Skip to main content

Advertisement

Springer Nature Link
Log in

Three-dimensional context regulation of metastasis

  • Review
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Tumor progression ensues within a three-dimensional microenvironment that consists of cellular and non-cellular components. The extracellular matrix (ECM) and hypoxia are two non-cellular components that potently influence metastasis. ECM remodeling and collagen cross-linking stiffen the tissue stroma to promote transformation, tumor growth, motility and invasion, enhance cancer cell survival, enable metastatic dissemination, and facilitate the establishment of tumor cells at distant sites. Matrix degradation can additionally promote malignant progression and metastasis. Tumor hypoxia is functionally linked to altered stromal-epithelial interactions. Hypoxia additionally induces the expression of pro-migratory, survival and invasion genes, and up-regulates expression of ECM components and modifying enzymes, to enhance tumor progression and metastasis. Synergistic interactions between matrix remodeling and tumor hypoxia influence common mechanisms that maximize tumor progression and cooperate to drive metastasis. Thus, clarifying the molecular pathways by which ECM remodeling and tumor hypoxia intersect to promote tumor progression should identify novel therapeutic targets.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

2D, 3D:

2- and 3-dimensional

Pa:

Pascals

ECM:

Extracellular matrix

MMP:

Matrix metalloproteinase

LOX:

Lysyl oxidase

HIF:

Hypoxia-inducible factor

CAF:

Cancer-associated fibroblast

TAM:

Tumor-associated macrophage

TGF:

Tissue growth factor

BMDC:

Bone marrow-derived cell

MEC:

Mammary epithelial cell

HMEC:

Human mammary epithelial cell

References

  1. Bissell MJ, Radisky D (2001) Putting tumours in context. Nat Rev Cancer 1:46–54. doi:10.1038/35094059

    PubMed  CAS  Google Scholar 

  2. Mintz B, Illmensee K (1975) Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA 72:3585–3589. doi:10.1073/pnas.72.9.3585

    PubMed  CAS  Google Scholar 

  3. Dolberg DS, Bissell MJ (1984) Inability of Rous sarcoma virus to cause sarcomas in the avian embryo. Nature 309:552–556. doi:10.1038/309552a0

    PubMed  CAS  Google Scholar 

  4. Weaver VM, Petersen OW, Wang F, Larabell CA, Briand P, Damsky C et al (1997) Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol 137:231–245. doi:10.1083/jcb.137.1.231

    PubMed  CAS  Google Scholar 

  5. Barcellos-Hoff MH, Ravani SA (2000) Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 60:1254–1260

    PubMed  CAS  Google Scholar 

  6. Wiseman BS, Werb Z (2002) Stromal effects on mammary gland development and breast cancer. Science 296:1046–1049. doi:10.1126/science.1067431

    PubMed  CAS  Google Scholar 

  7. Burdelya LG, Komarova EA, Hill JE, Browder T, Tararova ND, Mavrakis L et al (2006) Inhibition of p53 response in tumor stroma improves efficacy of anticancer treatment by increasing antiangiogenic effects of chemotherapy and radiotherapy in mice. Cancer Res 66:9356–9361. doi:10.1158/0008-5472.CAN-06-1223

    PubMed  CAS  Google Scholar 

  8. Bhowmick NA, Moses HL (2005) Tumor-stroma interactions. Curr Opin Genet Dev 15:97–101. doi:10.1016/j.gde.2004.12.003

    PubMed  CAS  Google Scholar 

  9. Haass NK, Smalley KS, Herlyn M (2004) The role of altered cell-cell communication in melanoma progression. J Mol Histol 35:309–318. doi:10.1023/B:HIJO.0000032362.35354.bb

    PubMed  CAS  Google Scholar 

  10. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW et al (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449:557–563. doi:10.1038/nature06188

    PubMed  CAS  Google Scholar 

  11. Coussens LM, Raymond WW, Bergers G, Laig-Webster M, Behrendtsen O, Werb Z et al (1999) Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev 13:1382–1397. doi:10.1101/gad.13.11.1382

    PubMed  CAS  Google Scholar 

  12. Iyengar P, Combs TP, Shah SJ, Gouon-Evans V, Pollard JW, Albanese C et al (2003) Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization. Oncogene 22:6408–6423. doi:10.1038/sj.onc.1206737

    PubMed  CAS  Google Scholar 

  13. Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT et al (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440:1222–1226. doi:10.1038/nature04695

    PubMed  CAS  Google Scholar 

  14. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254. doi:10.1016/j.ccr.2005.08.010

    PubMed  CAS  Google Scholar 

  15. Bissell MJ, Aggeler J (1987) Dynamic reciprocity: how do extracellular matrix and hormones direct gene expression? Prog Clin Biol Res 249:251–262

    PubMed  CAS  Google Scholar 

  16. Tlsty TD, Coussens LM (2006) Tumor stroma and regulation of cancer development. Annu Rev Pathol 1:119–150. doi:10.1146/annurev.pathol.1.110304.100224

    PubMed  CAS  Google Scholar 

  17. Aumailley M, Gayraud B (1998) Structure and biological activity of the extracellular matrix. J Mol Med 76:253–265. doi:10.1007/s001090050215

    PubMed  CAS  Google Scholar 

  18. Kass L, Erler JT, Dembo M, Weaver VM (2007) Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis. Int J Biochem Cell Biol 39:1987–1994. doi:10.1016/j.biocel.2007.06.025

