Lysyl oxidase is essential for hypoxia-induced metastasis
Authors: Jen-Tsan Ashley Chi
Monica Nicolau
Amato J Giaccia
Nadja Dornhöfer
Quynh-Thu Le
Janine T Erler
Stefanie S Jeffrey
Christina Kong
Kevin L Bennewith
Journal: Nature (2006)
Discipline: Multidisciplinary
Keywords: Metastasis; Hypoxia; LOX; HIF; Tumours
Affiliations: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305, USA.

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. 

Retracted: Yes

PubPeer comments:
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 https: retractionwatch.com 2018 03 22 figures-in-cancer-paper-at-root-of-newly-failed-compound-called-into-question , 
 Documented evidence of the history of Figure 4c. https: forbetterscience.com 2018 08 13 janine-erler-dossiers-which-erc-doesnt-want ![file] ![file] , 
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 Citing from: https: www.nature.com articles nm.2208#supplementary-information 1.  In comparison, the use of LOX-specific monoclonal antibody M64 targeting a peptide sequence previously identified as generating an inhibitory polyclonal antisera26 provided little therapeutic benefit in models of oncology and fibrosis in our hands. 2.  Tumor-associated secreted and extracellular LOX may be more rapidly turned-over in vivo, rendering it a less amenable antibody therapeutic target, and LOX may have important intracellular functions that would not be addressed by an antibody therapeutic62,63. In addition, LOX research presents a mixed picture with respect to oncology, with some studies ascribing tumor-suppressor roles to the protein This study more or less blasts LOXs claim to fame...... in their hands ....obviously not in other  hands . , 
 Looks like Nature has just published a retraction https: www.ncbi.nlm.nih.gov pubmed 32188947 , 
 18th March Retraction Notice. https: www.nature.com articles s41586-020-2112-4 u201cWe, the authors, are retracting this Article owing to issues that have come to our attention regarding figure assembly and data availability. Image analysis of the data has showed several image anomalies in Fig. 4c, Supplementary Figs. 1a, e and 4a. Nature has informed us that the quality and integrity of these images are not in line with journal policies. In particular, the panels affected include Supplementary Fig. 4a, which demonstrates that the shRNA construct used in the manuscript induces a reduction of LOX protein. No original data are available for the affected panels or other data included in the manuscript. We believe that the key findings of the paper are still valid as replicated by others. However, given the issues described above and the absence of original data, we have concluded that the most appropriate course of action is to retract the Article. All authors agree with the Retraction.u201d , 
 https: retractionwatch.com 2020 03 23 nature-paper-on-cancer-retracted-after-years-of-scrutiny ,