Role of Tumor Stromal Interactions and Proteases in Oral Cancer Metastasis

  • J. Robert Newman
  • Eben L. RosenthalEmail author


To metastasize, tumor cells must migrate through the surrounding stroma which is composed of extracellular matrix (ECM) components, fibroblasts, inflammatory cells, and endothelial cells. Tumor-associated matrix permeability to tumor cells is thought to result from complex interactions between the tumor cell and the cellular and acellular components of the stroma. These interactions result in tumor cell changes in substrate adhesion, cell migration, and focused proteolysis of ECM components. Although the process of ECM degradation has been associated with multiple types of proteases including cathepsins, and serine proteases (such as plasmin), it is the matrix metalloproteinases (MMPs) that are most commonly upregulated and associated with the invasive process. Although tumor cells were originally thought to be the primary source of MMPs within the tumor, it was recently recognized that MMPs are expressed primarily by stromal cells when stimulated by tumor cell derived factors. One mechanism that tumor cells employ to stimulate MMPs from tumor-associated stroma is the expression of ECM metalloproteinase inducer (EMMPRIN). EMMPRIN is a tumor cell expressed protein known to induce growth factors and proteases in the surrounding fibroblasts and endothelial cells. In addition to an analysis of EMMPRIN as a paradigm for tumor–stromal interactions, this chapter will characterize the presence of stromal tissue in head and neck cancer on the basis of histological analysis, the role of proteases in tumor–stromal interactions, and the specific role of membrane type-1 MMP (MT1-MMP) in tumor invasion and metastasis. Furthermore, the clinical trials associated with MMP inhibitors in cancer have been disappointing, and some possible explanations for their failure and future directions are suggested.


Vascular Endothelial Growth Factor Tumor Cell Invasion Oral Cavity Squamous Cell Carcinoma Stromal Interaction Oral Tongue Squamous Cell Carcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by grants from the American Head and Neck Society and the National Cancer Institute (NCI K08CA102154).


  1. Ala-aho R, Ahonen M, George SJ et al (2004) Targeted inhibition of human collagenase-3 (MMP-13) expression inhibits squamous cell carcinoma growth in vivo. Oncogene 23(30):5111–5123PubMedGoogle Scholar
  2. Almholt K, Johnsen M (2003) Stromal cell involvement in cancer. Recent Results Cancer Res 162:31–42PubMedGoogle Scholar
  3. Arenas-Huertero FJ, Herrera-Goepfert R, Delgado-Chavez R et al (1999) Matrix metalloproteinases expressed in squamous cell carcinoma of the oral cavity: correlation with clinicopathologic features and neo-adjuvant chemotherapy response. J Exp Clin Cancer Res 18(3):279–284PubMedGoogle Scholar
  4. Aznavoorian S, Moore BA, Alexander-Lister LD, Hallit SL, Windsor LJ, Engler JA (2001) Membrane type I-matrix metalloproteinase-mediated degradation of type I collagen by oral squamous cell carcinoma cells. Cancer Res 61(16):6264–6275PubMedGoogle Scholar
  5. Barcellos-Hoff MH (2005) Integrative radiation carcinogenesis: interactions between cell and tissue responses to DNA damage. Semin Cancer Biol 15(2):138–148PubMedGoogle Scholar
  6. Barcellos-Hoff MH, Brooks AL (2001) Extracellular signaling through the microenvironment: a hypothesis relating carcinogenesis, bystander effects, and genomic instability. Radiat Res 156(5 Pt 2):618–627PubMedGoogle Scholar
