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PMID: 19083000 Published · ppublish English Journal Article Review

Cancer and the tumor microenvironment: a review of an essential relationship.

Cancer chemotherapy and pharmacology ·Vol. 63 ·No. 4 ·2009-03-00 ·Pages 571-82

Mbeunkui F, Johann DJ

Abstract

The role of the microenvironment during the initiation and progression of carcinogenesis is now realized to be of critical importance, both for enhanced understanding of fundamental cancer biology, as well as exploiting this source of relatively new knowledge for improved molecular diagnostics and therapeutics. This review focuses on: (1) the approaches of preparing and analyzing secreted proteins, (2) the contribution of tumor microenvironment elements in cancer, and (3) the potential molecular targets for cancer therapy. The microenvironment of a tumor is an integral part of its physiology, structure, and function. It is an essential aspect of the tumor proper, since it supplies a nurturing environment for the malignant process. A fundamental deranged relationship between tumor and stromal cells is essential for tumor cell growth, progression, and development of life threatening metastasis. Improved understanding of this interaction may provide new and valuable clinical targets for cancer management, as well as risk assessment and prevention. Non-malignant cells and secreted proteins from tumor and stromal cells are active participants in cancer progression. Monitoring the change in the tumor microenvironment via molecular and cellular profiles as tumor progresses would be vital for identifying cell or protein targets for cancer prevention and therapy.

MeSH Terms
Extracellular Matrix/pathology Humans Neoplasm Proteins/physiology Neoplasms/physiopathology Stromal Cells/pathology
Chemicals
Neoplasm Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Mbeunkui Flaubert
Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA. fmbeunk@ncsu.edu
Johann Donald J
References (99)
99 references, click to expand
  1. Friends or foes - bipolar effects of the tumour stroma in cancer.
    Nat Rev Cancer. 2004 Nov;4(11):839-49 PMID: 15516957
  2. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
    N Engl J Med. 2004 Jun 3;350(23):2335-42 PMID: 15175435
  3. The regulation and role of osteopontin in malignant transformation and cancer.
    Cytokine Growth Factor Rev. 2006 Dec;17(6):463-74 PMID: 17113338
  4. Identification of differentially secreted biomarkers using LC-MS/MS in isogenic cell lines representing a progression of breast cancer.
    J Proteome Res. 2007 Aug;6(8):2993-3002 PMID: 17608509
  5. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer.
    Nat Rev Drug Discov. 2004 May;3(5):391-400 PMID: 15136787
  6. Stable isotope labeling with amino acids in cell culture (SILAC) for studying dynamics of protein abundance and posttranslational modifications.
    Sci STKE. 2005 Jan 18;2005(267):pl2 PMID: 15657263
  7. The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent.
    FASEB J. 2002 Feb;16(2):147-54 PMID: 11818362
  8. Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis.
    Biochim Biophys Acta. 2004 Mar 11;1697(1-2):17-27 PMID: 15023347
  9. Point: Proteomic patterns in biological fluids: do they represent the future of cancer diagnostics?
    Clin Chem. 2003 Aug;49(8):1272-5 PMID: 12881441
  10. Thrombin-cleaved COOH(-) terminal osteopontin peptide binds with cyclophilin C to CD147 in murine breast cancer cells.
    Cancer Res. 2007 May 1;67(9):4088-97 PMID: 17483319
  11. Differential proteome analysis of conditioned media to detect Smad4 regulated secreted biomarkers in colon cancer.
    Proteomics. 2005 Jul;5(10):2587-601 PMID: 15912508
  12. Toward a better analysis of secreted proteins: the example of the myeloid cells secretome.
    Proteomics. 2007 Jun;7(11):1757-70 PMID: 17464941
  13. Obesity, adipocytokines, and insulin resistance in breast cancer.
    Obes Rev. 2004 Aug;5(3):153-65 PMID: 15245384
  14. The microenvironment of the tumour-host interface.
    Nature. 2001 May 17;411(6835):375-9 PMID: 11357145
  15. A Standard Operating Procedure (SOP) for the preparation of intra- and extracellular proteins of Clostridium acetobutylicum for proteome analysis.
