tumour cells.  Nature. 1994;  370 61-65
    CrossrefPubMedGoogle Scholar
  • 20 Seiki M, Yana I. Roles of pericellular proteolysis by membrane type-1 matrix metalloproteinase in cancer invasion and angiogenesis.  Cancer Sci. 2003;  94 569-574
    PubMedGoogle Scholar
  • 21 Holmbeck K, Bianco P, Birkedal-Hansen H. MT1-MMP: a collagenase essential for tumor cell invasive growth.  Cancer Cell. 2003;  4 83-84
    CrossrefPubMedGoogle Scholar
  • 22 Pei D, Weiss S J. Transmembrane-deletion mutants of the membrane-type matrix metalloproteinase-1 process progelatinase A and express intrinsic matrix-degrading activity.  J Biol Chem. 1996;  271 9135-9140
    CrossrefPubMedGoogle Scholar
  • 23 Hiraoka N, Allen E, Apel I J, Gyetko M R, Weiss S J. Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins.  Cell. 1998;  95 365- 377
    CrossrefPubMedGoogle Scholar
  • 24 Koshikawa N, Giannelli G, Cirulli V, Miyazaki K, Quaranta V. Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5.  J Cell Biol. 2000;  148 615-624
    CrossrefPubMedGoogle Scholar
  • 25 Ohuchi E, Imai K, Fujii Y, Sato H, Seiki M, Okada Y. Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules.  J Biol Chem. 1997;  272 2446-2451
    CrossrefPubMedGoogle Scholar
  • 26 Imai K, Ohuchi E, Aoki T, Nomura H, Fujii Y, Sato H, Seiki M, Okada Y. Membrane-type matrix metalloproteinase 1 is a gelatinolytic enzyme and is secreted in a complex with tissue inhibitor of metalloproteinases 2.  Cancer Res. 1996;  56 2707- 2710
    PubMedGoogle Scholar
  • 27 Will H, Atkinson S J, Butler G S, Smith B, Murphy G. The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by TIMP-2 and TIMP-3.  J Biol Chem. 1996;  271 17 119-17 123
    PubMedGoogle Scholar
  • 28 Seiki M. Membrane-type matrix metalloproteinases.  APMIS. 1999;  107 137-143
    PubMedGoogle Scholar
  • 29 Atkinson S J, Crabbe T, Cowell S, Ward R V, Butler M J, Sato H, Seiki M, Reynolds J J, Murphy G. Intermolecular autolytic cleavage can contribute to the activation of progelatinase A by cell membranes.  J Biol Chem. 1995;  270 30 479 - 30 485
    PubMedGoogle Scholar
  • 30 Holmbeck K, Bianco P, Caterina J, Yamada S, Kromer M, Kuznetsov S A, Mankani M, Robey P G, Poole A R, Pidoux I, Ward J M, Birkedal-Hansen H. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover.  Cell. 1999;  99 81-92
    CrossrefPubMedGoogle Scholar
  • 31 Graham C H, Connelly I, MacDougall J R, Kerbel R S, Stetler-Stevenson W G, Lala P K. Resistance of malignant trophoblast cells to both the anti-proliferative and anti-invasive effects of transforming growth factor-beta.  Exp Cell Res. 1994;  214 93-99
    CrossrefPubMedGoogle Scholar
  • 32 Bar-Eli M. Role of interleukin-8 in tumor growth and metastasis of human melanoma.  Pathobiology. 1999;  67 12-18
    PubMedGoogle Scholar
  • 33 Lohi J, Lehti K, Westermarck J, Kahari V M, Keski-Oja J. Regulation of membrane-type matrix metalloproteinase-1 expression by growth factors and phorbol 12-myristate 13-acetate.  Eur J Biochem. 1996;  239 239-247
    CrossrefPubMedGoogle Scholar
  • 34 Long L, Rubin R, Baserga R, Brodt P. Loss of the metastatic phenotype in murine carcinoma cells expressing an antisense RNA to the insulin-like growth factor receptor.  Cancer Res. 1995;  55 1006-1009
    PubMedGoogle Scholar
  • 35 Long L, Rubin R, Brodt P. Enhanced invasion and liver colonization by lung carcinoma cells overexpressing the type 1 insulin-like growth factor receptor.  Exp Cell Res. 1998;  238 116-121
    CrossrefPubMedGoogle Scholar
  • 36 Long L, Navab R, Brodt P. Regulation of the Mr 72,000 type IV collagenase by the type I insulin-like growth factor receptor.  Cancer Res. 1998;  58 3243-3247
    PubMedGoogle Scholar
  • 37 Brodt P, Fallavollita L, Khatib A M, Samani A A, Zhang D. Cooperative regulation of the invasive and metastatic phenotypes by different domains of the type I insulin-like growth factor receptor beta subunit.  J Biol Chem. 2001;  276 33 608-33 615
    PubMedGoogle Scholar