  7. Barcellos-Hoff MH, Ravani SA (2000) Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 60(5):1254–1260PubMedGoogle Scholar
  8. Bassi DE, Mahloogi H, Al-Saleem L, Lopez De Cicco R, Ridge JA, Klein-Szanto AJ (2001) Elevated furin expression in aggressive human head and neck tumors and tumor cell lines. Mol Carcinog 31(4):224–232PubMedGoogle Scholar
  9. Bassi DE, Mahloogi H, Lopez De Cicco R, Klein-Szanto A (2003) Increased furin activity enhances the malignant phenotype of human head and neck cancer cells. Am J Pathol 162(2):439–447PubMedGoogle Scholar
  10. Birkedal-Hansen H (1995) Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol 7(5):728–735PubMedGoogle Scholar
  11. Biswas C, Zhang Y, DeCastro R et al (1995) The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res 55(2):434–439PubMedGoogle Scholar
  12. Bodey B, Bodey B Jr, Groger AM, Siegel SE, Kaiser HE (2001) Invasion and metastasis: the expression and significance of matrix metalloproteinases in carcinomas of the lung. In Vivo 15(2):175–180PubMedGoogle Scholar
  13. Bordador LC, Li X, Toole B et al (2000) Expression of emmprin by oral squamous cell carcinoma. Int J Cancer 85(3):347–352PubMedGoogle Scholar
  14. Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA (2002a) A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 87(2):161–167PubMedGoogle Scholar
  15. Bramhall SR, Hallissey MT, Whiting J et al (2002b) Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Br J Cancer 86(12):1864–1870PubMedGoogle Scholar
  16. Braundmeier AG, Fazleabas AT, Lessey BA, Guo H, Toole BP, Nowak RA (2006) Extracellular matrix metalloproteinase inducer regulates metalloproteinases in human uterine endometrium. J Clin Endocrinol Metab 91(6):2358–2365PubMedGoogle Scholar
  17. Camps JL, Chang SM, Hsu TC et al (1990) Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc Natl Acad Sci USA 87(1):75–79PubMedGoogle Scholar
  18. Casiglia J, Woo SB (2001) A comprehensive review of oral cancer. Gen Dent 49(1):72–82PubMedGoogle Scholar
  19. Caudroy S, Polette M, Nawrocki-Raby B et al (2002) EMMPRIN-mediated MMP regulation in tumor and endothelial cells. Clin Exp Metastasis 19(8):697–702PubMedGoogle Scholar
  20. Chenard MP, Lutz Y, Mechine-Neuville A et al (1999) Presence of high levels of MT1-MMP protein in fibroblastic cells of human invasive carcinomas. Int J Cancer 82(2):208–212PubMedGoogle Scholar
  21. Cheng MF, Tzao C, Tsai WC et al (2006) Expression of EMMPRIN and matriptase in esophageal squamous cell carcinoma: correlation with clinicopathological parameters. Dis Esophagus 19(6):482–486PubMedGoogle Scholar
  22. Clark JC, Thomas DM, Choong PF, Dass CR (2007) RECK-a newly discovered inhibitor of metastasis with prognostic significance in multiple forms of cancer. Cancer Metastasis Rev 26(3–4):675–683PubMedGoogle Scholar
  23. Coussens LM, Tinkle CL, Hanahan D, Werb Z (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103(3):481–490PubMedGoogle Scholar
  24. Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295(5564):2387–2392PubMedGoogle Scholar
  25. Crowe DL, Hacia JG, Hsieh CL, Sinha UK, Rice H (2002) Molecular pathology of head and neck cancer. Histol Histopathol 17:909–914PubMedGoogle Scholar
  26. Cunha GR, Matrisian LM (2002) It’s not my fault, blame it on my microenvironment. Differentiation 70(9–10):469–472PubMedGoogle Scholar
