Hypoxia, inflammation, and the tumor microenvironment in metastatic disease
First Online: 15 April 2010 DOI:
10.1007/s10555-010-9224-5 Cite this article as: Finger, E.C. & Giaccia, A.J. Cancer Metastasis Rev (2010) 29: 285. doi:10.1007/s10555-010-9224-5 Abstract
Metastasis, the leading cause of cancer deaths, is an intricate process involving many important tumor and stromal proteins that have yet to be fully defined. This review discusses critical components necessary for the metastatic cascade, including hypoxia, inflammation, and the tumor microenvironment. More specifically, this review focuses on tumor cell and stroma interactions, which allow cell detachment from a primary tumor, intravasation to the blood stream, and extravasation at a distant site where cells can seed and tumor metastases can form. Central players involved in this process and discussed in this review include integrins, matrix metalloproteinases, and soluble growth factors/matrix proteins, including the connective tissue growth factor and lysyl oxidase.
Keywords Connective tissue growth factor Lysyl oxidase Metastasis Hypoxia References
Jemal, A., et al. (2009). Cancer statistics, 2009.
CA: A Cancer Journal for Clinicians, 59
Krug, E. L., Mjaatvedt, C. H., & Markwald, R. R. (1987). Extracellular matrix from embryonic myocardium elicits an early morphogenetic event in cardiac endothelial differentiation.
Developmental Biology, 120
Hay, E. D. (1995). An overview of epithelio-mesenchymal transformation.
Acta Anatomica (Basel), 154
Tarin, D., Thompson, E. W., & Newgreen, D. F. (2005). The fallacy of epithelial mesenchymal transition in neoplasia.
Cancer Research, 65
(14), 5996–6000. discussion 6000-1.
Birchmeier, W., & Behrens, J. (1994). Cadherin expression in carcinomas: Role in the formation of cell junctions and the prevention of invasiveness.
Biochimica et Biophysica Acta, 1198
Hotz, B., et al. (2007). Epithelial to mesenchymal transition: Expression of the regulators snail, slug, and twist in pancreatic cancer.
Clinical Cancer Research, 13
Gravdal, K., et al. (2007). A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer.
Clinical Cancer Research, 13
Margulis, A., et al. (2005). E-cadherin suppression accelerates squamous cell carcinoma progression in three-dimensional, human tissue constructs.
Cancer Research, 65
Yilmaz, M., & Christofori, G. (2009). EMT, the cytoskeleton, and cancer cell invasion.
Cancer and Metastasis Reviews, 28
Haraguchi, M., et al. (2008). Snail regulates cell-matrix adhesion by regulation of the expression of integrins and basement membrane proteins.
Journal of Biological Chemistry, 283
Gordon, K. J., et al. (2008). Loss of type III transforming growth factor beta receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression.
Ozdamar, B., et al. (2005). Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity.
Dumont, N., Bakin, A. V., & Arteaga, C. L. (2003). Autocrine transforming growth factor-beta signaling mediates Smad-independent motility in human cancer cells.
Journal of Biological Chemistry, 278
Kalluri, R. (2003). Basement membranes: Structure, assembly and role in tumour angiogenesis.
Nature Reviews Cancer, 3
Bhowmick, N. A., Neilson, E. G., & Moses, H. L. (2004). Stromal fibroblasts in cancer initiation and progression.
Desgrosellier, J. S., & Cheresh, D. A. (2010). Integrins in cancer: Biological implications and therapeutic opportunities.
Nataure Reviews Cancer, 10
Takayama, S., et al. (2005). The relationship between bone metastasis from human breast cancer and integrin alpha(v)beta3 expression.
Anticancer Research, 25
Liapis, H., Flath, A., & Kitazawa, S. (1996). Integrin alpha V beta 3 expression by bone-residing breast cancer metastases.
Diagnostic Molecular Pathology, 5
McCabe, N. P., et al. (2007). Prostate cancer specific integrin alphavbeta3 modulates bone metastatic growth and tissue remodeling.
Hosotani, R., et al. (2002). Expression of integrin alphaVbeta3 in pancreatic carcinoma: Relation to MMP-2 activation and lymph node metastasis.