  • 38 Zhang D, Brodt P. Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI 3-kinase/Akt signaling.  Oncogene. 2003;  22 974-982
    CrossrefPubMedGoogle Scholar
  • 39 Brodt P, Samani A, Navab R. Inhibition of the type I insulin-like growth factor receptor expression and signaling: novel strategies for antimetastatic therapy.  Biochem Pharmacol. 2000;  60 1101-1107
    CrossrefPubMedGoogle Scholar
  • 40 Macaulay V M. Insulin-like growth factors and cancer.  Br J Cancer. 1992;  65 311-320
    PubMedGoogle Scholar
  • 41 Lopez T, Hanahan D. Elevated levels of IGF-I receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis.  Cancer Cell. 2002;  1 339-353
    CrossrefPubMedGoogle Scholar
  • 42 Samani A A, Brodt P. The receptor for the type I insulin-like growth factor and its ligands regulate multiple cellular functions that impact on metastasis.  Surg Oncol Clin N Am. 2001;  10 289-312
    PubMedGoogle Scholar
  • 43 Barozzi C, Ravaioli M, D'Errico A, Grazi G L, Poggioli G, Cavrini G, Mazziotti A, Grigioni W F. Relevance of biologic markers in colorectal carcinoma: a comparative study of a broad panel.  Cancer. 2002;  94 647-657
    CrossrefPubMedGoogle Scholar
  • 44 Xie Y, Skytting B, Nilsson G, Brodin B, Larsson O. Expression of insulin-like growth factor-1 receptor in synovial sarcoma: association with an aggressive phenotype.  Cancer Res. 1999;  59 3588-3591
    PubMedGoogle Scholar
  • 45 All-Ericsson C, Girnita L, Seregard S, Bartolazzi A, Jager M J, Larsson O. Insulin-like growth factor-1 receptor in uveal melanoma: a predictor for metastatic disease and a potential therapeutic target.  Invest Ophthalmol Vis Sci. 2002;  43 1-8
    PubMedGoogle Scholar
  • 46 Samani A A, Fallavollita L, Jaalouk D E, Galipeau J, Brodt P. Inhibition of carcinoma cell growth and metastasis by a vesicular stomatitis virus G-pseudotyped retrovector expressing type I insulin-like growth factor receptor antisense.  Hum Gene Ther. 2001;  12 1969-1977
    CrossrefPubMedGoogle Scholar
  • 47 Tang Y, Zhang D, Fallavollita L, Brodt P. Vascular endothelial growth factor C expression and lymph node metastasis are regulated by the type I insulin-like growth factor receptor.  Cancer Res. 2003;  63 1166-1171
    PubMedGoogle Scholar
  • 48 Kiely P A, Sant A, O'Connor R. RACK1 is an insulin-like growth factor 1 (IGF-I) receptor-interacting protein that can regulate IGF-I-mediated Akt activation and protection from cell death.  J Biol Chem. 2002;  277 22 581-22 589
    PubMedGoogle Scholar
  • 49 Yoon A, Hurta R A. Insulin like growth factor-1 selectively regulates the expression of matrix metalloproteinase-2 in malignant H-ras transformed cells.  Mol Cell Biochem. 2001;  223 1-6
    PubMedGoogle Scholar
  • 50 Fowlkes J L, Enghild J J, Suzuki K, Nagase H. Matrix metalloproteinases degrade insulin-like growth factor-binding protein-3 in dermal fibroblast cultures.  J Biol Chem. 1994;  269 25 742-25 746
    PubMedGoogle Scholar
  • 51 Thrailkill K M, Quarles L D, Nagase H, Suzuki K, Serra D M, Fowlkes J L. Characterization of insulin-like growth factor-binding protein 5-degrading proteases produced throughout murine osteoblast differentiation.  Endocrinology. 1995;  136 3527-3533
    CrossrefPubMedGoogle Scholar
  • 52 Manes S, Llorente M, Lacalle R A, Gomez-Mouton C, Kremer L, Mira E, Martinez A C. The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells.  J Biol Chem. 1999;  274 6935-6945
    CrossrefPubMedGoogle Scholar
  • 53 Butler A A, Yakar S, Gewolb I H, Karas M, Okubo Y, LeRoith D. Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology.  Comp Biochem Physiol B Biochem Mol Biol. 1998;  121 19- 26
    PubMedGoogle Scholar
  • 54 Petley T, Graff K, Jiang W, Yang H, Florini J. Variation among cell types in the signaling pathways by which IGF-I stimulates specific cellular responses.  Horm Metab Res. 1999;  31 70-76
    Article in Thieme ConnectPubMedGoogle Scholar
  • 55 Walsh P T, Smith L M, O'Connor R. Insulin-like growth factor-1 activates Akt and Jun N-terminal kinases (JNKs) in promoting the survival of T lymphocytes.  Immunology. 2002;  107 461-471