  27. Dalberg K, Eriksson E, Enberg U, Kjellman M, Backdahl M, Gelatinase A (2000) membrane type 1 matrix metalloproteinase, and extracellular matrix metalloproteinase inducer mRNA expression: correlation with invasive growth of breast cancer. World J Surg 24(3):334–340PubMedGoogle Scholar
  28. DeClerck YA, Mercurio AM, Stack MS et al (2004) Proteases, extracellular matrix, and cancer: a workshop of the path B study section. Am J Pathol 164(4):1131–1139PubMedGoogle Scholar
  29. Douillard JY, Peschel C, Shepherd F et al (2004) Randomized phase II feasibility study of combining the matrix metalloproteinase inhibitor BMS-275291 with paclitaxel plus carboplatin in advanced non-small cell lung cancer. Lung Cancer 46(3):361–368PubMedGoogle Scholar
  30. Dumont N, Arteaga CL (2002) The tumor microenvironment: a potential arbitrator of the tumor suppressive and promoting actions of TGFbeta. Differentiation 70(9–10):574–582PubMedGoogle Scholar
  31. Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2(3):161–174PubMedGoogle Scholar
  32. Elenbaas B, Weinberg RA (2001) Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res 264:169–184PubMedGoogle Scholar
  33. Evans JD, Stark A, Johnson CD et al (2001) A phase II trial of marimastat in advanced pancreatic cancer. Br J Cancer 85(12):1865–1870PubMedGoogle Scholar
  34. Fingleton B, Vargo-Gogola T, Crawford HC, Matrisian LM (2001) Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis. Neoplasia 3(6):459–468PubMedGoogle Scholar
  35. Fukino K, Shen L, Patocs A, Mutter GL, Eng C (2007) Genomic instability within tumor stroma and clinicopathological characteristics of sporadic primary invasive breast carcinoma. JAMA 297(19):2103–2111PubMedGoogle Scholar
  36. Fukumura D, Xavier R, Sugiura T et al (1998) Tumor induction of VEGF promoter activity in stromal cells. Cell 94(6):715–725PubMedGoogle Scholar
  37. Gocht A, Bosmuller HC, Bassler R et al (1999) Breast tumors with myofibroblastic differentiation: clinico-pathological observations in myofibroblastoma and myofibrosarcoma. Pathol Res Pract 195(1):1–10PubMedGoogle Scholar
  38. Grandis JR, Melhem MF, Gooding WE et al (1998) Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90(11):824–832Google Scholar
  39. Gruss CJ, Satyamoorthy K, Berking C et al (2003) Stroma formation and angiogenesis by overexpression of growth factors, cytokines, and proteolytic enzymes in human skin grafted to SCID mice. J Invest Dermatol 120(4):683–692PubMedGoogle Scholar
  40. Guidi AJ, Abu-Jawdeh G, Tognazzi K, Dvorak HF, Brown LF (1996) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in endometrial carcinoma. Cancer 78(3):454–460PubMedGoogle Scholar
  41. Guo H, Zucker S, Gordon MK, Toole BP, Biswas C (1997) Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cells. J Biol Chem 272(1):24–27PubMedGoogle Scholar
  42. Hagedorn H, Sauer U, Schleicher E, Nerlich A (1999) Expression of TGF-beta 1 protein and mRNA and the effect on the tissue remodeling in laryngeal carcinomas. Anticancer Res 19(5B):4265–4272PubMedGoogle Scholar
  43. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364PubMedGoogle Scholar
  44. Heppner KJ, Matrisian LM, Jensen RA, Rodgers WH (1996) Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol 149(1):273–282PubMedGoogle Scholar
  45. Herold C, Reck T, Fischler P et al (2002) Prognosis of a large cohort of patients with hepatocellular carcinoma in a single European centre. Liver 22(1):23–28PubMedGoogle Scholar