Gruber, G., et al. (2005). Correlation between the tumoral expression of beta3-integrin and outcome in cervical cancer patients who had undergone radiotherapy.
British Journal of Cancer, 92
Landen, C. N., et al. (2008). Tumor-selective response to antibody-mediated targeting of alphavbeta3 integrin in ovarian cancer.
Bello, L., et al. (2001). Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery.
(2), 380–9. discussion 390.
Mullamitha, S. A., et al. (2007). Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors.
Clinincal Cancer Reseach, 13
Ricart, A. D., et al. (2008). Volociximab, a chimeric monoclonal antibody that specifically binds alpha5beta1 integrin: A phase I, pharmacokinetic, and biological correlative study.
Clinical Cancer Research, 14
Gross, J., & Lapiere, C. M. (1962). Collagenolytic activity in amphibian tissues: A tissue culture assay.
Proceedings of the National Academy of Science of the United States America, 48
Brinckerhoff, C. E., & Matrisian, L. M. (2002). Matrix metalloproteinases: A tail of a frog that became a prince.
Nature Reviews Molecular Cell Biology, 3
Burrage, P., et al. (2006). Matrix metalloproteinases: Role in arthritis.
Frontiers in Bioscience, 11, 529–543.
Zucker, S., et al. (1999). Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications.
Annals of the New York Academy of Sciences, 878
Koc, M., et al. (2006). Matrix metalloproteinase-9 (MMP-9) elevated in serum but not in bronchial lavage fluid in patients with lung cancer.
Hilska, M., et al. (2007). Prognostic significance of matrix metalloproteinases-1, -2, -7 and -13 and tissue inhibitors of metalloproteinases-1, -2, -3 and -4 in colorectal cancer.
International Journal of Cancer, 121
Lengyel, E., et al. (2001). Expression of latent matrix metalloproteinase 9 (MMP-9) predicts survival in advanced ovarian cancer.
Gynecologic Oncology, 82
Roy, R., Yang, J., & Moses, M. A. (2009). Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer.
Journal of Clinical Oncology, 27
Dublanchet, A. C., et al. (2005). Structure-based design and synthesis of novel non-zinc chelating MMP-12 inhibitors.
Bioorganic & Medicinal Chemistry Letters, 15
Chan, D. A., & Giaccia, A. J. (2007). Hypoxia, gene expression, and metastasis.
Cancer and Metastasis Reviews, 26
Masson, N., et al. (2001). Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation.
EMBO Journal, 20
Chan, D. A., et al. (2002). Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha.
Journal Biological Chemistry, 277
Bedogni, B., & Powell, M. B. (2009). Hypoxia, melanocytes and melanoma—Survival and tumor development in the permissive microenvironment of the skin.
Pigment Cell Melanoma Research, 22
Epstein, A. C., et al. (2001).
EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.
Jaakkola, P., et al. (2001). Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.
Mole, D. R., et al. (2009). Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts.
Journal of Biological Chemistry, 284
Michieli, P. (2009). Hypoxia, angiogenesis and cancer therapy: To breathe or not to breathe?
Cell Cycle, 8
Kim, J. W., et al. (2006). HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia.
Cell Metabolism, 3
Bindra, R. S., et al. (2005). Alterations in DNA repair gene expression under hypoxia: Elucidating the mechanisms of hypoxia-induced genetic instability.
Annals of the New York Academy of Sciences, 1059
Tang, N., et al. (2004). Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis.
Cancer Cell, 6
Pennacchietti, S., et al. (2003). Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene.
Cancer Cell, 3
Canning, M. T., et al. (2001). Oxygen-mediated regulation of gelatinase and tissue inhibitor of metalloproteinases-1 expression by invasive cells.
Experimental Cell Research, 267
Esteban, M. A., et al. (2006). Regulation of E-cadherin expression by VHL and hypoxia-inducible factor.
Cancer Research, 66
Imai, T., et al. (2003). Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells.
American Journal of Pathology, 163
Jiang, Y. G., et al. (2007). Role of Wnt/beta-catenin signaling pathway in epithelial–mesenchymal transition of human prostate cancer induced by hypoxia-inducible factor-1alpha.
International Journal of Urology, 14
Erler, J. T., et al. (2006). Lysyl oxidase is essential for hypoxia-induced metastasis.
