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A Digest on the Role of the Tumor Microenvironment in Gastrointestinal Cancers

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  • Published:
Cancer Microenvironment

Abstract

Experimental studies and analyses of clinical material have convincingly demonstrated that tumor formation and progression occurs through a concerted action of malignant cells and the surrounding microenvironment of the tumor stroma. The tumor microenvironment is comprised of various cell types like fibroblasts, immune cells, vascular cells and bone-marrow-derived cells embedded in the extracellular matrix. This review, focusing on recent findings in the context of gastrointestinal tumors, introduces the different stromal cell types and delineates their contributions to cancer initiation, growth and metastasis. By selected examples we also present how the tumor microenvironment is emerging as a promising target for therapeutic intervention.

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References

  1. Gatenby RA, Gillies RJ (2008) A microenvironmental model of carcinogenesis. Nat Rev Cancer 8:56–61

    Article  CAS  PubMed  Google Scholar 

  2. Tahara E (2008) Abnormal growth factor/cytokine network in gastric cancer. Cancer Microenviron 1:85–91

    Article  PubMed  CAS  Google Scholar 

  3. Kitadai Y (2009) Cancer-stromal cell interaction and tumor angiogenesis in gastric cancer. Cancer Microenviron. doi:10.1007/s12307-009-0032-9

  4. Yashiro M, Hirakawa K (2010) Cancer-stromal interactions in scirrhous gastric carcinoma. doi:10.1007/s12307-010-0036-5

  5. Gout S, Huot J (2008) Role of cancer microenvironment in metastasis: focus on colon cancer. Cancer Microenviron 1:69–83

    Article  PubMed  CAS  Google Scholar 

  6. Ronnov-Jessen L, Petersen OW, Koteliansky VE et al (1995) The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest 95:859–873

    Article  CAS  PubMed  Google Scholar 

  7. Spaeth EL, Dembinski JL, Sasser AK et al (2009) Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS ONE 4:e4992

    Article  PubMed  CAS  Google Scholar 

  8. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

    Article  CAS  PubMed  Google Scholar 

  9. Ostman A, Augsten M (2009) Cancer-associated fibroblasts and tumor growth-bystanders turning into key players. Curr Opin Genet Dev 19:67–73

    Article  PubMed  CAS  Google Scholar 

  10. Paulsson J, Sjoblom T, Micke P et al (2009) Prognostic significance of stromal platelet-derived growth factor beta-receptor expression in human breast cancer. Am J Pathol 175:334–341

    Article  PubMed  Google Scholar 

  11. Sugimoto H, Mundel TM, Kieran MW et al (2006) Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol Ther 5:1640–1646

    CAS  PubMed  Google Scholar 

  12. Anderberg C, Li H, Fredriksson L et al (2009) Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts. Cancer Res 69:369–378

    Article  CAS  PubMed  Google Scholar 

  13. Ronnov-Jessen L, van Deurs B, Celis JE et al (1990) Smooth muscle differentiation in cultured human breast gland stromal cells. Lab Invest 63:532–543

    CAS  PubMed  Google Scholar 

  14. Worthley DL, Ruszkiewicz A, Davies R et al (2009) Human gastrointestinal neoplasia-associated myofibroblasts can develop from bone marrow-derived cells following allogeneic stem cell transplantation. Stem Cells 27:1463–1468

    Article  CAS  PubMed  Google Scholar 

  15. Ishii K, Yoshida Y, Akechi Y et al (2008) Hepatic differentiation of human bone marrow-derived mesenchymal stem cells by tetracycline-regulated hepatocyte nuclear factor 3beta. Hepatology 48:597–606

    Article  CAS  PubMed  Google Scholar 

  16. Direkze NC, Hodivala-Dilke K, Jeffery R et al (2004) Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res 64:8492–8495