    PubMed  CAS  Google Scholar 

  19. Sinkus R, Lorenzen J, Schrader D, Lorenzen M, Dargatz M, Holz D (2000) High-resolution tensor MR elastography for breast tumour detection. Phys Med Biol 45:1649–1664. doi:10.1088/0031-9155/45/6/317

    PubMed  CAS  Google Scholar 

  20. Myllyharju J, Kivirikko KI (2004) Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet 20:33–43. doi:10.1016/j.tig.2003.11.004

    PubMed  CAS  Google Scholar 

  21. Vuorio E, de Crombrugghe B (1990) The family of collagen genes. Annu Rev Biochem 59:837–872. doi:10.1146/annurev.bi.59.070190.004201

    PubMed  CAS  Google Scholar 

  22. Bosman FT, Stamenkovic I (2003) Functional structure and composition of the extracellular matrix. J Pathol 200:423–428. doi:10.1002/path.1437

    PubMed  CAS  Google Scholar 

  23. Howe A, Aplin AE, Alahari SK, Juliano RL (1998) Integrin signaling and cell growth control. Curr Opin Cell Biol 10:220–231. doi:10.1016/S0955-0674(98)80144-0

    PubMed  CAS  Google Scholar 

  24. Weaver VM, Lelievre S, Lakins JN, Chrenek MA, Jones JC, Giancotti F et al (2002) beta4 Integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell 2:205–216. doi:10.1016/S1535-6108(02)00125-3

    PubMed  CAS  Google Scholar 

  25. Bissell MJ, Radisky DC, Rizki A, Weaver VM, Petersen OW (2002) The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation 70:537–546. doi:10.1046/j.1432-0436.2002.700907.x

    PubMed  Google Scholar 

  26. Sugawara K, Tsuruta D, Ishii M, Jones JC, Kobayashi H (2008) Laminin-332 and -511 in skin. Exp Dermatol 17:473–480. doi:10.1111/j.1600-0625.2008.00721.x

    PubMed  CAS  Google Scholar 

  27. Kalluri R (2003) Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 3:422–433. doi:10.1038/nrc1094

    PubMed  CAS  Google Scholar 

  28. Paszek MJ, Weaver VM (2004) The tension mounts: mechanics meets morphogenesis and malignancy. J Mammary Gland Biol Neoplasia 9:325–342. doi:10.1007/s10911-004-1404-x

    PubMed  Google Scholar 

  29. Discher DE, Janmey P, Wang YL (2005) Tissue cells feel and respond to the stiffness of their substrate. Science 310:1139–1143. doi:10.1126/science.1116995

    PubMed  CAS  Google Scholar 

  30. Pedersen JA, Swartz MA (2005) Mechanobiology in the third dimension. Ann Biomed Eng 33:1469–1490. doi:10.1007/s10439-005-8159-4

    PubMed  Google Scholar 

  31. Georges PC, Janmey PA (2005) Cell type-specific response to growth on soft materials. J Appl Physiol 98:1547–1553. doi:10.1152/japplphysiol.01121.2004

    PubMed  Google Scholar 

  32. Janmey PA, Weitz DA (2004) Dealing with mechanics: mechanisms of force transduction in cells. Trends Biochem Sci 29:364–370. doi:10.1016/j.tibs.2004.05.003

    PubMed  CAS  Google Scholar 

  33. Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126:677–689. doi:10.1016/j.cell.2006.06.044

    PubMed  CAS  Google Scholar 

  34. Zahir N, Lakins JN, Russell A, Ming W, Chatterjee C, Rozenberg GI et al (2003) Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors. J Cell Biol 163:1397–1407. doi:10.1083/jcb.200302023

    PubMed  CAS  Google Scholar 

  35. 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 114:33–45. doi:10.1016/S0092-8674(03)00513-0

    PubMed  CAS  Google Scholar 

  36. O’Brien LE, Jou TS, Pollack AL, Zhang Q, Hansen SH, Yurchenco P et al (2001) Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nat Cell Biol 3:831–838. doi:10.1038/ncb0901-831

    PubMed  CAS  Google Scholar 

  37. Cukierman E, Pankov R, Stevens DR, Yamada KM (2001) Taking cell-matrix adhesions to the third dimension. Science 294:1708–1712. doi:10.1126/science.1064829

    PubMed  CAS  Google Scholar 

  38. Yamada KM, Pankov R, Cukierman E (2003) Dimensions and dynamics in integrin function. Braz J Med Biol Res 36:959–966. doi:10.1590/S0100-879X2003000800001

    PubMed  CAS  Google Scholar 

  39. Beacham DA, Cukierman E (2005) Stromagenesis: the changing face of fibroblastic microenvironments during tumor progression. Semin Cancer Biol 15:329–341. doi:10.1016/j.semcancer.2005.05.003

    PubMed  Google Scholar 

  40. Bogenrieder T, Herlyn M (2002) Cell-surface proteolysis, growth factor activation and intercellular communication in the progression of melanoma. Crit Rev Oncol Hematol 44:1–15. doi:10.1016/S1040-8428(01)00196-2

    PubMed  Google Scholar 

  41. Haass NK, Smalley KS, Li L, Herlyn M (2005) Adhesion, migration and communication in melanocytes and melanoma. Pigment Cell Res 18:150–159. doi:10.1111/j.1600-0749.2005.00235.x