Dewhirst, M. W., et al. (1989). Morphologic and hemodynamic comparison of tumor and healing normal tissue microvasculature.
International Journal of Radiation Oncology, Biology, Physics, 17
Jain, R. K. (2005). Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy.
Hanahan, D., & Folkman, J. (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.
Shweiki, D., et al. (1992). Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.
Holash, J., et al. (1999). Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.
Ruan, K., Song, G., & Ouyang, G. (2009). Role of hypoxia in the hallmarks of human cancer.
Journal Cell Biochemistry, 107
Laderoute, K. R., et al. (2000). Opposing effects of hypoxia on expression of the angiogenic inhibitor thrombospondin 1 and the angiogenic inducer vascular endothelial growth factor.
Clinincal Cancer Research, 6(7), 2941–2950.
Talks, K. L., et al. (2000). The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages.
American Journal of Pathology, 157
Kallman, R. F., & Dorie, M. J. (1986). Tumor oxygenation and reoxygenation during radiation therapy: Their importance in predicting tumor response.
International Journal of Radiation Oncology, Biology, Physics, 12
Daruwalla, J., & Christophi, C. (2006). Hyperbaric oxygen therapy for malignancy: A review.
World Journal of Surgery, 30
Engert, A. (2005). Recombinant human erythropoietin in oncology: Current status and further developments.
Annals of Oncology, 16
Galluzzo, M., et al. (2009). Prevention of hypoxia by myoglobin expression in human tumor cells promotes differentiation and inhibits metastasis.
Journal of Clinical Investigative, 119
Csiszar, K. (2001). Lysyl oxidases: A novel multifunctional amine oxidase family.
Progress in Nucleic Acid Research and Molecular Biology, 70
Pinnell, S. R., & Martin, G. R. (1968). The cross-linking of collagen and elastin: Enzymatic conversion of lysine in peptide linkage to alpha-aminoadipic-delta-semialdehyde (allysine) by an extract from bone.
Proceedings of the National Academy of Science of the United States of America, 61
Trackman, P. C., et al. (1992). Post-translational glycosylation and proteolytic processing of a lysyl oxidase precursor.
Journal of Biological Chemistry, 267
Cronshaw, A. D., Fothergill-Gilmore, L. A., & Hulmes, D. J. (1995). The proteolytic processing site of the precursor of lysyl oxidase.
Biochemical Journal, 306
(Pt 1), 279–284.
Panchenko, M. V., et al. (1996). Metalloproteinase activity secreted by fibrogenic cells in the processing of prolysyl oxidase. Potential role of procollagen C-proteinase.
Journal of Biological Chemistry, 271
Nellaiappan, K., et al. (2000). Fully processed lysyl oxidase catalyst translocates from the extracellular space into nuclei of aortic smooth-muscle cells.
Journal of Cell Biochemistry, 79
Kagan, H. M., & Li, W. (2003). Lysyl oxidase: Properties, specificity, and biological roles inside and outside of the cell.
Journal of Cell Biochemistry, 88
Kagan, H. M., et al. (1983). Histone H1 is a substrate for lysyl oxidase and contains endogenous sodium borotritide-reducible residues.
Biochemical and Biophysical Research Communications, 115
Giampuzzi, M., Oleggini, R., & Di Donato, A. (2003). Demonstration of in vitro interaction between tumor suppressor lysyl oxidase and histones H1 and H2: Definition of the regions involved.
Biochimica et Biophysica Acta, 1647
Warburton, D., & Shi, W. (2005). Lo, and the niche is knit: Lysyl oxidase activity and maintenance of lung, aorta, and skin integrity.
American Journal of Pathology, 167
Maki, J. M., et al. (2005). Lysyl oxidase is essential for normal development and function of the respiratory system and for the integrity of elastic and collagen fibers in various tissues.
American Journal of Pathology, 167
Maki, J. M., et al. (2002). Inactivation of the lysyl oxidase gene Lox leads to aortic aneurysms, cardiovascular dysfunction, and perinatal death in mice.
Hornstra, I. K., et al. (2003). Lysyl oxidase is required for vascular and diaphragmatic development in mice.