    Article  CAS  PubMed  Google Scholar 

  17. Zeisberg EM, Potenta S, Xie L et al (2007) Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67:10123–10128

    Article  CAS  PubMed  Google Scholar 

  18. Radisky DC, Kenny PA, Bissell MJ (2007) Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem 101:830–839

    Article  CAS  PubMed  Google Scholar 

  19. Tsujino T, Seshimo I, Yamamoto H et al (2007) Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clin Cancer Res 13:2082–2090

    Article  CAS  PubMed  Google Scholar 

  20. Henry LR, Lee HO, Lee JS et al (2007) Clinical implications of fibroblast activation protein in patients with colon cancer. Clin Cancer Res 13:1736–1741

    Article  CAS  PubMed  Google Scholar 

  21. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  CAS  PubMed  Google Scholar 

  22. Mantovani A, Allavena P, Sica A et al (2008) Cancer-related inflammation. Nature 454:436–444

    Article  CAS  PubMed  Google Scholar 

  23. Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252

    Article  CAS  PubMed  Google Scholar 

  24. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78

    Article  CAS  PubMed  Google Scholar 

  25. Allavena P, Sica A, Garlanda C et al (2008) The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev 222:155–161

    Article  CAS  PubMed  Google Scholar 

  26. Oguma K, Oshima H, Aoki M et al (2008) Activated macrophages promote Wnt signalling through tumour necrosis factor-alpha in gastric tumour cells. Embo J 27:1671–1681

    Article  CAS  PubMed  Google Scholar 

  27. Pukrop T, Klemm F, Hagemann T et al (2006) Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. Proc Natl Acad Sci U S A 103:5454–5459

    Article  CAS  PubMed  Google Scholar 

  28. Salvesen HB, Akslen LA (1999) Significance of tumour-associated macrophages, vascular endothelial growth factor and thrombospondin-1 expression for tumour angiogenesis and prognosis in endometrial carcinomas. Int J Cancer 84:538–543

    Article  CAS  PubMed  Google Scholar 

  29. Ono M, Torisu H, Fukushi J et al (1999) Biological implications of macrophage infiltration in human tumor angiogenesis. Cancer Chemother Pharmacol 43 Suppl:S69–71

    Article  CAS  PubMed  Google Scholar 

  30. Leek RD, Lewis CE, Whitehouse R et al (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56:4625–4629

    CAS  PubMed  Google Scholar 

  31. Nakayama Y, Nagashima N, Minagawa N et al (2002) Relationships between tumor-associated macrophages and clinicopathological factors in patients with colorectal cancer. Anticancer Res 22:4291–4296

    PubMed  Google Scholar 

  32. Ohtani H, Jin Z, Takegawa S et al (2009) Abundant expression of CXCL9 (MIG) by stromal cells that include dendritic cells and accumulation of CXCR3+ T cells in lymphocyte-rich gastric carcinoma. J Pathol 217:21–31

    Article  CAS  PubMed  Google Scholar 

  33. Garlanda C, Riva F, Polentarutti N et al (2004) Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc Natl Acad Sci U S A 101:3522–3526

    Article  CAS  PubMed  Google Scholar 

  34. Garlanda C, Anders HJ, Mantovani A (2009) TIR8/SIGIRR: an IL-1R/TLR family member with regulatory functions in inflammation and T cell polarization. Trends Immunol 30:439–446

    Article  CAS  PubMed  Google Scholar 

  35. Fridlender ZG, Sun J, Kim S et al (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell 16:183–194

    Article  CAS  PubMed  Google Scholar 

  36. Nielsen BS, Timshel S, Kjeldsen L et al (1996) 92 kDa type IV collagenase (MMP-9) is expressed in neutrophils and macrophages but not in malignant epithelial cells in human colon cancer. Int J Cancer 65:57–62

    Article  CAS  PubMed  Google Scholar 

  37. Eck M, Schmausser B, Scheller K et al (2003) Pleiotropic effects of CXC chemokines in gastric carcinoma: differences in CXCL8 and CXCL1 expression between diffuse and intestinal types of gastric carcinoma. Clin Exp Immunol 134:508–515