    PubMed  CAS  Google Scholar 

  42. Yamada KM, Cukierman E (2007) Modeling tissue morphogenesis and cancer in 3D. Cell 130:601–610. doi:10.1016/j.cell.2007.08.006

    PubMed  CAS  Google Scholar 

  43. Emerman JT, Pitelka DR (1977) Maintenance and induction of morphological differentiation in dissociated mammary epithelium on floating collagen membranes. In Vitro 13:316–328. doi:10.1007/BF02616178

    PubMed  CAS  Google Scholar 

  44. Barcellos-Hoff MH, Aggeler J, Ram TG, Bissell MJ (1989) Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane. Development 105:223–235

    PubMed  CAS  Google Scholar 

  45. Leitinger B, Hohenester E (2007) Mammalian collagen receptors. Matrix Biol 26:146–155. doi:10.1016/j.matbio.2006.10.007

    PubMed  CAS  Google Scholar 

  46. Vogel WF, Abdulhussein R, Ford CE (2006) Sensing extracellular matrix: an update on discoidin domain receptor function. Cell Signal 18:1108–1116. doi:10.1016/j.cellsig.2006.02.012

    PubMed  CAS  Google Scholar 

  47. Avraamides CJ, Garmy-Susini B, Varner JA (2008) Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8(8):604–617

    PubMed  CAS  Google Scholar 

  48. Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687. doi:10.1016/S0092-8674(02)00971-6

    PubMed  CAS  Google Scholar 

  49. Morgan MR, Humphries MJ, Bass MD (2007) Synergistic control of cell adhesion by integrins and syndecans. Nat Rev Mol Cell Biol 8:957–969. doi:10.1038/nrm2289

    PubMed  CAS  Google Scholar 

  50. Miranti CK, Brugge JS (2002) Sensing the environment: a historical perspective on integrin signal transduction. Nat Cell Biol 4:E83–E90. doi:10.1038/ncb0402-e83

    PubMed  CAS  Google Scholar 

  51. Clark EA, Brugge JS (1995) Integrins and signal transduction pathways: the road taken. Science 268:233–239. doi:10.1126/science.7716514

    PubMed  CAS  Google Scholar 

  52. Caswell PT, Norman JC (2006) Integrin trafficking and the control of cell migration. Traffic 7:14–21. doi:10.1111/j.1600-0854.2005.00362.x

    PubMed  CAS  Google Scholar 

  53. Huang LE, Bindra RS, Glazer PM, Harris AL (2007) Hypoxia-induced genetic instability—a calculated mechanism underlying tumor progression. J Mol Med 85:139–148. doi:10.1007/s00109-006-0133-6

    PubMed  CAS  Google Scholar 

  54. Lunt SJ, Chaudary N, Hill RP (2008) The tumor microenvironment and metastatic disease. Clin Exp Metastasis. doi:10.1007/s10585-008-9182-2

    PubMed  Google Scholar 

  55. Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD (2007) Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA 104:5431–5436. doi:10.1073/pnas.0701152104

    PubMed  CAS  Google Scholar 

  56. Axelson H, Fredlund E, Ovenberger M, Landberg G, Pahlman S (2005) Hypoxia-induced dedifferentiation of tumor cells–a mechanism behind heterogeneity and aggressiveness of solid tumors. Semin Cell Dev Biol 16:554–563. doi:10.1016/j.semcdb.2005.03.007

    PubMed  CAS  Google Scholar 

  57. Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93:266–276. doi:10.1093/jnci/93.4.266

    PubMed  CAS  Google Scholar 

  58. Rodriguez PG, Felix FN, Woodley DT, Shim EK (2008) The role of oxygen in wound healing: a review of the literature. Dermatol Surg

  59. Simon MC, Keith B (2008) The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol 9:285–296. doi:10.1038/nrm2354

    PubMed  CAS  Google Scholar 

  60. Cartwright JE, Keogh RJ, Tissot van Patot MC (2007) Hypoxia and placental remodelling. Adv Exp Med Biol 618:113–126. doi:10.1007/978-0-387-75434-5_9

    PubMed  Google Scholar 

  61. van Tuyl M, Liu J, Wang J, Kuliszewski M, Tibboel D, Post M (2005) Role of oxygen and vascular development in epithelial branching morphogenesis of the developing mouse lung. Am J Physiol Lung Cell Mol Physiol 288:L167–L178. doi:10.1152/ajplung.00185.2004

    PubMed  Google Scholar 

  62. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361. doi:10.1016/S1535-6108(03)00085-0

    PubMed  Google Scholar 

  63. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732. doi:10.1038/nrc1187

    PubMed  CAS  Google Scholar 

  64. Provot S, Schipani E (2007) Fetal growth plate: a developmental model of cellular adaptation to hypoxia. Ann NY Acad Sci 1117:26–39. doi:10.1196/annals.1402.076

    PubMed  CAS  Google Scholar 

  65. Cowden Dahl KD, Robertson SE, Weaver VM, Simon MC (2005) Hypoxia-inducible factor regulates alphavbeta3 integrin cell surface expression. Mol Biol Cell 16:1901–1912. doi:10.1091/mbc.E04-12-1082

    PubMed  CAS  Google Scholar 

  66. Radisky D, Hagios C, Bissell MJ (2001) Tumors are unique organs defined by abnormal signaling and context. Semin Cancer Biol 11:87–95. doi:10.1006/scbi.2000.0360

