The tumour microenvironment as a target for chemoprevention

New data indicate that primary dysfunction in the tumour microenvironment, in addition to epithelial dysfunction, can be crucial for carcinogenesis. These recent findings make a compelling case for targeting the microenvironment for cancer chemoprevention. We review new insights into the pathophysiology of the microenvironment and new approaches to control it with chemopreventive agents. The microenvironment of a cancer is an integral part of its anatomy and physiology, and functionally, one cannot totally dissociate this microenvironment from what have traditionally been called 'cancer cells'. Finally, we make suggestions for more effective clinical implementation of this knowledge in preventive strategies.

[1]  S. Solomon,et al.  Effect of Celecoxib on Cardiovascular Events and Blood Pressure in Two Trials for the Prevention of Colorectal Adenomas , 2006, Circulation.

[2]  R. Gutiérrez,et al.  Angiogenesis: an update. , 1994, Histology and histopathology.

[3]  S. Solomon,et al.  Celecoxib for the prevention of sporadic colorectal adenomas. , 2006, The New England journal of medicine.

[4]  H. Moses,et al.  Stromal fibroblasts in cancer initiation and progression , 2004, Nature.

[5]  D. Noonan,et al.  Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  S. Robbins,et al.  Pathologic basis of disease , 1974 .

[7]  E Marubini,et al.  Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[8]  C. Wiele,et al.  Receptor Imaging in Oncology by Means of Nuclear Medicine: Current Status , 2004 .

[9]  H. Bartsch,et al.  Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention , 2006, Molecular Cancer Therapeutics.

[10]  Jawed Alam,et al.  Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. , 2006, Physiological reviews.

[11]  C. Bucana,et al.  Nuclear Factor-κB Activity Correlates with Growth, Angiogenesis, and Metastasis of Human Melanoma Cells in Nude Mice , 2000 .

[12]  Miguel A Esteban,et al.  HIF, a missing link between metabolism and cancer , 2005, Nature Medicine.

[13]  Ulrich Pfeffer,et al.  The Transforming Growth Factor-β Family Members Bone Morphogenetic Protein-2 and Macrophage Inhibitory Cytokine-1 as Mediators of the Antiangiogenic Activity of N-(4-Hydroxyphenyl)Retinamide , 2005, Clinical Cancer Research.

[14]  G. Semenza Targeting HIF-1 for cancer therapy , 2003, Nature Reviews Cancer.

[15]  S. Lippman,et al.  Reducing the "risk" of chemoprevention: defining and targeting high risk--2005 AACR Cancer Research and Prevention Foundation Award Lecture. , 2006, Cancer research.

[16]  Michael J Thun,et al.  Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. , 2003, The New England journal of medicine.

[17]  M. Sporn,et al.  The Synthetic Triterpenoid CDDO-Imidazolide Suppresses STAT Phosphorylation and Induces Apoptosis in Myeloma and Lung Cancer Cells , 2006, Clinical Cancer Research.

[18]  K. Wellen,et al.  Inflammation, stress, and diabetes. , 2005, The Journal of clinical investigation.

[19]  S. Akira,et al.  Macrophage/Cancer Cell Interactions Mediate Hormone Resistance by a Nuclear Receptor Derepression Pathway , 2006, Cell.

[20]  N. Sang,et al.  Histone Deacetylase Inhibitors Induce VHL and Ubiquitin-Independent Proteasomal Degradation of Hypoxia-Inducible Factor 1α , 2006, Molecular and Cellular Biology.

[21]  J. Collins Imaging and other biomarkers in early clinical studies: one step at a time or re-engineering drug development? , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  M. Karin NF‐κB and cancer: Mechanisms and targets , 2006 .

[23]  D. Noonan,et al.  Neutrophils and angiogenesis: potential initiators of the angiogenic cascade. , 2003, Chemical immunology and allergy.

[24]  E Farber,et al.  Cellular adaptation in the origin and development of cancer. , 1991, Cancer research.

[25]  R. Kerbel Antiangiogenic Therapy: A Universal Chemosensitization Strategy for Cancer? , 2006, Science.

[26]  S. De Flora,et al.  Overview of mechanisms of cancer chemopreventive agents. , 2005, Mutation research.

[27]  G. Semenza,et al.  Hypoxia, Clonal Selection, and the Role of HIF-1 in Tumor Progression , 2000, Critical reviews in biochemistry and molecular biology.

[28]  E. Crivellato,et al.  Angiogenesis in rheumatoid arthritis. , 2006, Histology and histopathology.

