Lysyl oxidase is essential for hypoxia-induced metastasis

Metastasis is a multistep process responsible for most cancer deaths, and it can be influenced by both the immediate microenvironment (cell–cell or cell–matrix interactions) and the extended tumour microenvironment (for example vascularization). Hypoxia (low oxygen) is clinically associated with metastasis and poor patient outcome, although the underlying processes remain unclear. Microarray studies have shown the expression of lysyl oxidase (LOX) to be elevated in hypoxic human tumour cells. Paradoxically, LOX expression is associated with both tumour suppression and tumour progression, and its role in tumorigenesis seems dependent on cellular location, cell type and transformation status. Here we show that LOX expression is regulated by hypoxia-inducible factor (HIF) and is associated with hypoxia in human breast and head and neck tumours. Patients with high LOX-expressing tumours have poor distant metastasis-free and overall survivals. Inhibition of LOX eliminates metastasis in mice with orthotopically grown breast cancer tumours. Mechanistically, secreted LOX is responsible for the invasive properties of hypoxic human cancer cells through focal adhesion kinase activity and cell to matrix adhesion. Furthermore, LOX may be required to create a niche permissive for metastatic growth. Our findings indicate that LOX is essential for hypoxia-induced metastasis and is a good therapeutic target for preventing and treating metastases.

[1]  Howard Y. Chang,et al.  Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Krawetz,et al.  Somatic mutations of the lysyl oxidase gene on chromosome 5q23.1 in colorectal tumors , 2002, International journal of cancer.

[3]  R. Altman,et al.  Investigating hypoxic tumor physiology through gene expression patterns , 2003, Oncogene.

[4]  Ruth E. Hartley,et al.  An integrated view. , 1973 .

[5]  Daniel F. Brayton,et al.  Disulfiram facilitates intracellular Cu uptake and induces apoptosis in human melanoma cells. , 2004, Journal of medicinal chemistry.

[6]  Robert D Cardiff,et al.  The transcriptional repressor Snail promotes mammary tumor recurrence. , 2005, Cancer cell.

[7]  S. Steinberg,et al.  Medroxyprogesterone acetate elevation of Nm23-H1 metastasis suppressor expression in hormone receptor-negative breast cancer. , 2005, Journal of the National Cancer Institute.

[8]  R. Khokha,et al.  Molecular mechanisms of tumor invasion and metastasis: an integrated view. , 2003, Current molecular medicine.

[9]  G. Gilad,et al.  Beta-aminopropionitrile treatment can accelerate recovery of mice after spinal cord injury. , 2001, European journal of pharmacology.

[10]  A. Kaneda,et al.  Lysyl Oxidase Is a Tumor Suppressor Gene Inactivated by Methylation and Loss of Heterozygosity in Human Gastric Cancers , 2004, Cancer Research.

[11]  A. Mercurio,et al.  Hypoxia stimulates carcinoma invasion by stabilizing microtubules and promoting the Rab11 trafficking of the alpha6beta4 integrin. , 2005, Cancer research.

[12]  M. Bihl,et al.  Collagenase expression and activity is modulated by the interaction of collagen types, hypoxia, and nutrition in human lung cells , 2005, Journal of cellular physiology.

[13]  S. Rafii,et al.  VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche , 2005, Nature.

[14]  J. Downward,et al.  Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. , 2002, The Journal of cell biology.

[15]  P. Friedl,et al.  Tumour-cell invasion and migration: diversity and escape mechanisms , 2003, Nature Reviews Cancer.

[16]  P. Sommer,et al.  The Propeptide Domain of Lysyl Oxidase Induces Phenotypic Reversion of Ras-transformed Cells* , 2004, Journal of Biological Chemistry.

[17]  P. Vaupel,et al.  Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. , 2001, Journal of the National Cancer Institute.

[18]  Crispin J. Miller,et al.  Hypoxia-Mediated Down-Regulation of Bid and Bax in Tumors Occurs via Hypoxia-Inducible Factor 1-Dependent and -Independent Mechanisms and Contributes to Drug Resistance , 2004, Molecular and Cellular Biology.

[19]  L. Giudice,et al.  Hypoxia stimulates insulin-like growth factor binding protein 1 (IGFBP-1) gene expression in HepG2 cells: a possible model for IGFBP-1 expression in fetal hypoxia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[20]  G. Gilad,et al.  β-Aminopropionitrile treatment can accelerate recovery of mice after spinal cord injury , 2001 .

[21]  H. Kagan,et al.  Lysyl oxidase: Properties, specificity, and biological roles inside and outside of the cell , 2003, Journal of cellular biochemistry.

[22]  S. Welford,et al.  Topical Treatment with Inhibitors of the Phosphatidylinositol 3′-Kinase/Akt and Raf/Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Pathways Reduces Melanoma Development in Severe Combined Immunodeficient Mice , 2004, Cancer Research.

[23]  E. Bottinger,et al.  Gene expression analysis on small numbers of invasive cells collected by chemotaxis from primary mammary tumors of the mouse , 2003, BMC biotechnology.

[24]  K. Csiszȧr,et al.  Cellular Fibronectin Binds to Lysyl Oxidase with High Affinity and Is Critical for Its Proteolytic Activation* , 2005, Journal of Biological Chemistry.

[25]  Trevor Hastie,et al.  Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers , 2006, PLoS medicine.

[26]  G. Semenza,et al.  Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. , 2003, Cancer research.

[27]  Shuchun Zhao,et al.  Identification of Hypoxia-Regulated Proteins in Head and Neck Cancer by Proteomic and Tissue Array Profiling , 2004, Cancer Research.

[28]  M. Hendrix,et al.  A molecular role for lysyl oxidase in breast cancer invasion. , 2002, Cancer research.

[29]  H. Blau,et al.  Highly Conserved RNA Sequences That Are Sensors of Environmental Stress , 1998, Molecular and Cellular Biology.

[30]  K. Csiszȧr,et al.  Lysyl oxidases: a novel multifunctional amine oxidase family. , 2001, Progress in nucleic acid research and molecular biology.

[31]  M. Hendrix,et al.  Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism. , 2005, Cancer research.

[32]  J. Downward,et al.  Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis , 2002, The Journal of Cell Biology.