    Article  CAS  PubMed  Google Scholar 

  38. Juan TY, Roffler SR, Hou HS et al (2009) Antiangiogenesis targeting tumor microenvironment synergizes glucuronide prodrug antitumor activity. Clin Cancer Res 15:4600–4611

    Article  CAS  PubMed  Google Scholar 

  39. Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A 103:12493–12498

    Article  CAS  PubMed  Google Scholar 

  40. Koshida Y, Kuranami M, Watanabe M (2006) Interaction between stromal fibroblasts and colorectal cancer cells in the expression of vascular endothelial growth factor. J Surg Res 134:270–277

    Article  CAS  PubMed  Google Scholar 

  41. Shibuya M (2008) Vascular endothelial growth factor-dependent and-independent regulation of angiogenesis. BMB Rep 41:278–286

    CAS  PubMed  Google Scholar 

  42. Asahara T, Masuda H, Takahashi T et al (1999) Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85:221–228

    CAS  PubMed  Google Scholar 

  43. Lyden D, Hattori K, Dias S et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201

    Article  CAS  PubMed  Google Scholar 

  44. Hendrix MJ, Seftor EA, Hess AR et al (2003) Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 3:411–421

    Article  CAS  PubMed  Google Scholar 

  45. di Tomaso E, Capen D, Haskell A et al (2005) Mosaic tumor vessels: cellular basis and ultrastructure of focal regions lacking endothelial cell markers. Cancer Res 65:5740–5749

    Article  PubMed  Google Scholar 

  46. Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410

    Article  CAS  PubMed  Google Scholar 

  47. Ruoslahti E (2002) Specialization of tumour vasculature. Nat Rev Cancer 2:83–90

    Article  PubMed  Google Scholar 

  48. St Croix B, Rago C, Velculescu V et al (2000) Genes expressed in human tumor endothelium. Science 289:1197–1202

    Article  CAS  PubMed  Google Scholar 

  49. Hida K, Klagsbrun M (2005) A new perspective on tumor endothelial cells: unexpected chromosome and centrosome abnormalities. Cancer Res 65:2507–2510

    Article  CAS  PubMed  Google Scholar 

  50. Hida K, Hida Y, Amin DN et al (2004) Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res 64:8249–8255

    Article  CAS  PubMed  Google Scholar 

  51. Akino T, K Hida, Y Hida, et al. (2009) Cytogenetic Abnormalities of Tumor-Associated Endothelial Cells in Human Malignant Tumors. Am J Pathol.

  52. Gaengel K, Genove G, Armulik A et al (2009) Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 29:630–638

    Article  CAS  PubMed  Google Scholar 

  53. Morikawa S, Baluk P, Kaidoh T et al (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160:985–1000

    PubMed  Google Scholar 

  54. Furuhashi M, Sjoblom T, Abramsson A et al (2004) Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate. Cancer Res 64:2725–2733

    Article  CAS  PubMed  Google Scholar 

  55. Abramsson A, Lindblom P, Betsholtz C (2003) Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Invest 112:1142–1151

    CAS  PubMed  Google Scholar 

  56. Xian X, Hakansson J, Stahlberg A et al (2006) Pericytes limit tumor cell metastasis. J Clin Invest 116:642–651

    Article  CAS  PubMed  Google Scholar 

  57. Song S, Ewald AJ, Stallcup W et al (2005) PDGFRbeta+perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 7:870–879

    Article  CAS  PubMed  Google Scholar 

  58. Hasumi Y, Klosowska-Wardega A, Furuhashi M et al (2007) Identification of a subset of pericytes that respond to combination therapy targeting PDGF and VEGF signaling. Int J Cancer 121:2606–2614

    Article  CAS  PubMed  Google Scholar 

  59. Yonenaga Y, Mori A, Onodera H et al (2005) Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncology 69:159–166

    Article  PubMed  Google Scholar 

  60. Vlodavsky I, Elkin M, Abboud-Jarrous G et al (2008) Heparanase: one molecule with multiple functions in cancer progression. Connect Tissue Res 49:207–210