    PubMed  CAS  Google Scholar 

  67. Mackie EJ, Chiquet-Ehrismann R, Pearson CA, Inaguma Y, Taya K, Kawarada Y et al (1987) Tenascin is a stromal marker for epithelial malignancy in the mammary gland. Proc Natl Acad Sci USA 84:4621–4625. doi:10.1073/pnas.84.13.4621

    PubMed  CAS  Google Scholar 

  68. Kauppila S, Stenback F, Risteli J, Jukkola A, Risteli L (1998) Aberrant type I and type III collagen gene expression in human breast cancer in vivo. J Pathol 186:262–268. doi:10.1002/(SICI)1096-9896(1998110)186:3<262::AID-PATH191>3.0.CO;2-3

    PubMed  CAS  Google Scholar 

  69. Zhu GG, Risteli L, Makinen M, Risteli J, Kauppila A, Stenback F (1995) Immunohistochemical study of type I collagen and type I pN-collagen in benign and malignant ovarian neoplasms. Cancer 75:1010–1017. doi:10.1002/1097-0142(19950215)75:4<1010::AID-CNCR2820750417>3.0.CO;2-O

    PubMed  CAS  Google Scholar 

  70. Strongin AY (2006) Mislocalization and unconventional functions of cellular MMPs in cancer. Cancer Metastasis Rev 25:87–98. doi:10.1007/s10555-006-7892-y

    PubMed  CAS  Google Scholar 

  71. Jodele S, Blavier L, Yoon JM, DeClerck YA (2006) Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progression. Cancer Metastasis Rev 25:35–43. doi:10.1007/s10555-006-7887-8

    PubMed  CAS  Google Scholar 

  72. Biondi ML, Turri O, Leviti S, Seminati R, Cecchini F, Bernini M et al (2000) MMP1 and MMP3 polymorphisms in promoter regions and cancer. Clin Chem 46:2023–2024

    PubMed  CAS  Google Scholar 

  73. Sternlicht MD, Lochter A, Sympson CJ, Huey B, Rougier JP, Gray JW et al (1999) The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98:137–146. doi:10.1016/S0092-8674(00)81009-0

    PubMed  CAS  Google Scholar 

  74. Seandel M, Noack-Kunnmann K, Zhu D, Aimes RT, Quigley JP (2001) Growth factor-induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen. Blood 97:2323–2332. doi:10.1182/blood.V97.8.2323

    PubMed  CAS  Google Scholar 

  75. Santala M, Simojoki M, Risteli J, Risteli L, Kauppila A (1999) Type I and III collagen metabolites as predictors of clinical outcome in epithelial ovarian cancer. Clin Cancer Res 5:4091–4096

    PubMed  CAS  Google Scholar 

  76. Burns-Cox N, Avery NC, Gingell JC, Bailey AJ (2001) Changes in collagen metabolism in prostate cancer: a host response that may alter progression. J Urol 166:1698–1701. doi:10.1016/S0022-5347(05)65656-X

    PubMed  CAS  Google Scholar 

  77. Ylisirnio S, Hoyhtya M, Makitaro R, Paaakko P, Risteli J, Kinnula VL et al (2001) Elevated serum levels of type I collagen degradation marker ICTP and tissue inhibitor of metalloproteinase (TIMP) 1 are associated with poor prognosis in lung cancer. Clin Cancer Res 7:1633–1637

    PubMed  CAS  Google Scholar 

  78. Clarijs R, Ruiter DJ, De Waal RM (2003) Pathophysiological implications of stroma pattern formation in uveal melanoma. J Cell Physiol 194:267–271. doi:10.1002/jcp.10214

    PubMed  CAS  Google Scholar 

  79. Ruiter D, Bogenrieder T, Elder D, Herlyn M (2002) Melanoma-stroma interactions: structural and functional aspects. Lancet Oncol 3:35–43. doi:10.1016/S1470-2045(01)00620-9

    PubMed  CAS  Google Scholar 

  80. Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266. doi:10.1016/j.cell.2006.01.007

    PubMed  CAS  Google Scholar 

  81. Jain RK (2005) Antiangiogenic therapy for cancer: current and emerging concepts. Oncology 19:7–16 Williston Park

    PubMed  Google Scholar 

  82. Clarijs R, Schalkwijk L, Ruiter DJ, de Waal RM (2001) Lack of lymphangiogenesis despite coexpression of VEGF-C and its receptor Flt-4 in uveal melanoma. Invest Ophthalmol Vis Sci 42:1422–1428

    PubMed  CAS  Google Scholar 

  83. Clarijs R, Otte-Holler I, Ruiter DJ, de Waal RM (2002) Presence of a fluid-conducting meshwork in xenografted cutaneous and primary human uveal melanoma. Invest Ophthalmol Vis Sci 43:912–918

    PubMed  Google Scholar 

  84. Hendrix MJ, Seftor EA, Hess AR, Seftor RE (2003) Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 3:411–421. doi:10.1038/nrc1092

    PubMed  CAS  Google Scholar 

  85. Krouskop TA, Wheeler TM, Kallel F, Garra BS, Hall T (1998) Elastic moduli of breast and prostate tissues under compression. Ultrason Imaging 20:260–274

    PubMed  CAS  Google Scholar 

  86. Khaled W, Reichling S, Bruhns OT, Boese H, Baumann M, Monkman G et al (2004) Palpation imaging using a haptic system for virtual reality applications in medicine. Stud Health Technol Inform 98:147–153