  46. Hotary K, Allen E, Punturieri A, Yana I, Weiss SJ (2000) Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. J Cell Biol 149(6):1309–1323PubMedGoogle Scholar
  47. Hotary KB, Yana I, Sabeh F et al (2002) Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes. J Exp Med 195(3):295–308PubMedGoogle Scholar
  48. Hotary KB, Allen ED, Brooks PC, Datta NS, Long MW, Weiss SJ (2003) Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 114(1):33–45PubMedGoogle Scholar
  49. Imanishi Y, Fujii M, Tokumaru Y et al (2000) Clinical significance of expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 in human head and neck squamous cell carcinoma. Hum Pathol 31(8):895–904PubMedGoogle Scholar
  50. Janot F, Klijanienko J, Russo A et al (1996) Prognostic value of clinicopathological parameters in head and neck squamous cell carcinoma: a prospective analysis. Br J Cancer 73(4):531–538PubMedGoogle Scholar
  51. Jiang A, Pei D (2003) Distinct roles of catalytic and pexin-like domains in MT-MMP mediated proMMP-2 activation and collagenolysis. J Biol Chem 278(40):38765–38771PubMedGoogle Scholar
  52. Jiang A, Lehti K, Wang X, Weiss SJ, Keski-Oja J, Pei D (2001) Regulation of membrane-type matrix metalloproteinase 1 activity by dynamin-mediated endocytosis. Proc Natl Acad Sci USA 98(24):13693–13698PubMedGoogle Scholar
  53. Jin JS, Yao CW, Loh SH, Cheng MF, Hsieh DS, Bai CY (2006) Increasing expression of extracellular matrix metalloprotease inducer in ovary tumors: tissue microarray analysis of immunostaining score with clinicopathological parameters. Int J Gynecol Pathol 25(2):140–146PubMedGoogle Scholar
  54. Johansson N, Airola K, Grenman R, Kariniemi AL, Saarialho-Kere U, Kahari VM (1997) Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck. Am J Pathol 151(2):499–508PubMedGoogle Scholar
  55. Kajita M, Itoh Y, Chiba T et al (2001) Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J Cell Biol 153(5):893–904PubMedGoogle Scholar
  56. Katori H, Baba Y, Imagawa Y et al (2002) Reduction of in vivo tumor growth by MMI-166, a selective matrix metalloproteinase inhibitor, through inhibition of tumor angiogenesis in squamous cell carcinoma cell lines of head and neck. Cancer Lett 178(2):151–159PubMedGoogle Scholar
  57. Kishnani NS, Staskus PW, Yang T-T, Masiarz FR, Hawkes SP (1995) Identification and characterization of human tissue inhibitor of metalloproteinase-3 and detection of three additional metalloproteinase inhibitor activities in extracellular matrix. Matrix Biol 14(6):479–488PubMedGoogle Scholar
  58. Klein CA, Seidl S, Petat-Dutter K et al (2002) Combined transcriptome and genome analysis of single micrometastatic cells. Nat Biotechnol 20(4):387–392PubMedGoogle Scholar
  59. Kurahara S, Shinohara M, Ikebe T et al (1999) Expression of MMPS, MT-MMP, and TIMPs in squamous cell carcinoma of the oral cavity: correlations with tumor invasion and metastasis. Head Neck 21(7):627–638PubMedGoogle Scholar
  60. Kuriakose MA, Loree TR, Rubenfeld A et al (2002) Simultaneously presenting head and neck and lung cancer: a diagnostic and treatment dilemma. Laryngoscope 112(1):120–123PubMedGoogle Scholar
  61. Kurose K, Hoshaw-Woodard S, Adeyinka A, Lemeshow S, Watson PH, Eng C (2001) Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions. Hum Mol Genet 10(18):1907–1913PubMedGoogle Scholar
  62. Latreille J, Batist G, Laberge F et al (2003) Phase I/II trial of the safety and efficacy of AE-941 (Neovastat) in the treatment of non-small-cell lung cancer. Clin Lung Cancer 4(4):231–236PubMedGoogle Scholar