    J Microbiol Methods. 2007 Feb;68(2):396-402 PMID: 17098314
  16. Differential exoprotease activities confer tumor-specific serum peptidome patterns.
    J Clin Invest. 2006 Jan;116(1):271-84 PMID: 16395409
  17. Central obesity and breast cancer risk: a systematic review.
    Obes Rev. 2003 Aug;4(3):157-73 PMID: 12916817
  18. Precision proteomics: the case for high resolution and high mass accuracy.
    Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18132-8 PMID: 18818311
  19. Prognostic significance of the metastasis-associated protein osteopontin in human breast cancer.
    Cancer Res. 2002 Jun 15;62(12):3417-27 PMID: 12067984
  20. Integrins: roles in cancer development and as treatment targets.
    Br J Cancer. 2004 Feb 9;90(3):561-5 PMID: 14760364
  21. A proteomic approach to the identification of lung cancer markers.
    Dis Markers. 2001;17(4):295-300 PMID: 11790896
  22. Alterations in components of the TGF-beta superfamily signaling pathways in human cancer.
    Cytokine Growth Factor Rev. 2006 Feb-Apr;17(1-2):41-58 PMID: 16310402
  23. Quantitative proteomic analysis of proteins released by neoplastic prostate epithelium.
    Cancer Res. 2004 Jan 1;64(1):347-55 PMID: 14729644
  24. Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis.
    Cancer Cell. 2004 May;5(5):443-53 PMID: 15144952
  25. Molecular characterization of the tumor microenvironment in breast cancer.
    Cancer Cell. 2004 Jul;6(1):17-32 PMID: 15261139
  26. Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer.
    Oncogene. 2000 Feb 21;19(8):1002-9 PMID: 10713683
  27. Fibroblasts in cancer.
    Nat Rev Cancer. 2006 May;6(5):392-401 PMID: 16572188
  28. Osteopontin-induced migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways.
    Oncogene. 2003 Feb 27;22(8):1198-205 PMID: 12606946
  29. Matrix metalloproteinase inhibitors and cancer: trials and tribulations.
    Science. 2002 Mar 29;295(5564):2387-92 PMID: 11923519
  30. A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer.
    J Clin Oncol. 2005 Feb 10;23(5):939-52 PMID: 15557593
  31. Targeted inhibition of osteopontin expression in the mammary gland causes abnormal morphogenesis and lactation deficiency.
    J Biol Chem. 2000 Jan 14;275(2):969-76 PMID: 10625634
  32. Comprehensive proteomic analysis of human pancreatic juice.
    J Proteome Res. 2004 Sep-Oct;3(5):1042-55 PMID: 15473694
  33. Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells.
    Oncogene. 2007 Apr 12;26(17):2459-70 PMID: 17043648
  34. Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin.
    Cancer Cell. 2003 Jun;3(6):589-601 PMID: 12842087
  35. Degradation of basement membrane type IV collagen and lung subendothelial matrix by rat mammary adenocarcinoma cell clones of differing metastatic potentials.
    Cancer Res. 1987 Sep 15;47(18):4869-76 PMID: 3621180
  36. NF-kappaB and cancer: mechanisms and targets.
    Mol Carcinog. 2006 Jun;45(6):355-61 PMID: 16673382
  37. A proteomic analysis of human bile.
    Mol Cell Proteomics. 2004 Jul;3(7):715-28 PMID: 15084671
  38. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration.
    Cancer Res. 2002 Aug 15;62(16):4645-55 PMID: 12183421
  39. Neovastat--a novel antiangiogenic drug for cancer therapy.
    Anticancer Drugs. 2003 Feb;14(2):91-6 PMID: 12569294
  40. Metalloproteinases and their inhibitors in tumor angiogenesis.
    Int J Cancer. 2005 Jul 20;115(6):849-60 PMID: 15729716
  41. Secretory protein enrichment and analysis: an optimized approach applied on cancer cell lines using 2D LC-MS/MS.
    J Proteome Res. 2006 Apr;5(4):899-906 PMID: 16602697
  42. Proteome analysis of low-abundance proteins using multidimensional chromatography and isotope-coded affinity tags.
    J Proteome Res. 2002 Jan-Feb;1(1):47-54 PMID: 12643526
  43. Reduced risk of colorectal cancer among long-term users of aspirin and nonaspirin nonsteroidal antiinflammatory drugs.
