The rationale for targeting the LOX family in cancer

• Published in: Nature reviews. Cancer Vol. 12; no. 8; pp. 540 - 552
• Main Authors: Barker, Holly E., Cox, Thomas R., Erler, Janine T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2012; Nature Publishing Group
• Subjects: 692/420/755; 692/699/67/1059/602; Animals; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Care and treatment; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cellular proteins; Drug targeting; Health aspects; Humans; Lysyl oxidase; Metastases; Microenvironments; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasms - enzymology; Neoplasms - pathology; Neoplasms - therapy; Protein-Lysine 6-Oxidase - metabolism; review-article; Tumor Microenvironment; Tumorigenesis; Denmark; United Kingdom
• ISSN: 1474-175X; 1474-1768; 1474-1768
• DOI: 10.1038/nrc3319

Key Points The lysyl oxidase (LOX) family of proteins are secreted amine oxidases, the primary function of which is the covalent crosslinking of collagens and elastin in the extracellular matrix. The function of these enzymes is required for the structural integrity of many tissues. Inappropriate expression of these enzymes has been observed in a number of human diseases (many involving a fibrotic response), in particular cancer. Increased fibrotic foci have been associated with the progression of several cancers. Increased expression of LOX and LOX-like 2 (LOXL2) has been linked to regions of desmoplasia observed in aggressive cancers. Most importantly, increased expression of LOX and LOXL2 significantly correlates with decreased survival in a number of clinical cancer studies. Conflicting results have been reported for the LOX family functioning as both tumour suppressors and metastasis promoters, possibly as a result of their multiple temporal and spatial expression patterns, which may confer differential functions. However, strong evidence suggests that the extracellular activity of these proteins in remodelling the extracellular matrix facilitates tumour cell invasion and metastasis. Preclinical studies involving the targeting of LOX or LOXL2 by small irreversible competitive inhibitors, as well as specific function-blocking antibodies to prevent metastasis, have been efficacious. So far, no detrimental side effects or tumour progression (owing to the proposed tumour suppressive roles of these proteins) have been noted with the use of specific antibody inhibitors. Targeting the LOX family is an exciting prospect in the development of new drugs to prevent the progression and metastasis of cancer. The family of lysyl oxidases (LOX) seem to have dichotomous roles in tumour progression: suppressing tumorigenesis and promoting metastasis. This Review discusses the functions of the LOX family and the rationale for targeting them. The therapeutic targeting of extracellular proteins is becoming hugely attractive in light of evidence implicating the tumour microenvironment as pivotal in all aspects of tumour initiation and progression. Members of the lysyl oxidase (LOX) family of proteins are secreted by tumours and are the subject of much effort to understand their roles in cancer. In this Review we discuss the roles of members of this family in the remodelling of the tumour microenvironment and their paradoxical roles in tumorigenesis and metastasis. We also discuss how targeting this family of proteins might lead to a new avenue of cancer therapeutics.