  63. Leon X, Quer M, Orus C, del Prado Venegas M (2001) Can cure be achieved in patients with head and neck carcinomas? The problem of second neoplasm. Expert Rev Anticancer Ther 1(1):125–133PubMedGoogle Scholar
  64. Lewis AM, Varghese S, Xu H, Alexander HR (2006) Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment. J Transl Med 4:48PubMedGoogle Scholar
  65. Li SL, Gao DL, Zhao ZH et al (2007) Correlation of matrix metalloproteinase suppressor genes RECK, VEGF, and CD105 with angiogenesis and biological behavior in esophageal squamous cell carcinoma. World J Gastroenterol 13(45):6076–6081PubMedGoogle Scholar
  66. Liotta LA (1986) Tumor invasion and metastases – role of the extracellular matrix: Rhoads Memorial Award lecture. Cancer Res 46(1):1–7PubMedGoogle Scholar
  67. Liotta LA, Kohn EC (2001) The microenvironment of the tumour-host interface. Nature 411(6835):375–379PubMedGoogle Scholar
  68. Lu SL, Herrington H, Reh D et al (2006) Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev 20(10):1331–1342PubMedGoogle Scholar
  69. Lynch CC, Matrisian LM (2002) Matrix metalloproteinases in tumor-host cell communication. Differentiation 70(9–10):561–573PubMedGoogle Scholar
  70. Mabjeesh NJ, Amir S (2007) Hypoxia-inducible factor (HIF) in human tumorigenesis. Histol Histopathol 22(5):559–572PubMedGoogle Scholar
  71. Mandic R, Dunne AA, Eikelkamp N et al (2002) Expression of MMP-3, MMP-13, TIMP-2 and TIMP-3 in the VX2 carcinoma of the New Zealand white rabbit. Anticancer Res 22(6A):3281–3284PubMedGoogle Scholar
  72. Marcus B, Arenberg D, Lee J et al (2004) Prognostic factors in oral cavity and oropharyngeal squamous cell carcinoma. Cancer 101(12):2779–2787PubMedGoogle Scholar
  73. Matrisian LM, Wright J, Newell K, Witty JP (1994) Matrix-degrading metalloproteinases in tumor progression. Princess Takamatsu Symp 24:152–161PubMedGoogle Scholar
  74. McCawley LJ, Matrisian LM (2001) Tumor progression: defining the soil round the tumor seed. Curr Biol 11(1):R25–R27PubMedGoogle Scholar
  75. McDonald DM, Teicher BA, Stetler-Stevenson W et al (2004) Report from the society for biological therapy and vascular biology faculty of the NCI workshop on angiogenesis monitoring. J Immunother 27(2):161–175PubMedGoogle Scholar
  76. Micke P, Ostman A (2005) Exploring the tumour environment: cancer-associated fibroblasts as targets in cancer therapy. Expert Opin Ther Targets 9(6):1217–1233PubMedGoogle Scholar
  77. Moinfar F, Man YG, Arnould L, Bratthauer GL, Ratschek M, Tavassoli FA (2000) Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res 60(9):2562–2566PubMedGoogle Scholar
  78. Moinfar F, Kremser ML, Man YG, Zatloukal K, Tavassoli FA, Denk H (2004) Allelic imbalances in endometrial stromal neoplasms: frequent genetic alterations in the nontumorous normal-appearing endometrial and myometrial tissues. Gynecol Oncol 95(3):662–671PubMedGoogle Scholar
  79. Mori H, Tomari T, Koshikawa N et al (2002) CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain. EMBO J 21(15):3949–3959PubMedGoogle Scholar
  80. Mueller MM, Fusenig NE (2002) Tumor-stroma interactions directing phenotype and progression of epithelial skin tumor cells. Differentiation 70(9–10):486–497PubMedGoogle Scholar
  81. Mueller MM, Peter W, Mappes M et al (2001) Tumor progression of skin carcinoma cells in vivo promoted by clonal selection, mutagenesis, and autocrine growth regulation by granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Am J Pathol 159(4):1567–1579PubMedGoogle Scholar