[29]  Sowmya R. Rao,et al.  Estimates of the number of US women who could benefit from tamoxifen for breast cancer chemoprevention. , 2003, Journal of the National Cancer Institute.

[30]  R. Agarwal,et al.  Silibinin strongly inhibits growth and survival of human endothelial cells via cell cycle arrest and downregulation of survivin, Akt and NF-κB: implications for angioprevention and antiangiogenic therapy , 2005, Oncogene.

[31]  G. Mills,et al.  Progress in Chemoprevention Drug Development: The Promise of Molecular Biomarkers for Prevention of Intraepithelial Neoplasia and Cancer—A Plan to Move Forward , 2006, Clinical Cancer Research.

[32]  D. Bar-Sagi,et al.  Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. , 2004, Cancer cell.

[33]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[34]  M. Sporn,et al.  Cancer chemoprevention: scientific promise, clinical uncertainty , 2005, Nature Clinical Practice Oncology.

[35]  Hua Yu,et al.  The STATs of cancer — new molecular targets come of age , 2004, Nature Reviews Cancer.

[36]  Elizabeth Fox,et al.  Clinical trial design for target-based therapy. , 2002, The oncologist.

[37]  J. Joyce,et al.  Therapeutic Targeting of the Tumor Microenvironment. , 2021, Cancer discovery.

[38]  A B West,et al.  Myofibroblasts: paracrine cells important in health and disease. , 2000, Transactions of the American Clinical and Climatological Association.

[39]  J. Bartlett Pharmacodiagnostic Testing in Breast Cancer , 2005, American journal of pharmacogenomics : genomics-related research in drug development and clinical practice.

[40]  A. Kong,et al.  Suppression of NF-κB and NF-κB-regulated gene expression by sulforaphane and PEITC through IκBα, IKK pathway in human prostate cancer PC-3 cells , 2005, Oncogene.

[41]  Y. Ba,et al.  A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication. , 2005, Cancer research.

[42]  Bing-Hua Jiang,et al.  Apigenin inhibits VEGF and HIF‐1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[43]  M. Backlund,et al.  Mechanisms of Disease: inflammatory mediators and cancer prevention , 2005, Nature Clinical Practice Oncology.

[44]  Tarik Tihan,et al.  The hypoxic response of tumors is dependent on their microenvironment. , 2003, Cancer cell.

[45]  N. Sang,et al.  Histone Deacetylase Inhibitors Repress the Transactivation Potential of Hypoxia-inducible Factors Independently of Direct Acetylation of HIF-α* , 2006, Journal of Biological Chemistry.

[46]  P. Glazer,et al.  Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis. , 2005, Mutation research.

[47]  John Condeelis,et al.  Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis , 2006, Cell.

[48]  L. Kopelovich,et al.  The epigenome as a target for cancer chemoprevention. , 2003, Journal of the National Cancer Institute.

[49]  Shah Ebrahim,et al.  European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. , 2003 .

[50]  N. Sang,et al.  Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha. , 2006, Molecular and cellular biology.

[51]  D. Noonan,et al.  Tumor inflammatory angiogenesis and its chemoprevention. , 2005, Cancer research.

[52]  B. Aggarwal,et al.  Curcumin (Diferuloylmethane) Down-Regulates Expression of Cell Proliferation and Antiapoptotic and Metastatic Gene Products through Suppression of IκBα Kinase and Akt Activation , 2006, Molecular Pharmacology.

[53]  Xudong Tang,et al.  Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1α and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells , 2005, Molecular Cancer Therapeutics.

[54]  W. Irwin "Where do we go from here?". , 1951, Radiography.

[55]  E. Ho,et al.  Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apcmin mice , 2006 .

[56]  I. Kola,et al.  Can the pharmaceutical industry reduce attrition rates? , 2004, Nature Reviews Drug Discovery.

[57]  P. Loehrer Celecoxib for the Prevention of Colorectal Adenomatous Polyps , 2008 .

[58]  J Folkman,et al.  Transplacental carcinogenesis by stilbestrol. , 1971, The New England journal of medicine.

[59]  Bruno C. Hancock,et al.  Suppression of Intestinal Polyposis in Apc Δ716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2) , 1996, Cell.

[60]  P. Carmeliet,et al.  Genetic evidence for a tumor suppressor role of HIF-2alpha. , 2005, Cancer cell.

[61]  R. Jaenisch,et al.  HIF-1α Is Essential for Myeloid Cell-Mediated Inflammation , 2003, Cell.

