Top

Cancer Chemotherapy and Pharmacology

Published in:

01-03-2009 | Review

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

Authors: Flaubert Mbeunkui, Donald J. Johann Jr

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2009

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

World Health Organization (2006) 297 edn

Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70PubMedCrossRef

Kuper H, Adami HO, Trichopoulos D (2000) Infections as a major preventable cause of human cancer. J Intern Med 248(3):171–183PubMedCrossRef

Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867PubMedCrossRef

Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6(5):392–401PubMedCrossRef

Liotta LA, Kohn EC (2001) The microenvironment of the tumour-host interface. Nature 411(6835):375–379PubMedCrossRef

Weinberg RA (2007) The biology of cancer. Garland Science. Taylor & Francis Group, LLC

Handsley MM, Edwards DR (2005) Metalloproteinases and their inhibitors in tumor angiogenesis. Int J Cancer 115(6):849–860PubMedCrossRef

Albini A, Sporn MB (2007) The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 7(2):139–147PubMedCrossRef

10.

Joyce JA (2005) Therapeutic targeting of the tumor microenvironment. Cancer Cell 7(6):513–520PubMedCrossRef

11.

Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4(11):839–849PubMedCrossRef

12.

Volmer MW, Radacz Y, Hahn SA et al (2004) 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 4(5):1324–1334PubMedCrossRef

13.

Chevallet M, Diemer H, Van Dorssealer A, Villiers C, Rabilloud T (2007) Toward a better analysis of secreted proteins: the example of the myeloid cells secretome. Proteomics 7(11):1757–1770PubMedCrossRef

14.

Mbeunkui F, Fodstad O, Pannell LK (2006) Secretory protein enrichment and analysis: an optimized approach applied on cancer cell lines using 2D LC–MS/MS. J Proteome Res 5(4):899–906PubMedCrossRef

15.

Mbeunkui F, Metge BJ, Shevde LA, Pannell LK (2007) Identification of differentially secreted biomarkers using LC-MS/MS in isogenic cell lines representing a progression of breast cancer. J Proteome Res 6(8):2993–3002PubMedCrossRef

16.

Pardo M, Garcia A, Antrobus R, Blanco MJ, Dwek RA, Zitzmann N (2007) Biomarker discovery from uveal melanoma secretomes: identification of gp100 and cathepsin D in patient serum. J Proteome Res 6(7):2802–2811PubMedCrossRef

17.

Volmer MW, Stuhler K, Zapatka M et al (2005) Differential proteome analysis of conditioned media to detect Smad4 regulated secreted biomarkers in colon cancer. Proteomics 5(10):2587–2601PubMedCrossRef

18.

Khwaja FW, Svoboda P, Reed M, Pohl J, Pyrzynska B, Van Meir EG (2006) Proteomic identification of the wt-p53-regulated tumor cell secretome. Oncogene 25(58):7650–7661PubMedCrossRef

19.

Gronborg M, Kristiansen TZ, Iwahori A et al (2006) Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach. Mol Cell Proteomics 5(1):157–171PubMed

20.

Zwickl H, Traxler E, Staettner S et al (2005) A novel technique to specifically analyze the secretome of cells and tissues. Electrophoresis 26(14):2779–2785PubMedCrossRef

21.

Jiang L, He L, Fountoulakis M (2004) Comparison of protein precipitation methods for sample preparation prior to proteomic analysis. J Chromatogr A 1023(2):317–320PubMedCrossRef

22.

Schwarz K, Fiedler T, Fischer RJ, Bahl H (2007) A standard operating procedure (SOP) for the preparation of intra- and extracellular proteins of Clostridium acetobutylicum for proteome analysis. J Microbiol Methods 68(2):396–402PubMedCrossRef

23.

Diamandis EP (2003) Point: Proteomic patterns in biological fluids: do they represent the future of cancer diagnostics? Clin Chem 49(8):1272–1275PubMedCrossRef

24.

Villanueva J, Shaffer DR, Philip J et al (2006) Differential exoprotease activities confer tumor-specific serum peptidome patterns. J Clin Invest 116(1):271–284PubMedCrossRef

25.

Gerner C, Vejda S, Gelbmann D et al (2002) Concomitant determination of absolute values of cellular protein amounts, synthesis rates, and turnover rates by quantitative proteome profiling. Mol Cell Proteomics 1(7):528–537PubMedCrossRef

26.

Hanash S, Brichory F, Beer D (2001) A proteomic approach to the identification of lung cancer markers. Dis Markers 17(4):295–300PubMed

27.