  82. Muller D, Wolf C, Abecassis J et al (1993) Increased stromelysin 3 gene expression is associated with increased local invasiveness in head and neck squamous cell carcinomas. Cancer Res 53(1):165–169PubMedGoogle Scholar
  83. Noda M, Oh J, Takahashi R, Kondo S, Kitayama H, Takahashi C (2003) RECK: a novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling. Cancer Metastasis Rev 22(2–3):167–175PubMedGoogle Scholar
  84. O-Charoenrat P, Rhys-Evans P, Modjtahedi H, Court W, Box G, Eccles S (2000) Overexpression of epidermal growth factor receptor in human head and neck squamous carcinoma cell lines correlates with matrix metalloproteinase-9 expression and in vitro invasion. Int J Cancer 86(3):307–317PubMedGoogle Scholar
  85. O-Charoenrat P, Rhys-Evans P, Eccles SA (2001a) Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis. Cancer 92(3):556–568PubMedGoogle Scholar
  86. O-Charoenrat P, Rhys-Evans PH, Eccles SA (2001b) Expression of matrix metalloproteinases and their inhibitors correlates with invasion and metastasis in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 127(7):813–820PubMedGoogle Scholar
  87. O-Charoenrat P, Rhys-Evans P, Eccles S (2002) A synthetic matrix metalloproteinase inhibitor prevents squamous carcinoma cell proliferation by interfering with epidermal growth factor receptor autocrine loops. Int J Cancer 100(5):527–533PubMedGoogle Scholar
  88. Oh J, Takahashi R, Kondo S et al (2001) The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 107(6):789–800PubMedGoogle Scholar
  89. Okada A, Bellocq JP, Rouyer N et al (1995) Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas. Proc Natl Acad Sci USA 92(7):2730–2734PubMedGoogle Scholar
  90. Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR (1999) Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 59(19):5002–5011PubMedGoogle Scholar
  91. Ondruschka C, Buhtz P, Motsch C et al (2002) Prognostic value of MMP-2, -9 and TIMP-1,-2 immunoreactive protein at the invasive front in advanced head and neck squamous cell carcinomas. Pathol Res Pract 198(8):509–515PubMedGoogle Scholar
  92. Orimo A, Gupta PB, Sgroi DC et al (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121(3):335–348PubMedGoogle Scholar
  93. Patel BP, Shah PM, Rawal UM et al (2005) Activation of MMP-2 and MMP-9 in patients with oral squamous cell carcinoma. J Surg Oncol 90(2):81–88PubMedGoogle Scholar
  94. Pauli BU, Knudson W (1988) Tumor invasion: a consequence of destructive and compositional matrix alterations. Hum Pathol 19(6):628–639PubMedGoogle Scholar
  95. Pei D, Weiss SJ (1996) Transmembrane-deletion mutants of the membrane-type matrix metalloproteinase-1 process progelatinase A and express intrinsic matrix-degrading activity. J Biol Chem 271(15):9135–9140PubMedGoogle Scholar
  96. Peterson JT (2004) Matrix metalloproteinase inhibitor development and the remodeling of drug discovery. Heart Fail Rev 9(1):63–79PubMedGoogle Scholar
  97. Picard O, Rolland Y, Poupon MF (1986) Fibroblast-dependent tumorigenicity of cells in nude mice: implication for implantation of metastases. Cancer Res 46(7):3290–3294PubMedGoogle Scholar
  98. Polette M, Gilles C, Marchand V et al (1997) Tumor collagenase stimulatory factor (TCSF) expression and localization in human lung and breast cancers. J Histochem Cytochem 45(5):703–709PubMedGoogle Scholar