    PubMed  CAS  Google Scholar 

  87. Decitre M, Gleyzal C, Raccurt M, Peyrol S, Aubert-Foucher E, Csiszar K et al (1998) Lysyl oxidase-like protein localizes to sites of de novo fibrinogenesis in fibrosis and in the early stromal reaction of ductal breast carcinomas. Lab Invest 78:143–151

    PubMed  CAS  Google Scholar 

  88. Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK (2004) Pathology: cancer cells compress intratumour vessels. Nature 427:695. doi:10.1038/427695a

    PubMed  CAS  Google Scholar 

  89. Huang S, Ingber DE (2005) Cell tension, matrix mechanics, and cancer development. Cancer Cell 8:175–176. doi:10.1016/j.ccr.2005.08.009

    PubMed  CAS  Google Scholar 

  90. Ingber DE (2008) Can cancer be reversed by engineering the tumor microenvironment? Semin Cancer Biol 18:356–364. doi:10.1016/j.semcancer.2008.03.016

    PubMed  CAS  Google Scholar 

  91. Bischoff F, Bryson G (1964) Carcinogenesis through solid state surfaces. Prog Exp Tumor Res 5:85–133

    PubMed  CAS  Google Scholar 

  92. Ingber DE, Madri JA, Jamieson JD (1981) Role of basal lamina in neoplastic disorganization of tissue architecture. Proc Natl Acad Sci USA 78:3901–3905. doi:10.1073/pnas.78.6.3901

    PubMed  CAS  Google Scholar 

  93. Maffini MV, Calabro JM, Soto AM, Sonnenschein C (2005) Stromal regulation of neoplastic development: age-dependent normalization of neoplastic mammary cells by mammary stroma. Am J Pathol 167:1405–1410

    PubMed  Google Scholar 

  94. Kenny PA, Bissell MJ (2003) Tumor reversion: correction of malignant behavior by microenvironmental cues. Int J Cancer 107:688–695. doi:10.1002/ijc.11491

    PubMed  CAS  Google Scholar 

  95. Watanabe TK, Hansen LJ, Reddy NK, Kanwar YS, Reddy JK (1984) Differentiation of pancreatic acinar carcinoma cells cultured on rat testicular seminiferous tubular basement membranes. Cancer Res 44:5361–5368

    PubMed  CAS  Google Scholar 

  96. Ingber DE, Madri JA, Jamieson JD (1986) Basement membrane as a spatial organizer of polarized epithelia. Exogenous basement membrane reorients pancreatic epithelial tumor cells in vitro. Am J Pathol 122:129–139

    PubMed  CAS  Google Scholar 

  97. Young SD, Marshall RS, Hill RP (1988) Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc Natl Acad Sci USA 85:9533–9537. doi:10.1073/pnas.85.24.9533

    PubMed  CAS  Google Scholar 

  98. Erler JT, Cawthorne CJ, Williams KJ, Koritzinsky M, Wouters BG, Wilson C et al (2004) Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. Mol Cell Biol 24:2875–2889. doi:10.1128/MCB.24.7.2875-2889.2004

    PubMed  CAS  Google Scholar 

  99. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW et al (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379:88–91. doi:10.1038/379088a0

    PubMed  CAS  Google Scholar 

  100. Tamamori M, Ito H, Hiroe M, Marumo F, Hata RI (1997) Stimulation of collagen synthesis in rat cardiac fibroblasts by exposure to hypoxic culture conditions and suppression of the effect by natriuretic peptides. Cell Biol Int 21:175–180. doi:10.1006/cbir.1997.0130

    PubMed  CAS  Google Scholar 

  101. Lu SY, Wang DS, Zhu MZ, Zhang QH, Hu YZ, Pei JM (2005) Inhibition of hypoxia-induced proliferation and collagen synthesis by vasonatrin peptide in cultured rat pulmonary artery smooth muscle cells. Life Sci 77:28–38. doi:10.1016/j.lfs.2004.11.026

    PubMed  CAS  Google Scholar 

  102. Horino Y, Takahashi S, Miura T, Takahashi Y (2002) Prolonged hypoxia accelerates the posttranscriptional process of collagen synthesis in cultured fibroblasts. Life Sci 71:3031–3045. doi:10.1016/S0024-3205(02)02142-2

    PubMed  CAS  Google Scholar 

  103. Kukacka J, Bibova J, Ruskoaho H, Pelouch V (2007) Protein remodeling of extracellular matrix in rat myocardium during four-day hypoxia: the effect of concurrent hypercapnia. Gen Physiol Biophys 26:133–142

    PubMed  CAS  Google Scholar 

  104. Takahashi Y, Takahashi S, Shiga Y, Yoshimi T, Miura T (2000) Hypoxic induction of prolyl 4-hydroxylase alpha (I) in cultured cells. J Biol Chem 275:14139–14146. doi:10.1074/jbc.275.19.14139

    PubMed  CAS  Google Scholar 

  105. Myllyharju J (2003) Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis. Matrix Biol 22:15–24. doi:10.1016/S0945-053X(03)00006-4

    PubMed  CAS  Google Scholar 

  106. Le QT, Denko NC, Giaccia AJ (2004) Hypoxic gene expression and metastasis. Cancer Metastasis Rev 23:293–310. doi:10.1023/B:CANC.0000031768.89246.d7

    PubMed  CAS  Google Scholar 

  107. Denko NC, Fontana LA, Hudson KM, Sutphin PD, Raychaudhuri S, Altman R et al (2003) Investigating hypoxic tumor physiology through gene expression patterns. Oncogene 22:5907–5914. doi:10.1038/sj.onc.1206703

