Lysyl oxidase is essential for hypoxia-induced metastasis

Abstract

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.

Hypoxia and cancer

“…In addition, cells that survive acidosis not only develop a growth advantage but also become more aggressive and invasive [6,44]. This occurs in part through the activation of HIF-up-regulated proteins implicated in matrix remodeling, such as lysyl oxydase (LOX) [12,45], metalloproteases that disrupt cellcell and cell-matrix (ECM) interactions [46]. HIF also activates other genes known to be involved in metastasis and invasion such as the c-met proto-oncogene, the chemokine receptor CXCR4 and the autocrine motility factor (AMF) [41,47].…”

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…HIF-1α-dependent activation of TGF-β1 signaling and upregulation of survivin also contributes to EMT and resistance to apoptosis, respectively, in human NSCLC cells [79,80]. Recently, hypoxia-induced metastasis has been linked to activation of the c-Myc pathway, upregulation of membrane-type 4 MMP via Slug and induction of LOX, which acts both extracellularly to stabilize collagen deposition and intracellularly to foster EMT thru stabilization of Snail [75,[81][82][83].…”

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…Another interesting aspect of tumor hypoxia is the well-documented association between oxygen shortage and tumor aggressiveness (reviewed in Bertout et al 2008) . The mechanistic background is probably very complex, but involves cytotoxic resistance, insensitivity to radiation, decreased DNA repair capacity, increased vascularization and increased metastatic potential (reviewed in Semenza 2003;Erler et al 2006;Löfstedt et al 2007) and, as will be discussed in more detail below, dedifferentiation or loss of a differentiated tumor phenotype.…”