Mann M, Kelleher NL (2008) Special feature: precision proteomics: the case for high resolution and high mass accuracy. Proc Natl Acad Sci USA

28.

Gronborg M, Bunkenborg J, Kristiansen TZ et al (2004) Comprehensive proteomic analysis of human pancreatic juice. J Proteome Res 3(5):1042–1055PubMedCrossRef

29.

Kristiansen TZ, Bunkenborg J, Gronborg M et al (2004) A proteomic analysis of human bile. Mol Cell Proteomics 3(7):715–728PubMedCrossRef

30.

Fenn JB, Mann M, Meng CK, Wong SF, Whitehouse CM (1989) Electrospray ionization for mass spectrometry of large biomolecules. Science 246(4926):64–71PubMedCrossRef

31.

Gygi SP, Rist B, Gerber SA, Turecek F, Gelb MH, Aebersold R (1999) Quantitative analysis of complex protein mixtures using isotope-coded affinity tags. Nat Biotechnol 17(10):994–999PubMedCrossRef

32.

Gygi SP, Rist B, Griffin TJ, Eng J, Aebersold R (2002) Proteome analysis of low-abundance proteins using multidimensional chromatography and isotope-coded affinity tags. J Proteome Res 1(1):47–54PubMedCrossRef

33.

Amanchy R, Kalume DE, Pandey A (2005) Stable isotope labeling with amino acids in cell culture (SILAC) for studying dynamics of protein abundance and posttranslational modifications. Sci STKE 2005(267):l2CrossRef

34.

Ong SE, Blagoev B, Kratchmarova I et al (2002) Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol Cell Proteomics 1(5):376–386PubMedCrossRef

35.

DeClerck YA, Mercurio AM, Stack MS et al (2004) Proteases, extracellular matrix, and cancer: a workshop of the path B study section. Am J Pathol 164(4):1131–1139PubMed

36.

Devy L, Blacher S, Grignet-Debrus C et al (2002) The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J 16(2):147–154PubMedCrossRef

37.

Etzioni R, Urban N, Ramsey S et al (2003) The case for early detection. Nat Rev Cancer 3(4):243–252PubMedCrossRef

38.

Li Y, Hively WP, Varmus HE (2000) Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer. Oncogene 19(8):1002–1009PubMedCrossRef

39.

Harvie M, Hooper L, Howell AH (2003) Central obesity and breast cancer risk: a systematic review. Obes Rev 4(3):157–173PubMedCrossRef

40.

Rose DP, Komninou D, Stephenson GD (2004) Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev 5(3):153–165PubMedCrossRef

41.

Nemir M, Bhattacharyya D, Li X, Singh K, Mukherjee AB, Mukherjee BB (2000) Targeted inhibition of osteopontin expression in the mammary gland causes abnormal morphogenesis and lactation deficiency. J Biol Chem 275(2):969–976PubMedCrossRef

42.

Rittling SR, Matsumoto HN, McKee MD et al (1998) Mice lacking osteopontin show normal development and bone structure but display altered osteoclast formation in vitro. J Bone Miner Res 13(7):1101–1111PubMedCrossRef

43.

Liaw L, Birk DE, Ballas CB, Whitsitt JS, Davidson JM, Hogan BL (1998) Altered wound healing in mice lacking a functional osteopontin gene (spp1). J Clin Invest 101(7):1468–1478PubMed

44.

Rudland PS, Platt-Higgins A, El Tanani M et al (2002) Prognostic significance of the metastasis-associated protein osteopontin in human breast cancer. Cancer Res 62(12):3417–3427PubMed

45.

El Tanani MK, Campbell FC, Kurisetty V, Jin D, McCann M, Rudland PS (2006) The regulation and role of osteopontin in malignant transformation and cancer. Cytokine Growth Factor Rev 17(6):463–474PubMedCrossRef

46.

Tuck AB, Chambers AF (2001) The role of osteopontin in breast cancer: clinical and experimental studies. J Mammary Gland Biol Neoplasia 6(4):419–429PubMedCrossRef

47.

Weber GF (2001) The metastasis gene osteopontin: a candidate target for cancer therapy. Biochim Biophys Acta 1552(2):61–85PubMed

48.

Mangala LS, Fok JY, Zorrilla-Calancha IR, Verma A, Mehta K (2007) Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells. Oncogene 26(17):2459–2470PubMedCrossRef

49.

Mi Z, Oliver T, Guo H, Gao C, Kuo PC (2007) Thrombin-cleaved COOH(–) terminal osteopontin peptide binds with cyclophilin C to CD147 in murine breast cancer cells. Cancer Res 67(9):4088–4097PubMedCrossRef

50.