    PubMed  CAS  Google Scholar 

  108. Kagan HM, Li W (2003) Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem 88:660–672. doi:10.1002/jcb.10413

    PubMed  CAS  Google Scholar 

  109. van den Hooff A (1988) Stromal involvement in malignant growth. Adv Cancer Res 50:159–196. doi:10.1016/S0065-230X(08)60437-6

    PubMed  Google Scholar 

  110. Sappino AP, Schurch W, Gabbiani G (1990) Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as marker of phenotypic modulations. Lab Invest 63:144–161

    PubMed  CAS  Google Scholar 

  111. Ronnov-Jessen L, Petersen OW, Bissell MJ (1996) Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev 76:69–125

    PubMed  CAS  Google Scholar 

  112. Ingber DE, Madri JA, Jamieson JD (1985) Neoplastic disorganization of pancreatic epithelial cell-cell relations. Role of basement membrane. Am J Pathol 121:248–260

    PubMed  CAS  Google Scholar 

  113. Lu S, Huang M, Kobayashi Y, Komiyama A, Li X, Katoh R et al (2000) Alterations of basement membrane in di-isopropanolnitrosamine-induced carcinogenesis of the rat thyroid gland: an immunohistochemical study. Virchows Arch 436:595–601. doi:10.1007/s004280000180

    PubMed  CAS  Google Scholar 

  114. Ozzello L (1959) The behavior of basement membranes in intraductal carcinoma of the breast. Am J Pathol 35:887–899

    PubMed  CAS  Google Scholar 

  115. Luibel FJ, Sanders E, Ashworth CT (1960) An electron microscopic study of carcinoma in situ and invasive carcinoma of the cervix uteri. Cancer Res 20:357–361

    PubMed  CAS  Google Scholar 

  116. Rubio CA, Biberfeld P (1979) The basement membrane in experimentally induced atypias and carcinoma of the uterine cervix in mice. An immunofluorescence study. Virchows Arch A Pathol Anat Histol 381:205–209. doi:10.1007/BF01257885

    PubMed  CAS  Google Scholar 

  117. Lee JM, Dedhar S, Kalluri R, Thompson EW (2006) The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172:973–981. doi:10.1083/jcb.200601018

    PubMed  CAS  Google Scholar 

  118. Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B et al (2007) Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117:3810–3820

    PubMed  CAS  Google Scholar 

  119. Lester RD, Jo M, Montel V, Takimoto S, Gonias SL (2007) uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells. J Cell Biol 178:425–436. doi:10.1083/jcb.200701092

    PubMed  CAS  Google Scholar 

  120. Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ et al (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10:295–305. doi:10.1038/ncb1691

    PubMed  CAS  Google Scholar 

  121. Farge E (2003) Mechanical induction of twist in the Drosophila foregut/stomodeal primordium. Curr Biol 13:1365–1377. doi:10.1016/S0960-9822(03)00576-1

    PubMed  CAS  Google Scholar 

  122. Tschumperlin DJ, Shively JD, Kikuchi T, Drazen JM (2003) Mechanical stress triggers selective release of fibrotic mediators from bronchial epithelium. Am J Respir Cell Mol Biol 28:142–149. doi:10.1165/rcmb.2002-0121OC

    PubMed  CAS  Google Scholar 

  123. Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E (1996) TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 10:2462–2477. doi:10.1101/gad.10.19.2462

    PubMed  CAS  Google Scholar 

  124. Miettinen PJ, Ebner R, Lopez AR, Derynck R (1994) TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 127:2021–2036. doi:10.1083/jcb.127.6.2021

    PubMed  CAS  Google Scholar 

  125. Hosobuchi M, Stampfer MR (1989) Effects of transforming growth factor beta on growth of human mammary epithelial cells in culture. In Vitro Cell Dev Biol 25:705–713. doi:10.1007/BF02623723

    PubMed  CAS  Google Scholar 

  126. Akhurst RJ, Derynck R (2001) TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol 11:S44–S51

    PubMed  CAS  Google Scholar 

  127. Waerner T, Alacakaptan M, Tamir I, Oberauer R, Gal A, Brabletz T et al (2006) ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell 10:227–239. doi:10.1016/j.ccr.2006.07.020

    PubMed  CAS  Google Scholar 

  128. Huang H, Kamm RD, Lee RT (2004) Cell mechanics and mechanotransduction: pathways, probes, and physiology. Am J Physiol Cell Physiol 287:C1–C11. doi:10.1152/ajpcell.00559.2003

    PubMed  CAS  Google Scholar 

  129. Bershadsky AD, Balaban NQ, Geiger B (2003) Adhesion-dependent cell mechanosensitivity. Annu Rev Cell Dev Biol 19:677–695. doi:10.1146/annurev.cellbio.19.111301.153011

    PubMed  CAS  Google Scholar 

  130. Bellovin DI, Simpson KJ, Danilov T, Maynard E, Rimm DL, Oettgen P et al (2006) Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma. Oncogene 25:6959–6967. doi:10.1038/sj.onc.1209682

    PubMed  CAS  Google Scholar 

  131. Reno F, Grazianetti P, Stella M, Magliacani G, Pezzuto C, Cannas M (2002) Release and activation of matrix metalloproteinase-9 during in vitro mechanical compression in hypertrophic scars. Arch Dermatol 138:475–478. doi:10.1001/archderm.138.4.475