  99. Ponec M, Hoekman K, Lowik C (1991) Cell-cell communication: parathyroid hormone-like protein production by squamous carcinoma cells is modulated by fibroblasts. A possible mechanism in the development of humoral hypercalcemia of malignancy. Curr Probl Dermatol 20:1–10PubMedGoogle Scholar
  100. Pries R, Wollenberg B (2006) Cytokines in head and neck cancer. Cytokine Growth Factor Rev 17(3):141–146PubMedGoogle Scholar
  101. Pries R, Nitsch S, Wollenberg B (2006) Role of cytokines in head and neck squamous cell carcinoma. Expert Rev Anticancer Ther 6(9):1195–1203PubMedGoogle Scholar
  102. Rhee JS, Coussens LM (2002) RECKing MMP function: implications for cancer development. Trends Cell Biol 12(5):209–211PubMedGoogle Scholar
  103. Riethdorf S, Reimers N, Assmann V et al (2006) High incidence of EMMPRIN expression in human tumors. Int J Cancer 119(8):1800–1810PubMedGoogle Scholar
  104. Rofstad EK (2000) Microenvironment-induced cancer metastasis. Int J Radiat Biol 76(5):589–605PubMedGoogle Scholar
  105. Rosenthal EL, Hotary K, Bradford C, Weiss SJ (1999) Role of membrane type 1-matrix metalloproteinase and gelatinase A in head and neck squamous cell carcinoma invasion in vitro. Otolaryngol Head Neck Surg 121(4):337–343PubMedGoogle Scholar
  106. Rosenthal EL, Shreenivas S, Peters GE, Grizzle WE, Desmond R, Gladson CL (2003) Expression of extracellular matrix metalloprotease inducer in laryngeal squamous cell carcinoma. Laryngoscope 113(8):1406–1410PubMedGoogle Scholar
  107. Rosenthal E, McCrory A, Talbert M, Young G, Murphy-Ullrich J, Gladson C (2004a) Elevated expression of TGF-beta1 in head and neck cancer-associated fibroblasts. Mol Carcinog 40(2):116–121PubMedGoogle Scholar
  108. Rosenthal EL, McCrory A, Talbert M, Carroll W, Magnuson JS, Peters GE (2004b) Expression of proteolytic enzymes in head and neck cancer-associated fibroblasts. Arch Otolaryngol Head Neck Surg 130(8):943–947PubMedGoogle Scholar
  109. Rosenthal EL, Vidrine DM, Zhang W (2006) Extracellular matrix metalloprotease inducer stimulates fibroblast-mediated tumor growth in vivo. Laryngoscope 116(7):1086–1092PubMedGoogle Scholar
  110. Sasahara RM, Brochado SM, Takahashi C et al (2002) Transcriptional control of the RECK metastasis/angiogenesis suppressor gene. Cancer Detect Prev 26(6):435–443PubMedGoogle Scholar
  111. Scherubl H, Scherer H, Hoffmeister B (2002) Head and neck cancer. N Engl J Med 346(18):1416–1417PubMedGoogle Scholar
  112. Senger DR, Claffey KP, Benes JE, Perruzzi CA, Sergiou AP, Detmar M (1997) Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins. Proc Natl Acad Sci USA 94(25):13612–13617PubMedGoogle Scholar
  113. Skobe M, Fusenig NE (1998) Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. Proc Natl Acad Sci USA 95(3):1050–1055PubMedGoogle Scholar
  114. Sledge GW Jr, Qulali M, Goulet R, Bone EA, Fife R (1995) Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J Natl Cancer Inst 87(20):1546–1550PubMedGoogle Scholar
  115. Span PN, Sweep CG, Manders P, Beex LV, Leppert D, Lindberg RL (2003) Matrix metalloproteinase inhibitor reversion-inducing cysteine-rich protein with Kazal motifs: a prognostic marker for good clinical outcome in human breast carcinoma. Cancer 97(11):2710–2715PubMedGoogle Scholar
  116. Sparano JA, Bernardo P, Stephenson P et al (2004) Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol 22(23):4683–4690PubMedGoogle Scholar
  117. Stamenkovic I (2000) Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol 10(6):415–433PubMedGoogle Scholar