Tuck AB, Elliott BE, Hota C, Tremblay E, Chambers AF (2000) Osteopontin-induced, integrin-dependent migration of human mammary epithelial cells involves activation of the hepatocyte growth factor receptor (Met). J Cell Biochem 78(3):465–475PubMedCrossRef

51.

Tuck AB, Hota C, Wilson SM, Chambers AF (2003) Osteopontin-induced migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways. Oncogene 22(8):1198–1205PubMedCrossRef

52.

Matarrese P, Fusco O, Tinari N et al (2000) Galectin-3 overexpression protects from apoptosis by improving cell adhesion properties. Int J Cancer 85(4):545–554PubMedCrossRef

53.

Inohara H, Honjo Y, Yoshii T et al (1999) Expression of galectin-3 in fine-needle aspirates as a diagnostic marker differentiating benign from malignant thyroid neoplasms. Cancer 85(11):2475–2484PubMedCrossRef

54.

Honjo Y, Nangia-Makker P, Inohara H, Raz A (2001) Down-regulation of galectin-3 suppresses tumorigenicity of human breast carcinoma cells. Clin Cancer Res 7(3):661–668PubMed

55.

Moses HL, Branum EL, Proper JA, Robinson RA (1981) Transforming growth factor production by chemically transformed cells. Cancer Res 41(7):2842–2848PubMed

56.

Roberts AB, Wakefield LM (2003) The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci USA 100(15):8621–8623PubMedCrossRef

57.

Levy L, Hill CS (2006) Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev 17(1–2):41–58PubMedCrossRef

58.

Bhowmick NA, Chytil A, Plieth D et al (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303(5659):848–851PubMedCrossRef

59.

Nakajima M, Welch DR, Belloni PN, Nicolson GL (1987) Degradation of basement membrane type IV collagen and lung subendothelial matrix by rat mammary adenocarcinoma cell clones of differing metastatic potentials. Cancer Res 47(18):4869–4876PubMed

60.

Fingleton B, Vargo-Gogola T, Crawford HC, Matrisian LM (2001) Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis. Neoplasia 3(6):459–468PubMedCrossRef

61.

Noe V, Fingleton B, Jacobs K et al (2001) Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 114(Pt 1):111–118PubMed

62.

Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295(5564):2387–2392PubMedCrossRef

63.

Remacle A, McCarthy K, Noel A et al (2000) High levels of TIMP-2 correlate with adverse prognosis in breast cancer. Int J Cancer 89(2):118–121PubMedCrossRef

64.

Garcia-Rodriguez LA, Huerta-Alvarez C (2001) Reduced risk of colorectal cancer among long-term users of aspirin and nonaspirin nonsteroidal antiinflammatory drugs. Epidemiology 12(1):88–93PubMedCrossRef

65.

Koki AT, Masferrer JL (2002) Celecoxib: a specific COX-2 inhibitor with anticancer properties. Cancer Control 9(2 Suppl):28–35PubMed

66.

Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9(6):653–660PubMedCrossRef

67.

Joyce JA, Baruch A, Chehade K et al (2004) Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell 5(5):443–453PubMedCrossRef

68.

Joyce JA, Freeman C, Meyer-Morse N, Parish CR, Hanahan D (2005) A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. Oncogene 24(25):4037–4051PubMed

69.

Hamano Y, Zeisberg M, Sugimoto H et al (2003) 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 3(6):589–601PubMedCrossRef

70.

Guo W, Giancotti FG (2004) Integrin signalling during tumour progression. Nat Rev Mol Cell Biol 5(10):816–826PubMedCrossRef

71.

Sethi T, Rintoul RC, Moore SM et al (1999) 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 5(6):662–668PubMedCrossRef

72.

Morin PJ (2003) Drug resistance and the microenvironment: nature and nurture. Drug Resist Updat 6(4):169–172PubMedCrossRef

73.

Park JE, Lenter MC, Zimmermann RN, Garin-Chesa P, Old LJ, Rettig WJ (1999) Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem 274(51):36505–36512PubMedCrossRef

74.

Allinen M, Beroukhim R, Cai L et al (2004) Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6(1):17–32PubMedCrossRef

75.

Scott AM, Wiseman G, Welt S et al (2003) A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res 9(5):1639–1647PubMed

76.

Yu H, Jove R (2004) The STATs of cancer-new molecular targets come of age. Nat Rev Cancer 4(2):97–105PubMedCrossRef

77.