    PubMed  CAS  Google Scholar 

  132. Sullivan R, Graham CH (2007) Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev 26:319–331. doi:10.1007/s10555-007-9062-2

    PubMed  CAS  Google Scholar 

  133. van Kempen LC, Ruiter DJ, van Muijen GN, Coussens LM (2003) The tumor microenvironment: a critical determinant of neoplastic evolution. Eur J Cell Biol 82:539–548. doi:10.1078/0171-9335-00346

    PubMed  Google Scholar 

  134. Berndt A, Borsi L, Hyckel P, Kosmehl H (2001) Fibrillary co-deposition of laminin-5 and large unspliced tenascin-C in the invasive front of oral squamous cell carcinoma in vivo and in vitro. J Cancer Res Clin Oncol 127:286–292. doi:10.1007/s004320000205

    PubMed  CAS  Google Scholar 

  135. Mammoto A, Mammoto T, Ingber DE (2008) Rho signaling and mechanical control of vascular development. Curr Opin Hematol 15:228–234. doi:10.1097/MOH.0b013e3282fa7445

    PubMed  CAS  Google Scholar 

  136. Milkiewicz M, Haas TL (2005) Effect of mechanical stretch on HIF-1{alpha} and MMP-2 expression in capillaries isolated from overloaded skeletal muscles: laser capture microdissection study. Am J Physiol Heart Circ Physiol 289:H1315–H1320. doi:10.1152/ajpheart.00284.2005

    PubMed  CAS  Google Scholar 

  137. Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47. doi:10.1038/nrc704

    PubMed  CAS  Google Scholar 

  138. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867. doi:10.1038/nature01322

    PubMed  CAS  Google Scholar 

  139. 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 60:2562–2566

    PubMed  CAS  Google Scholar 

  140. Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337. doi:10.1038/nature03096

    PubMed  CAS  Google Scholar 

  141. Yeung T, Georges PC, Flanagan LA, Marg B, Ortiz M, Funaki M et al (2005) Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil Cytoskeleton 60:24–34. doi:10.1002/cm.20041

    PubMed  Google Scholar 

  142. Huang S, Ingber DE (1999) The structural and mechanical complexity of cell-growth control. Nat Cell Biol 1:E131–E138. doi:10.1038/13043

    PubMed  CAS  Google Scholar 

  143. Ebihara T, Venkatesan N, Tanaka R, Ludwig MS (2000) Changes in extracellular matrix and tissue viscoelasticity in bleomycin-induced lung fibrosis. Temporal aspects. Am J Respir Crit Care Med 162:1569–1576

    PubMed  CAS  Google Scholar 

  144. Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K et al (2004) Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol 2:E7. doi:10.1371/journal.pbio.0020007

    PubMed  Google Scholar 

  145. 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 59:5002–5011

    PubMed  CAS  Google Scholar 

  146. Bauer EA, Uitto J, Walters RC, Eisen AZ (1979) Enhanced collagenase production by fibroblasts derived from human basal cell carcinomas. Cancer Res 39:4594–4599

    PubMed  CAS  Google Scholar 

  147. Knudson W, Biswas C, Toole BP (1984) Interactions between human tumor cells and fibroblasts stimulate hyaluronate synthesis. Proc Natl Acad Sci USA 81:6767–6771. doi:10.1073/pnas.81.21.6767

    PubMed  CAS  Google Scholar 

  148. Willis RA (1967) The unusual in tumour pathology. Can Med Assoc J 97:1466–1479

    PubMed  CAS  Google Scholar 

  149. Colpaert CG, Vermeulen PB, Fox SB, Harris AL, Dirix LY, Van Marck EA (2003) The presence of a fibrotic focus in invasive breast carcinoma correlates with the expression of carbonic anhydrase IX and is a marker of hypoxia and poor prognosis. Breast Cancer Res Treat 81:137–147. doi:10.1023/A:1025702330207

    PubMed  CAS  Google Scholar 

  150. Jacobs TW, Byrne C, Colditz G, Connolly JL, Schnitt SJ (1999) Radial scars in benign breast-biopsy specimens and the risk of breast cancer. N Engl J Med 340:430–436. doi:10.1056/NEJM199902113400604

    PubMed  CAS  Google Scholar 

  151. Sieweke MH, Thompson NL, Sporn MB, Bissell MJ (1990) Mediation of wound-related Rous sarcoma virus tumorigenesis by TGF-beta. Science 248:1656–1660. doi:10.1126/science.2163544

    PubMed  CAS  Google Scholar 

  152. Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM et al (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 83:4167–4171. doi:10.1073/pnas.83.12.4167

    PubMed  CAS  Google Scholar 

  153. Unger M, Weaver VM (2003) The tissue microenvironment as an epigenetic tumor modifier. Methods Mol Biol 223:315–347

    PubMed  CAS  Google Scholar 

  154. Fringer J, Grinnell F (2003) Fibroblast quiescence in floating collagen matrices: decrease in serum activation of MEK and Raf but not Ras. J Biol Chem 278:20612–20617. doi:10.1074/jbc.M212365200

    PubMed  CAS  Google Scholar 

  155. Erler JT, Giaccia AJ (2006) Lysyl oxidase mediates hypoxic control of metastasis. Cancer Res 66:10238–10241. doi:10.1158/0008-5472.CAN-06-3197