Journal of Biology Chemistry, 278
Hayashi, K., et al. (2004). Comparative immunocytochemical localization of lysyl oxidase (LOX) and the lysyl oxidase-like (LOXL) proteins: Changes in the expression of LOXL during development and growth of mouse tissues.
Journal of Molecular Histology, 35
Kagan, H. M., et al. (1986). Ultrastructural immunolocalization of lysyl oxidase in vascular connective tissue.
Journal of Cell Biology, 103
Sakai, M., et al. (2009). Expression of lysyl oxidase is correlated with lymph node metastasis and poor prognosis in esophageal squamous cell carcinoma.
Annals of Surgical Oncology, 16
Albinger-Hegyi, A., et al. (2009). Lysyl oxidase expression is an independent marker of prognosis and a predictor of lymph node metastasis in oral and oropharyngeal squamous cell carcinoma (OSCC).
International Journal of Cancer, 126(11), 2653–2662.
Le, Q. T., et al. (2009). Validation of lysyl oxidase as a prognostic marker for metastasis and survival in head and neck squamous cell carcinoma: Radiation Therapy Oncology Group trial 90-03.
Journal of Clinical Oncology, 27
Erler, J. T., & Giaccia, A. J. (2006). Lysyl oxidase mediates hypoxic control of metastasis.
Cancer Research, 66
Kirschmann, D. A., et al. (2002). A molecular role for lysyl oxidase in breast cancer invasion.
Cancer Research, 62
Giampuzzi, M., et al. (2005). Beta-catenin signaling and regulation of cyclin D1 promoter in NRK-49F cells transformed by down-regulation of the tumor suppressor lysyl oxidase.
Biochimica et Biophysica Acta, 1745
Peinado, H., et al. (2005). A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression.
EMBO Journal, 24
Higgins, D. F., et al. (2004). Hypoxic induction of Ctgf is directly mediated by Hif-1.
American Journal of Physiology. Renal Physiology, 287
Bork, P. (1993). The modular architecture of a new family of growth regulators related to connective tissue growth factor.
FEBS Letters, 327
Wenger, C., et al. (1999). Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells.
Xie, D., et al. (2004). Levels of expression of CYR61 and CTGF are prognostic for tumor progression and survival of individuals with gliomas.
Clinical Cancer Research, 10
Kubo, M., et al. (1998). Expression of fibrogenic cytokines in desmoplastic malignant melanoma.
British Journal of Dermatology, 139
Shimo, T., et al. (2001). Connective tissue growth factor as a major angiogenic agent that is induced by hypoxia in a human breast cancer cell line.
Cancer Letters, 174
Hartel, M., et al. (2004). Desmoplastic reaction influences pancreatic cancer growth behavior.
World Journal of Surgery, 28
Bennewith, K. L., et al. (2009). The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth.
Cancer Research, 69
Dornhofer, N., et al. (2006). Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis.
Cancer Research, 66
Dammeier, J., et al. (1998). Connective tissue growth factor: A novel regulator of mucosal repair and fibrosis in inflammatory bowel disease?
International Journal of Biochemistry and Cell Biology, 30
Igarashi, A., et al. (1996). Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders.
Journal of Investigative Dermatology, 106
Ito, Y., et al. (1998). Expression of connective tissue growth factor in human renal fibrosis.
Kidney International, 53
Kondo, S., et al. (2002). Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases.
Koliopanos, A., et al. (2002). Connective tissue growth factor gene expression alters tumor progression in esophageal cancer.
World Journal of Surgery, 26
Shakunaga, T., et al. (2000). Expression of connective tissue growth factor in cartilaginous tumors.
Kuper, H., Adami, H. O., & Trichopoulos, D. (2000). Infections as a major preventable cause of human cancer.
Journal of Internal Medicine, 248
Pisani, P., et al. (1997). Cancer and infection: Estimates of the attributable fraction in 1990.
Cancer Epidemiology, Biomarkers and Prevention, 6
Coussens, L. M., & Werb, Z. (2002). Inflammation and cancer.
Wu, Y., & Zhou, B. P. (2010). TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion.
British Journal of Cancer, 102
Schoppmann, S. F., et al. (2002). Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis.
American Journal of Pathology, 161
PubMed Copyright information
© Springer Science+Business Media, LLC 2010