    Article  CAS  PubMed  Google Scholar 

  61. Inaba T, Sano H, Kawahito Y et al (2003) Induction of cyclooxygenase-2 in monocyte/macrophage by mucins secreted from colon cancer cells. Proc Natl Acad Sci U S A 100:2736–2741

    Article  CAS  PubMed  Google Scholar 

  62. Avizienyte E, Wyke AW, Jones RJ et al (2002) Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nat Cell Biol 4:632–638

    CAS  PubMed  Google Scholar 

  63. Playford MP, Schaller MD (2004) The interplay between Src and integrins in normal and tumor biology. Oncogene 23:7928–7946

    Article  CAS  PubMed  Google Scholar 

  64. Ma C, Rong Y, Radiloff DR et al (2008) Extracellular matrix protein betaig-h3/TGFBI promotes metastasis of colon cancer by enhancing cell extravasation. Genes Dev 22:308–321

    Article  PubMed  CAS  Google Scholar 

  65. Butcher DT, Alliston T, Weaver VM (2009) A tense situation: forcing tumour progression. Nat Rev Cancer 9:108–122

    Article  CAS  PubMed  Google Scholar 

  66. Bauskin AR, Brown DA, Kuffner T et al (2006) Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer. Cancer Res 66:4983–4986

    Article  CAS  PubMed  Google Scholar 

  67. Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22:1276–1312

    Article  CAS  PubMed  Google Scholar 

  68. Ostman A, Heldin CH (2007) PDGF receptors as targets in tumor treatment. Adv Cancer Res 97:247–274

    Article  PubMed  CAS  Google Scholar 

  69. Kitadai Y, Sasaki T, Kuwai T et al (2006) Expression of activated platelet-derived growth factor receptor in stromal cells of human colon carcinomas is associated with metastatic potential. Int J Cancer 119:2567–2574

    Article  CAS  PubMed  Google Scholar 

  70. Leeb SN, Vogl D, Falk W et al (2002) Regulation of migration of human colonic myofibroblasts. Growth Factors 20:81–91

    Article  CAS  PubMed  Google Scholar 

  71. Powell DW, Mifflin RC, Valentich JD et al (1999) Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am J Physiol 277:C183–201

    CAS  PubMed  Google Scholar 

  72. Yauch RL, Gould SE, Scales SJ et al (2008) A paracrine requirement for hedgehog signalling in cancer. Nature 455:406–410

    Article  CAS  PubMed  Google Scholar 

  73. Massague J (2008) TGFbeta in Cancer. Cell 134:215–230

    Article  CAS  PubMed  Google Scholar 

  74. Pardali E, ten Dijke P (2009) Transforming growth factor-beta signaling and tumor angiogenesis. Front Biosci 14:4848–4861

    Article  PubMed  Google Scholar 

  75. De Wever O, Westbroek W, Verloes A et al (2004) Critical role of N-cadherin in myofibroblast invasion and migration in vitro stimulated by colon-cancer-cell-derived TGF-beta or wounding. J Cell Sci 117:4691–4703

    Article  PubMed  CAS  Google Scholar 

  76. Kuwai T, Nakamura T, Kim SJ et al (2008) Intratumoral heterogeneity for expression of tyrosine kinase growth factor receptors in human colon cancer surgical specimens and orthotopic tumors. Am J Pathol 172:358–366

    Article  PubMed  Google Scholar 

  77. Sasaki T, Kitadai Y, Nakamura T et al (2007) Inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation on tumor-associated endothelial cells leads to treatment of orthotopic human colon cancer in nude mice. Neoplasia 9:1066–1077

    Article  CAS  PubMed  Google Scholar 

  78. Sonvilla G, Allerstorfer S, Stattner S et al (2008) FGF18 in colorectal tumour cells: autocrine and paracrine effects. Carcinogenesis 29:15–24

    Article  CAS  PubMed  Google Scholar 

  79. Varro A, Kenny S, Hemers E et al (2007) Increased gastric expression of MMP-7 in hypergastrinemia and significance for epithelial-mesenchymal signaling. Am J Physiol Gastrointest Liver Physiol 292:G1133–1140