    Epidemiology. 2001 Jan;12(1):88-93 PMID: 11138826
  44. Comparison of protein precipitation methods for sample preparation prior to proteomic analysis.
    J Chromatogr A. 2004 Jan 16;1023(2):317-20 PMID: 14753699
  45. Clinical translation of angiogenesis inhibitors.
    Nat Rev Cancer. 2002 Oct;2(10):727-39 PMID: 12360276
  46. The evolution of thalidomide and its IMiD derivatives as anticancer agents.
    Nat Rev Cancer. 2004 Apr;4(4):314-22 PMID: 15057291
  47. Drug resistance and the microenvironment: nature and nurture.
    Drug Resist Updat. 2003 Aug;6(4):169-72 PMID: 12962682
  48. Electrospray ionization for mass spectrometry of large biomolecules.
    Science. 1989 Oct 6;246(4926):64-71 PMID: 2675315
  49. Atrasentan: targeting the endothelin axis in prostate cancer.
    Expert Opin Investig Drugs. 2004 Dec;13(12):1631-40 PMID: 15566319
  50. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia.
    Science. 2004 Feb 6;303(5659):848-51 PMID: 14764882
  51. Stat3 regulates genes common to both wound healing and cancer.
    Oncogene. 2005 May 12;24(21):3397-408 PMID: 15735721
  52. Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention.
    Mol Cancer Ther. 2006 Mar;5(3):575-85 PMID: 16546971
  53. The tumour microenvironment as a target for chemoprevention.
    Nat Rev Cancer. 2007 Feb;7(2):139-47 PMID: 17218951
  54. The role of osteopontin in breast cancer: clinical and experimental studies.
    J Mammary Gland Biol Neoplasia. 2001 Oct;6(4):419-29 PMID: 12013531
  55. Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis.
    Neoplasia. 2001 Nov-Dec;3(6):459-68 PMID: 11774028
  56. Combretastatin A4 phosphate: background and current clinical status.
    Expert Opin Investig Drugs. 2004 Sep;13(9):1171-82 PMID: 15330748
  57. The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts.
    Cancer Res. 2005 Aug 15;65(16):7462-9 PMID: 16103100
  58. Down-regulation of galectin-3 suppresses tumorigenicity of human breast carcinoma cells.
    Clin Cancer Res. 2001 Mar;7(3):661-8 PMID: 11297262
  59. A novel technique to specifically analyze the secretome of cells and tissues.
    Electrophoresis. 2005 Jul;26(14):2779-85 PMID: 15966010
  60. Proteomic identification of the wt-p53-regulated tumor cell secretome.
    Oncogene. 2006 Dec 7;25(58):7650-61 PMID: 17043663
  61. Infections as a major preventable cause of human cancer.
    J Intern Med. 2000 Sep;248(3):171-83 PMID: 10971784
  62. Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts.
    J Biol Chem. 1999 Dec 17;274(51):36505-12 PMID: 10593948
  63. Integrin signalling during tumour progression.
    Nat Rev Mol Cell Biol. 2004 Oct;5(10):816-26 PMID: 15459662
  64. Quantitative analysis of complex protein mixtures using isotope-coded affinity tags.
    Nat Biotechnol. 1999 Oct;17(10):994-9 PMID: 10504701
  65. Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3.
    Clin Cancer Res. 2000 Aug;6(8):3056-61 PMID: 10955784
  66. PDGF receptors as cancer drug targets.
    Cancer Cell. 2003 May;3(5):439-43 PMID: 12781361
  67. Inflammation and cancer.
    Nature. 2002 Dec 19-26;420(6917):860-7 PMID: 12490959
  68. High levels of TIMP-2 correlate with adverse prognosis in breast cancer.
    Int J Cancer. 2000 Mar 20;89(2):118-21 PMID: 10756061
  69. The case for early detection.
    Nat Rev Cancer. 2003 Apr;3(4):243-52 PMID: 12671663
  70. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship.
    Clin Cancer Res. 2003 Jan;9(1):327-37 PMID: 12538485
  71. A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer.
    Oncogene. 2005 Jun 9;24(25):4037-51 PMID: 15806157
  72. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies.
    J Clin Oncol. 2003 Nov 1;21(21):3955-64 PMID: 14517187
  73. Thalidomide in solid tumours: the resurrection of an old drug.
    Eur J Cancer. 2004 Nov;40(16):2377-82 PMID: 15519508
  74. Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics.
    Mol Cell Proteomics. 2002 May;1(5):376-86 PMID: 12118079
  75. Therapeutic targeting of the tumor microenvironment.
    Cancer Cell. 2005 Jun;7(6):513-20 PMID: 15950901
  76. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1.