[62]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[63]  Mace L. Rothenberg,et al.  Improving the evaluation of new cancer treatments: challenges and opportunities , 2003, Nature Reviews Cancer.

[64]  M. Klagsbrun,et al.  A new perspective on tumor endothelial cells: unexpected chromosome and centrosome abnormalities. , 2005, Cancer research.

[65]  Xin-Yuan Fu,et al.  Smad4 signalling in T cells is required for suppression of gastrointestinal cancer , 2006, Nature.

[66]  B. Chabner,et al.  Pharmacologically guided phase I clinical trials based upon preclinical drug development. , 1990, Journal of the National Cancer Institute.

[67]  E. Calle,et al.  Doctors and climate change , 2007, BMJ : British Medical Journal.

[68]  W. Kaelin,et al.  CANCER-RELEVANT CULLIN-RING UBIQUITIN LIGASES , 2005 .

[69]  M. Hidalgo,et al.  Matrix metalloproteinase inhibitors: how can we optimize their development? , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[70]  D. Noonan,et al.  Mechanisms of the antiangiogenic activity by the hop flavonoid xanthohumol: NF‐κB and Akt as targets , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[71]  M. Christian,et al.  Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials , 2001, British Journal of Cancer.

[72]  D. Lacombe,et al.  Integration of Translational Research in the European Organization for Research and Treatment of Cancer Research (EORTC) Clinical Trial Cooperative Group Mechanisms , 2003, Journal of Translational Medicine.

[73]  W. Clark,et al.  The nature of cancer: morphogenesis and progressive (self)-disorganization in neoplastic development and progression. , 1995, Acta oncologica.

[74]  Paul Workman,et al.  Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. , 2006, Journal of the National Cancer Institute.

[75]  S. De Flora,et al.  ‘Angioprevention’: angiogenesis is a common and key target for cancer chemopreventive agents , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[76]  M J Bissell,et al.  Microenvironmental Regulators of Tissue Structure and Function Also Regulate Tumor Induction and Progression : The Role of Extracellular Matrix and Its Degrading Enzymes , 2022 .

[77]  M. Karin Inflammation and cancer: the long reach of Ras , 2005, Nature Medicine.

[78]  J. Folkman Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[79]  Y. Numata,et al.  Epithelial and stromal genetic instability contributes to genesis of colorectal adenomas , 2005, Gut.

[80]  M. Sporn The war on cancer , 1996, The Lancet.

[81]  C. Eng,et al.  Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. , 2006, American journal of human genetics.

[82]  P Smith,et al.  Concordance of the toxicity of pharmaceuticals in humans and in animals. , 2000, Regulatory toxicology and pharmacology : RTP.

[83]  J. Dancey,et al.  Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[84]  A. Dinkova-Kostova,et al.  Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis. , 2003, Advances in enzyme regulation.

[85]  D. Noonan,et al.  Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. , 2005, Mutation research.

[86]  C. Bucana,et al.  Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis , 2001, Oncogene.

[87]  A. Mantovani,et al.  Smoldering and polarized inflammation in the initiation and promotion of malignant disease. , 2005, Cancer cell.

[88]  J. Pouysségur,et al.  The hypoxia-inducible factor and tumor progression along the angiogenic pathway. , 2005, International review of cytology.

[89]  J. Milanini,et al.  Transcriptional Regulation of Vascular Endothelial Growth Factor by Estradiol and Tamoxifen in Breast Cancer Cells: A Complex Interplay between Estrogen Receptors α and β , 2002 .

[90]  J. Pober,et al.  Control of apoptosis during angiogenesis by survivin expression in endothelial cells. , 2000, The American journal of pathology.

[91]  Y. Surh,et al.  Nrf2 as a novel molecular target for chemoprevention. , 2005, Cancer letters.

[92]  Zena Werb,et al.  Stromal Effects on Mammary Gland Development and Breast Cancer , 2002, Science.

[93]  D. Noonan,et al.  CXCL1/Macrophage Inflammatory Protein-2-Induced Angiogenesis In Vivo Is Mediated by Neutrophil-Derived Vascular Endothelial Growth Factor-A1 , 2004, The Journal of Immunology.

[94]  K. Seibert,et al.  Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. , 2000, Cancer research.

[95]  Oswald Wagner,et al.  Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. , 2004, The New England journal of medicine.

[96]  R. Jove,et al.  Stat3 regulates genes common to both wound healing and cancer , 2005, Oncogene.

[97]  F. Balkwill Cancer and the chemokine network , 2004, Nature Reviews Cancer.