    Article  CAS  PubMed  Google Scholar 

  80. Guo X, Oshima H, Kitmura T et al (2008) Stromal fibroblasts activated by tumor cells promote angiogenesis in mouse gastric cancer. J Biol Chem 283:19864–19871

    Article  CAS  PubMed  Google Scholar 

  81. Heidemann J, Ogawa H, Dwinell MB et al (2003) Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. J Biol Chem 278:8508–8515

    Article  CAS  PubMed  Google Scholar 

  82. Mueller L, Goumas FA, Affeldt M et al (2007) Stromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment. Am J Pathol 171:1608–1618

    Article  CAS  PubMed  Google Scholar 

  83. Koyama S (2005) Coordinate cell-surface expression of matrix metalloproteinases and their inhibitors on cancer-associated myofibroblasts from malignant ascites in patients with gastric carcinoma. J Cancer Res Clin Oncol 131:809–814

    Article  CAS  PubMed  Google Scholar 

  84. Mazzocca A, Coppari R, De Franco R et al (2005) A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions. Cancer Res 65:4728–4738

    Article  CAS  PubMed  Google Scholar 

  85. Sugiyama Y, Farrow B, Murillo C et al (2005) Analysis of differential gene expression patterns in colon cancer and cancer stroma using microdissected tissues. Gastroenterology 128:480–486

    Article  CAS  PubMed  Google Scholar 

  86. Doucas H, Garcea G, Neal CP et al (2005) Changes in the Wnt signalling pathway in gastrointestinal cancers and their prognostic significance. Eur J Cancer 41:365–379

    Article  CAS  PubMed  Google Scholar 

  87. Klapholz-Brown Z, Walmsley GG, Nusse YM et al (2007) Transcriptional program induced by Wnt protein in human fibroblasts suggests mechanisms for cell cooperativity in defining tissue microenvironments. PLoS ONE 2:e945

    Article  PubMed  CAS  Google Scholar 

  88. De Wever O, Nguyen QD, Van Hoorde L et al (2004) Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. Faseb J 18:1016–1018

    PubMed  Google Scholar 

  89. Nakagawa H, Liyanarachchi S, Davuluri RV et al (2004) Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles. Oncogene 23:7366–7377

    Article  CAS  PubMed  Google Scholar 

  90. Koukourakis MI, Giatromanolaki A, Harris AL et al (2006) Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 66:632–637

    Article  CAS  PubMed  Google Scholar 

  91. Sheehan KM, Gulmann C, Eichler GS et al (2008) Signal pathway profiling of epithelial and stromal compartments of colonic carcinoma reveals epithelial-mesenchymal transition. Oncogene 27:323–331

    Article  CAS  PubMed  Google Scholar 

  92. Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7:415–428

    Article  CAS  PubMed  Google Scholar 

  93. Segditsas S, Tomlinson I (2006) Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 25:7531–7537

    Article  CAS  PubMed  Google Scholar 

  94. Kirchner T, Brabletz T (2000) Patterning and nuclear beta-catenin expression in the colonic adenoma-carcinoma sequence. Analogies with embryonic gastrulation. Am J Pathol 157:1113–1121

    CAS  PubMed  Google Scholar 

  95. Gunji N, Oda T, Todoroki T et al (1998) Pancreatic carcinoma: correlation between E-cadherin and alpha-catenin expression status and liver metastasis. Cancer 82:1649–1656

    Article  CAS  PubMed  Google Scholar 

  96. Huang D, Du X (2008) Crosstalk between tumor cells and microenvironment via Wnt pathway in colorectal cancer dissemination. World J Gastroenterol 14:1823–1827

    Article  CAS  PubMed  Google Scholar 

  97. Giehl K, Menke A (2008) Microenvironmental regulation of E-cadherin-mediated adherens junctions. Front Biosci 13:3975–3985