    PubMed  CAS  Google Scholar 

  156. Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174. doi:10.1038/nrc745

    PubMed  CAS  Google Scholar 

  157. de Visser KE, Korets LV, Coussens LM (2004) Early neoplastic progression is complement independent. Neoplasia 6:768–776. doi:10.1593/neo.04250

    PubMed  Google Scholar 

  158. Dallas SL, Rosser JL, Mundy GR, Bonewald LF (2002) Proteolysis of latent transforming growth factor-beta (TGF-beta)-binding protein-1 by osteoclasts. A cellular mechanism for release of TGF-beta from bone matrix. J Biol Chem 277:21352–21360. doi:10.1074/jbc.M111663200

    PubMed  CAS  Google Scholar 

  159. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS et al (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285. doi:10.1016/S0092-8674(00)81848-6

    PubMed  CAS  Google Scholar 

  160. Ramchandran R, Dhanabal M, Volk R, Waterman MJ, Segal M, Lu H et al (1999) Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem Biophys Res Commun 255:735–739. doi:10.1006/bbrc.1999.0248

    PubMed  CAS  Google Scholar 

  161. Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K et al (2000) Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res 60:2520–2526

    PubMed  CAS  Google Scholar 

  162. Maeshima Y, Colorado PC, Torre A, Holthaus KA, Grunkemeyer JA, Ericksen MB et al (2000) Distinct antitumor properties of a type IV collagen domain derived from basement membrane. J Biol Chem 275:21340–21348. doi:10.1074/jbc.M001956200

    PubMed  CAS  Google Scholar 

  163. Coussens LM, Tinkle CL, Hanahan D, Werb Z (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103:481–490. doi:10.1016/S0092-8674(00)00139-2

    PubMed  CAS  Google Scholar 

  164. Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193:727–740. doi:10.1084/jem.193.6.727

    PubMed  CAS  Google Scholar 

  165. Lin EY, Gouon-Evans V, Nguyen AV, Pollard JW (2002) The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia 7:147–162. doi:10.1023/A:1020399802795

    PubMed  Google Scholar 

  166. Kobayashi A, Greenblatt RM, Anastos K, Minkoff H, Massad LS, Young M et al (2004) Functional attributes of mucosal immunity in cervical intraepithelial neoplasia and effects of HIV infection. Cancer Res 64:6766–6774. doi:10.1158/0008-5472.CAN-04-1091

    PubMed  CAS  Google Scholar 

  167. Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612. doi:10.1158/0008-5472.CAN-05-4005

    PubMed  CAS  Google Scholar 

  168. Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, Alitalo K et al (2001) Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol 159:893–903

    PubMed  CAS  Google Scholar 

  169. Schoppmann SF, Birner P, Stockl J, Kalt R, Ullrich R, Caucig C et al (2002) Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 161:947–956

    PubMed  CAS  Google Scholar 

  170. Knowles HJ, Harris AL (2007) Macrophages and the hypoxic tumour microenvironment. Front Biosci 12:4298–4314. doi:10.2741/2389

    PubMed  CAS  Google Scholar 

  171. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827. doi:10.1038/nature04186

    PubMed  CAS  Google Scholar 

  172. Hiratsuka S, Watanabe A, Aburatani H, Maru Y (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8:1369–1375. doi:10.1038/ncb1507

    PubMed  CAS  Google Scholar 

  173. Hiratsuka S, Nakamura K, Iwai S, Murakami M, Itoh T, Kijima H et al (2002) MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2:289–300. doi:10.1016/S1535-6108(02)00153-8

    PubMed  CAS  Google Scholar 

  174. Chantrain CF, Shimada H, Jodele S, Groshen S, Ye W, Shalinsky DR et al (2004) Stromal matrix metalloproteinase-9 regulates the vascular architecture in neuroblastoma by promoting pericyte recruitment. Cancer Res 64:1675–1686. doi:10.1158/0008-5472.CAN-03-0160

    PubMed  CAS  Google Scholar 

  175. Masson V, de la Ballina LR, Munaut C, Wielockx B, Jost M, Maillard C et al (2005) Contribution of host MMP-2 and MMP-9 to promote tumor vascularization and invasion of malignant keratinocytes. FASEB J 19:234–236

    PubMed  CAS  Google Scholar 

  176. Nelson CM, Jean RP, Tan JL, Liu WF, Sniadecki NJ, Spector AA et al (2005) Emergent patterns of growth controlled by multicellular form and mechanics. Proc Natl Acad Sci USA 102:11594–11599. doi:10.1073/pnas.0502575102

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We apologize to those authors whose excellent work could not be cited due to space limitations. This work was supported by DOD BCRP W81XWH-05-1-330, NCI CA078731, and DOE A107165 (VMW); and by The Institute of Cancer Research, and Cancer Research UK (JTE).

Author information

Authors and Affiliations

  1. Hypoxia and Metastasis Team, Section of Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK

    Janine T. Erler

  2. Departments of Surgery, Anatomy, Bioengineering and Therapeutic Sciences, Center for Bioengineering and Tissue Regeneration and Institute for Regenerative Medicine, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA, 94143-0456, USA

    Valerie M. Weaver

Authors
  1. Janine T. Erler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valerie M. Weaver
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Janine T. Erler or Valerie M. Weaver.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Erler, J.T., Weaver, V.M. Three-dimensional context regulation of metastasis. Clin Exp Metastasis 26, 35–49 (2009). https://doi.org/10.1007/s10585-008-9209-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-008-9209-8

Keywords

Search

Navigation