    J Cell Sci. 2001 Jan;114(Pt 1):111-118 PMID: 11112695
  77. The STATs of cancer--new molecular targets come of age.
    Nat Rev Cancer. 2004 Feb;4(2):97-105 PMID: 14964307
  78. VEGF-Trap: a VEGF blocker with potent antitumor effects.
    Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11393-8 PMID: 12177445
  79. Proteases, extracellular matrix, and cancer: a workshop of the path B study section.
    Am J Pathol. 2004 Apr;164(4):1131-9 PMID: 15039201
  80. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo.
    Nat Med. 1999 Jun;5(6):662-8 PMID: 10371505
  81. Osteopontin-induced, integrin-dependent migration of human mammary epithelial cells involves activation of the hepatocyte growth factor receptor (Met).
    J Cell Biochem. 2000 Jun 6;78(3):465-75 PMID: 10861844
  82. The hallmarks of cancer.
    Cell. 2000 Jan 7;100(1):57-70 PMID: 10647931
  83. Cilengitide targeting of alpha(v)beta(3) integrin receptor synergizes with radioimmunotherapy to increase efficacy and apoptosis in breast cancer xenografts.
    Cancer Res. 2002 Aug 1;62(15):4263-72 PMID: 12154028
  84. Imatinib as a paradigm of targeted therapies.
    Adv Cancer Res. 2004;91:1-30 PMID: 15327887
  85. The two faces of transforming growth factor beta in carcinogenesis.
    Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8621-3 PMID: 12861075
  86. The metastasis gene osteopontin: a candidate target for cancer therapy.
    Biochim Biophys Acta. 2001 Dec 28;1552(2):61-85 PMID: 11825687
  87. Expression of galectin-3 in fine-needle aspirates as a diagnostic marker differentiating benign from malignant thyroid neoplasms.
    Cancer. 1999 Jun 1;85(11):2475-84 PMID: 10357421
  88. Celecoxib: a specific COX-2 inhibitor with anticancer properties.
    Cancer Control. 2002 Mar-Apr;9(2 Suppl):28-35 PMID: 11965228
  89. Transforming growth factor production by chemically transformed cells.
    Cancer Res. 1981 Jul;41(7):2842-8 PMID: 6265069
  90. Biomarker discovery from uveal melanoma secretomes: identification of gp100 and cathepsin D in patient serum.
    J Proteome Res. 2007 Jul;6(7):2802-11 PMID: 17539671
  91. Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach.
    Mol Cell Proteomics. 2006 Jan;5(1):157-71 PMID: 16215274
  92. New insights into 2-methoxyestradiol, a promising antiangiogenic and antitumor agent.
    Curr Opin Oncol. 2003 Nov;15(6):425-30 PMID: 14624224
  93. Tumor suppressor Smad4 mediates downregulation of the anti-adhesive invasion-promoting matricellular protein SPARC: Landscaping activity of Smad4 as revealed by a "secretome" analysis.
    Proteomics. 2004 May;4(5):1324-34 PMID: 15188399
  94. Concomitant determination of absolute values of cellular protein amounts, synthesis rates, and turnover rates by quantitative proteome profiling.
    Mol Cell Proteomics. 2002 Jul;1(7):528-37 PMID: 12239281
  95. Altered wound healing in mice lacking a functional osteopontin gene (spp1).
    J Clin Invest. 1998 Apr 1;101(7):1468-78 PMID: 9525990
  96. A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer.
    Clin Cancer Res. 2003 May;9(5):1639-47 PMID: 12738716
  97. Mice lacking osteopontin show normal development and bone structure but display altered osteoclast formation in vitro.
    J Bone Miner Res. 1998 Jul;13(7):1101-11 PMID: 9661074
  98. Galectin-3 overexpression protects from apoptosis by improving cell adhesion properties.
    Int J Cancer. 2000 Feb 15;85(4):545-54 PMID: 10699929
  99. Angiogenesis in health and disease.
    Nat Med. 2003 Jun;9(6):653-60 PMID: 12778163
Article Info
Journal
Cancer chemotherapy and pharmacology
Abbr.
Cancer Chemother Pharmacol
ISSN
1432-0843
DOI
10.1007/s00280-008-0881-9
Email
fmbeunk@ncsu.edu
Published
2009-03-00
Epub
2008-00-14
Pages
571-82
Language
English
Region
Germany
NLM ID
7806519
PMCID
PMC2858592
Subset
IM
Grants
Intramural NIH HHS · Z99 CA999999 · United States
External Links
PubMed source DOI: 10.1007/s00280-008-0881-9 PMC Full Text View journal details
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