    Article  CAS  PubMed  Google Scholar 

  98. Wu Y, Deng J, Rychahou PG et al (2009) Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15:416–428

    Article  CAS  PubMed  Google Scholar 

  99. Luo JL, Maeda S, Hsu LC et al (2004) Inhibition of NF-kappaB in cancer cells converts inflammation-induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 6:297–305

    Article  CAS  PubMed  Google Scholar 

  100. Katoh M, Katoh M (2009) Integrative genomic analyses of ZEB2: Transcriptional regulation of ZEB2 based on SMADs, ETS1, HIF1alpha, POU/OCT, and NF-kappaB. Int J Oncol 34:1737–1742

    Article  CAS  PubMed  Google Scholar 

  101. Castellone MD, Teramoto H, Williams BO et al (2005) Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 310:1504–1510

    Article  CAS  PubMed  Google Scholar 

  102. Meads MB, Gatenby RA, Dalton WS (2009) Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer 9:665–674

    Article  CAS  PubMed  Google Scholar 

  103. Heldin CH, Rubin K, Pietras K et al (2004) High interstitial fluid pressure-an obstacle in cancer therapy. Nat Rev Cancer 4:806–813

    Article  CAS  PubMed  Google Scholar 

  104. Tong RT, Boucher Y, Kozin SV et al (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64:3731–3736

    Article  CAS  PubMed  Google Scholar 

  105. Wildiers H, Guetens G, De Boeck G et al (2003) Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer 88:1979–1986

    Article  CAS  PubMed  Google Scholar 

  106. Willett CG, Boucher Y, di Tomaso E et al (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145–147

    Article  CAS  PubMed  Google Scholar 

  107. Pietras K, Rubin K, Sjoblom T et al (2002) Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res 62:5476–5484

    CAS  PubMed  Google Scholar 

  108. Pietras K, Ostman A, Sjoquist M et al (2001) Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 61:2929–2934

    CAS  PubMed  Google Scholar 

  109. Olive KP, Jacobetz MA, Davidson CJ et al (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324:1457–1461

    Article  CAS  PubMed  Google Scholar 

  110. Tammi RH, Kultti A, Kosma VM et al (2008) Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal hyaluronan. Semin Cancer Biol 18:288–295

    Article  CAS  PubMed  Google Scholar 

  111. Tutton MG, George ML, Eccles SA et al (2003) Use of plasma MMP-2 and MMP-9 levels as a surrogate for tumour expression in colorectal cancer patients. Int J Cancer 107:541–550

    Article  CAS  PubMed  Google Scholar 

  112. Ngan CY, Yamamoto H, Seshimo I et al (2007) Quantitative evaluation of vimentin expression in tumour stroma of colorectal cancer. Br J Cancer 96:986–992

    Article  CAS  PubMed  Google Scholar 

  113. Gao J, Arbman G, Rearden A et al (2004) Stromal staining for PINCH is an independent prognostic indicator in colorectal cancer. Neoplasia 6:796–801

    Article  CAS  PubMed  Google Scholar 

  114. Degen M, Brellier F, Schenk S et al (2008) Tenascin-W, a new marker of cancer stroma, is elevated in sera of colon and breast cancer patients. Int J Cancer 122:2454–2461

    Article  CAS  PubMed  Google Scholar 

  115. Schwarz MK, Wells TN (2002) New therapeutics that modulate chemokine networks. Nat Rev Drug Discov 1:347–358

    Article  CAS  PubMed  Google Scholar 

  116. Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  CAS  PubMed  Google Scholar 

  117. Miller K, Wang M, Gralow J et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676

    Article  CAS  PubMed  Google Scholar 

  118. Sandler A, Gray R, Perry MC et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550

    Article  CAS  PubMed  Google Scholar 

  119. Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134

    Article  CAS  PubMed  Google Scholar 

  120. Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124

    Article  CAS  PubMed  Google Scholar 

  121. Hudes G, Carducci M, Tomczak P et al (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281

    Article  CAS  PubMed  Google Scholar 

  122. Motzer RJ, Basch E (2007) Targeted drugs for metastatic renal cell carcinoma. Lancet 370:2071–2073

    Article  CAS  PubMed  Google Scholar 

  123. Kitadai Y, Sasaki T, Kuwai T et al (2006) Targeting the expression of platelet-derived growth factor receptor by reactive stroma inhibits growth and metastasis of human colon carcinoma. Am J Pathol 169:2054–2065