    CrossrefPubMedGoogle Scholar
  • 56 Touyz R M, Cruzado M, Tabet F, Yao G, Salomon S, Schiffrin E L. Redox-dependent MAP kinase signaling by Ang II in vascular smooth muscle cells: role of receptor tyrosine kinase transactivation.  Can J Physiol Pharmacol. 2003;  81 159-167
    CrossrefPubMedGoogle Scholar
  • 57 Chang F, Lee J T, Navolanic P M, Steelman L S, Shelton J G, Blalock W L, Franklin R A, McCubrey J A. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy.  Leukemia. 2003;  17 590-603
    CrossrefPubMedGoogle Scholar
  • 58 Vivanco I, Sawyers C L. The phosphatidylinositol 3-kinase AKT pathway in human cancer.  Nat Rev Cancer. 2002;  2 489-501
    CrossrefPubMedGoogle Scholar
  • 59 Tanaka M, Grossman H B. In vivo gene therapy of human bladder cancer with PTEN suppresses tumor growth, downregulates phosphorylated Akt, and increases sensitivity to doxorubicin.  Gene Ther. 2003;  10 1636-1642
    CrossrefPubMedGoogle Scholar
  • 60 Zhang D, Brodt P. Dual-regulation of MMP-2 expression by the IGF-I receptor: The PI 3-kinase/Akt and Raf/MAP kinase pathways transmit opposing signals.  Proc Am Assoc Cancer Res. 2003;  44 R3263
    PubMedGoogle Scholar
  • 61 Huang S, Houghton P J. Targeting mTOR signaling for cancer therapy.  Curr Opin Pharmacol. 2003;  3 371-377
    PubMedGoogle Scholar
  • 62 Muller M, Dietel M, Turzynski A, Wiechen K. Antisense phosphorothioate oligodeoxynucleotide down-regulation of the insulin-like growth factor I receptor in ovarian cancer cells.  Int J Cancer. 1998;  77 567-571
    CrossrefPubMedGoogle Scholar
  • 63 Burfeind P, Chernicky C L, Rininsland F, Ilan J, Ilan J. Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo.  Proc Natl Acad Sci USA. 1996;  93 7263-7268
    CrossrefPubMedGoogle Scholar
  • 64 Neuenschwander S, Roberts C T Jr, LeRoith D. Growth inhibition of MCF-7 breast cancer cells by stable expression of an insulin-like growth factor I receptor antisense ribonucleic acid.  Endocrinology. 1995;  136 4298-4303
    CrossrefPubMedGoogle Scholar
  • 65 Lee C T, Wu S, Gabrilovich D, Chen H, Nadaf-Rahrov S, Ciernik I F, Carbone D P. Antitumor effects of an adenovirus expressing antisense insulin-like growth factor I receptor on human lung cancer cell lines.  Cancer Res. 1996;  56 3038-3041
    PubMedGoogle Scholar
  • 66 Nakamura K, Hongo A, Kodama J, Miyagi Y, Yoshinouchi M, Kudo T. Down-regulation of the insulin-like growth factor I receptor by antisense RNA can reverse the transformed phenotype of human cervical cancer cell lines.  Cancer Res. 2000;  60 760-765
    PubMedGoogle Scholar
  • 67 Kalebic T, Tsokos M, Helman L J. In vivo treatment with antibody against IGF-I receptor suppresses growth of human rhabdomyosarcoma and down-regulates p34cdc2.  Cancer Res. 1994;  54 5531-5534
    PubMedGoogle Scholar
  • 68 Pietrzkowski Z, Mulholland G, Gomella L, Jameson B A, Wernicke D, Baserga R. Inhibition of growth of prostatic cancer cell lines by peptide analogues of insulin-like growth factor 1.  Cancer Res. 1993;  53 1102-1106
    PubMedGoogle Scholar
  • 69 Kalebic T, Blakesley V, Slade C, Plasschaert S, LeRoith D, Helman L J. Expression of a kinase-deficient IGF-I-R suppresses tumorigenicity of habdomyosarcoma cells constitutively expressing a wild type IGF-I-R.  Int J Cancer. 1998;  76 223-227
    CrossrefPubMedGoogle Scholar
  • 70 Reiss K, D'Ambrosio C, Tu X, Tu C, Baserga R. Inhibition of tumor growth by a dominant negative mutant of the insulin-like growth factor I receptor with a bystander effect.  Clin Cancer Res. 1998;  4 2647-2655
    PubMedGoogle Scholar
  • 71 Garcia-Echeverria C, Grueggen J, Capraro H G, Evans D B, Ferrari S, Fabbro D, Furet P, Gelger T, Liebetanz J, Marti A, Martiny-Baron G, Mestan J, Pearson M A, Ruetz S, Stolz B, Holmann F. Characterization of potent and selective kinase inhibitor of IGF-IR.  Proc Am Assoc Cancer Res. 2003;  44 1008
    PubMedGoogle Scholar

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