[98]  Xudong Tang,et al.  Green tea extract and (−)-epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1α protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells , 2006, Molecular Cancer Therapeutics.

[99]  Peter Carmeliet,et al.  Angiogenesis in life, disease and medicine , 2005, Nature.

[100]  W. Lamph,et al.  A selective retinoid X receptor agonist bexarotene (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours , 2006, British Journal of Cancer.

[101]  Stephanie Birkey Reffey,et al.  Synthetic Triterpenoids Enhance Transforming Growth Factor β/Smad Signaling , 2003 .

[102]  J. Pollard,et al.  Distinct role of macrophages in different tumor microenvironments. , 2006, Cancer research.

[103]  J C Reed,et al.  The Survivin saga goes in vivo. , 2001, The Journal of clinical investigation.

[104]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[105]  D. Noonan,et al.  The Akt inhibitor deguelin, is an angiopreventive agent also acting on the NF-kappaB pathway. , 2006, Carcinogenesis.

[106]  A. Gill,et al.  Microarray gene expression and immunohistochemistry analyses of adrenocortical tumors identify IGF2 and Ki-67 as useful in differentiating carcinomas from adenomas. , 2009, Endocrine-related cancer.

[107]  H. Sheng,et al.  Roles of myofibroblasts in prostaglandin E2-stimulated intestinal epithelial proliferation and angiogenesis. , 2006, Cancer research.

[108]  Robyn M. B. Loureiro,et al.  Transcriptional regulation of vascular endothelial growth factor in cancer. , 2005, Cytokine & growth factor reviews.

[109]  R. Lotan,et al.  N-(4-Hydroxyphenyl)Retinamide Inhibits Invasion, Suppresses Osteoclastogenesis, and Potentiates Apoptosis through Down-regulation of IκBα Kinase and Nuclear Factor-κB–Regulated Gene Products , 2005 .

[110]  Stephen B. Gruber,et al.  Statins and cancer prevention , 2005, Nature Reviews Cancer.

[111]  G. Gordon,et al.  A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway. , 2004, Molecular cancer therapeutics.

[112]  Randall Harris,et al.  Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors , 2006, BMC Cancer.

[113]  M H Gail,et al.  Validating and improving models for projecting the absolute risk of breast cancer. , 2001, Journal of the National Cancer Institute.

[114]  N. Fusenig,et al.  Friends or foes — bipolar effects of the tumour stroma in cancer , 2004, Nature Reviews Cancer.

[115]  L. Trusolino,et al.  Cancer: the matrix is now in control , 2005, Nature Medicine.

[116]  D. Powell,et al.  Powell, D. W. et al. Myofibroblasts. I. Paracrine cells important in health and disease. Am. J. Physiol. 277, C1-C9 , 1999 .

[117]  E. Eisenhauer,et al.  Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: theory and practice. , 2004, Journal of the National Cancer Institute.

[118]  Raghu Kalluri,et al.  Fibroblasts in cancer , 2006, Nature Reviews Cancer.

[119]  Andrew W. Millar,et al.  Rethinking clinical trials for cytostatic drugs , 2003, Nature Reviews Cancer.

[120]  M. Cassatella The Neutrophil. An Emerging Regulator of Inflammatory and Immune Response. , 2003 .

[121]  Mina J Bissell,et al.  Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? , 2005, Cancer cell.

[122]  Rameen Beroukhim,et al.  Molecular characterization of the tumor microenvironment in breast cancer. , 2004, Cancer cell.

[123]  J. Doroshow,et al.  Drug development in oncology: classical cytotoxics and molecularly targeted agents. , 2006, British journal of clinical pharmacology.

[124]  Michael Karin,et al.  NF-κB: linking inflammation and immunity to cancer development and progression , 2005, Nature Reviews Immunology.

[125]  E. Szabo Selecting targets for cancer prevention: where do we go from here? , 2006, Nature Reviews Cancer.

[126]  D. Jackson,et al.  Spontaneous hematogenous and lymphatic metastasis, but not primary tumor growth or angiogenesis, is diminished in fibrinogen-deficient mice. , 2002, Cancer research.

[127]  H. Dvorak,et al.  Angiogenesis: update 2005 , 2005, Journal of thrombosis and haemostasis : JTH.

[128]  R. Kerbel,et al.  A role for survivin in chemoresistance of endothelial cells mediated by VEGF , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[129]  R. DuBois,et al.  COX-2: a molecular target for colorectal cancer prevention. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[130]  C. Grobstein Inductive tissue interaction in development. , 1956, Advances in cancer research.