    Article  CAS  PubMed  Google Scholar 

  124. Pietras K, Pahler J, Bergers G et al (2008) Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med 5:e19

    Article  PubMed  CAS  Google Scholar 

  125. Wu W, Luo Y, Sun C et al (2006) Targeting cell-impermeable prodrug activation to tumor microenvironment eradicates multiple drug-resistant neoplasms. Cancer Res 66:970–980

    Article  CAS  PubMed  Google Scholar 

  126. Kanagawa N, Niwa M, Hatanaka Y et al (2007) CC-chemokine ligand 17 gene therapy induces tumor regression through augmentation of tumor-infiltrating immune cells in a murine model of preexisting CT26 colon carcinoma. Int J Cancer 121:2013–2022

    Article  CAS  PubMed  Google Scholar 

  127. Loeffler M, Kruger JA, Niethammer AG et al (2006) Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest 116:1955–1962

    Article  CAS  PubMed  Google Scholar 

  128. Kaplan CD, Kruger JA, Zhou H et al (2006) A novel DNA vaccine encoding PDGFRbeta suppresses growth and dissemination of murine colon, lung and breast carcinoma. Vaccine 24:6994–7002

    Article  CAS  PubMed  Google Scholar 

  129. Sugiura D, Aida S, Denda-Nagai K et al (2008) Differential effector mechanisms induced by vaccination with MUC1 DNA in the rejection of colon carcinoma growth at orthotopic sites and metastases. Cancer Sci 99:2477–2484

    Article  CAS  PubMed  Google Scholar 

  130. Yokoi K, Sasaki T, Bucana CD et al (2005) Simultaneous inhibition of EGFR, VEGFR, and platelet-derived growth factor receptor signaling combined with gemcitabine produces therapy of human pancreatic carcinoma and prolongs survival in an orthotopic nude mouse model. Cancer Res 65:10371–10380

    Article  CAS  PubMed  Google Scholar 

  131. Blansfield JA, Caragacianu D, Alexander HR 3rd et al (2008) Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy. Clin Cancer Res 14:270–280

    Article  CAS  PubMed  Google Scholar 

  132. Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9:285–293

    Article  CAS  PubMed  Google Scholar 

  133. Hiratsuka S, Watanabe A, Aburatani H et al (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8:1369–1375

    Article  CAS  PubMed  Google Scholar 

  134. Hiratsuka S, Watanabe A, Sakurai Y et al (2008) The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 10:1349–1355

    Article  CAS  PubMed  Google Scholar 

  135. Erler JT, Bennewith KL, Cox TR et al (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15:35–44

    Article  CAS  PubMed  Google Scholar 

  136. Farmer P, Bonnefoi H, Anderle P et al (2009) A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med 15:68–74

    Article  CAS  PubMed  Google Scholar 

  137. Finak G, Bertos N, Pepin F et al (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14:518–527

    Article  CAS  PubMed  Google Scholar 

  138. Romano MF (2009) Targeting TGFbeta-mediated processes in cancer. Curr Opin Drug Discov Devel 12:253–263

    CAS  PubMed  Google Scholar 

  139. Rubin LL, de Sauvage FJ (2006) Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5:1026–1033

    Article  CAS  PubMed  Google Scholar 

  140. Ma WW, Adjei AA (2009) Novel agents on the horizon for cancer therapy. CA Cancer J Clin 59:111–137

    Article  PubMed  Google Scholar 

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Augsten, M., Hägglöf, C., Peña, C. et al. A Digest on the Role of the Tumor Microenvironment in Gastrointestinal Cancers. Cancer Microenvironment 3, 167–176 (2010). https://doi.org/10.1007/s12307-010-0040-9

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  • DOI: https://doi.org/10.1007/s12307-010-0040-9

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