Dauer DJ, Ferraro B, Song L et al (2005) Stat3 regulates genes common to both wound healing and cancer. Oncogene 24(21):3397–3408PubMedCrossRef

78.

Karin M (2006) NF-kappaB and cancer: mechanisms and targets. Mol Carcinog 45(6):355–361PubMedCrossRef

79.

Bertl E, Bartsch H, Gerhauser C (2006) Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention. Mol Cancer Ther 5(3):575–585PubMedCrossRef

80.

Martin DB, Gifford DR, Wright ME et al (2004) Quantitative proteomic analysis of proteins released by neoplastic prostate epithelium. Cancer Res 64(1):347–355PubMedCrossRef

81.

Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2(10):727–739PubMedCrossRef

82.

Young SL, Chaplin DJ (2004) Combretastatin A4 phosphate: background and current clinical status. Expert Opin Investig Drugs 13(9):1171–1182PubMedCrossRef

83.

Jimeno A, Carducci M (2004) Atrasentan: targeting the endothelin axis in prostate cancer. Expert Opin Investig Drugs 13(12):1631–1640PubMedCrossRef

84.

Mooberry SL (2003) New insights into 2-methoxyestradiol, a promising antiangiogenic and antitumor agent. Curr Opin Oncol 15(6):425–430PubMedCrossRef

85.

Jin H, Varner J (2004) Integrins: roles in cancer development and as treatment targets. Br J Cancer 90(3):561–565PubMedCrossRef

86.

Gutheil JC, Campbell TN, Pierce PR et al (2000) Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. Clin Cancer Res 6(8):3056–3061PubMed

87.

Burke PA, DeNardo SJ, Miers LA, Lamborn KR, Matzku S, DeNardo GL (2002) Cilengitide targeting of alpha(v)beta(3) integrin receptor synergizes with radioimmunotherapy to increase efficacy and apoptosis in breast cancer xenografts. Cancer Res 62(15):4263–4272PubMed

88.

Gingras D, Boivin D, Deckers C, Gendron S, Barthomeuf C, Beliveau R (2003) Neovastat-a novel antiangiogenic drug for cancer therapy. Anticancer Drugs 14(2):91–96PubMedCrossRef

89.

Bartlett JB, Dredge K, Dalgleish AG (2004) The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 4(4):314–322PubMedCrossRef

90.

Sleijfer S, Kruit WH, Stoter G (2004) Thalidomide in solid tumours: the resurrection of an old drug. Eur J Cancer 40(16):2377–2382PubMedCrossRef

91.

Druker BJ (2004) Imatinib as a paradigm of targeted therapies. Adv Cancer Res 91:1–30PubMedCrossRef

92.

Pietras K, Sjoblom T, Rubin K, Heldin CH, Ostman A (2003) PDGF receptors as cancer drug targets. Cancer Cell 3(5):439–443PubMedCrossRef

93.

Graff JR, McNulty AM, Hanna KR et al (2005) 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 65(16):7462–7469PubMedCrossRef

94.

Mendel DB, Laird AD, Xin X et al (2003) 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 9(1):327–337PubMed

95.

Pietras K, Hanahan D (2005) 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 23(5):939–952PubMedCrossRef

96.

Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3(5):391–400PubMedCrossRef

97.

Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342PubMedCrossRef

98.

Holash J, Davis S, Papadopoulos N et al (2002) VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 99(17):11393–11398PubMedCrossRef

99.

Manley PW, Bold G, Bruggen J et al (2004) Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis. Biochim Biophys Acta 1697(1–2):17–27PubMed

100.

Morgan B, Thomas AL, Drevs J et al (2003) 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 21(21):3955–3964PubMedCrossRef

101.

Wedge SR, Ogilvie DJ, Dukes M et al (2002) ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 62(16):4645–4655PubMed

Title: Cancer and the tumor microenvironment: a review of an essential relationship
Authors: Flaubert Mbeunkui
Donald J. Johann Jr
Publication date: 01-03-2009
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2009
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-008-0881-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 4/2009

Successful treatment with a rituximab-based regimen of a splenic marginal zone lymphoma with villous lymphocytes in a very frail patient on maintenance dialysis

Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc–Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice

Cannabinoid receptor-independent cytotoxic effects of cannabinoids in human colorectal carcinoma cells: synergism with 5-fluorouracil

ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair

Prognostic factor analysis in patients with brain metastases from breast cancer: how can we improve the treatment outcomes?

Hydralazine inhibits human cervical cancer cell growth in vitro in association with APC demethylation and re-expression

Keynote webinar | Spotlight on antibody–drug conjugates in cancer