  118. Sternlicht MD, Lochter A, Sympson CJ et al (1999) The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98(2):137–146PubMedGoogle Scholar
  119. Stetler-Stevenson WG (2008) The tumor microenvironment: regulation by MMP-independent effects of tissue inhibitor of metalloproteinases-2. Cancer Metastasis Rev 27(1):57–66PubMedGoogle Scholar
  120. Stetler-Stevenson WG, Seo DW (2005) TIMP-2: an endogenous inhibitor of angiogenesis. Trends Mol Med 11(3):97–103PubMedGoogle Scholar
  121. Sutinen M, Kainulainen T, Hurskainen T et al (1998) Expression of matrix metalloproteinases (MMP-1 and -2) and their inhibitors (TIMP-1, -2 and -3) in oral lichen planus, dysplasia, squamous cell carcinoma and lymph node metastasis. Br J Cancer 77(12):2239–2245PubMedGoogle Scholar
  122. Tang Y, Nakada MT, Kesavan P et al (2005) Extracellular matrix metalloproteinase inducer stimulates tumor angiogenesis by elevating vascular endothelial cell growth factor and matrix metalloproteinases. Cancer Res 65(8):3193–3199PubMedGoogle Scholar
  123. Taylor PM, Woodfield RJ, Hodgkin MN et al (2002) Breast cancer cell-derived EMMPRIN stimulates fibroblast MMP2 release through a phospholipase A(2) and 5-lipoxygenase catalyzed pathway. Oncogene 21(37):5765–5772PubMedGoogle Scholar
  124. Thomasset N, Lochter A, Sympson CJ et al (1998) Expression of autoactivated stromelysin-1 in mammary glands of transgenic mice leads to a reactive stroma during early development. Am J Pathol 153(2):457–467PubMedGoogle Scholar
  125. Tokumaru Y, Fujii M, Otani Y et al (2000) Activation of matrix metalloproteinase-2 in head and neck squamous cell carcinoma: studies of clinical samples and in vitro cell lines co-cultured with fibroblasts. Cancer Lett 150(1):15–21PubMedGoogle Scholar
  126. Tsukifuji R, Tagawa K, Hatamochi A, Shinkai H (1999) Expression of matrix metalloproteinase-1, -2 and -3 in squamous cell carcinoma and actinic keratosis. Br J Cancer 80(7):1087–1091PubMedGoogle Scholar
  127. Uria JA, Ferrando AA, Velasco G, Freije JM, Lopez-Otin C (1994) Structure and expression in breast tumors of human TIMP-3, a new member of the metalloproteinase inhibitor family. Cancer Res 54(8):2091–2094PubMedGoogle Scholar
  128. Vigneswaran N, Beckers S, Waigel S et al (2006) Increased EMMPRIN (CD 147) expression during oral carcinogenesis. Exp Mol Pathol 80(2):147–159PubMedGoogle Scholar
  129. Weber F, Xu Y, Zhang L et al (2007) Microenvironmental genomic alterations and clinicopathological behavior in head and neck squamous cell carcinoma. JAMA 297(2):187–195PubMedGoogle Scholar
  130. Werner JA, Rathcke IO, Mandic R (2002) The role of matrix metalloproteinases in squamous cell carcinomas of the head and neck. Clin Exp Metastasis 19(4):275–282PubMedGoogle Scholar
  131. Yoshizaki T, Sato H, Maruyama Y et al (1997) Increased expression of membrane type 1-matrix metalloproteinase in head and neck carcinoma. Cancer 79(1):139–144PubMedGoogle Scholar
  132. Zhang W, Matrisian LM, Holmbeck K, Vick CC, Rosenthal EL (2006) Fibroblast-derived MT1-MMP promotes tumor progression in vitro and in vivo. BMC Cancer 6:52PubMedGoogle Scholar
  133. Zucker S, Hymowitz M, Rollo EE et al (2001) Tumorigenic potential of extracellular matrix metalloproteinase inducer. Am J Pathol 158(6):1921–1928PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Division of OtolaryngologyUniversity of Alabama at BirminghamBirminghamUSA

Personalised recommendations