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  • Review Article
  • Published:

The rationale for targeting the LOX family in cancer

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.

Abstract

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.

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Figure 1: Structural homology of the LOX family members.
Figure 2: The role of the LOX family members in tumour progression.
Figure 3: The proposed roles of the LOX family.
Figure 4: Therapeutic targeting strategies of the LOX family.

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Acknowledgements

The authors would like to thank Biotech Research and Innovation Centre (BRIC), Institute of Cancer Research (ICR), Cancer Research UK (CRUK), Breast Cancer Campaign, Association for International Cancer Research (AICR) and Novo Nordisk Foundation for supporting Erler laboratory research.

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Barker, H., Cox, T. & Erler, J. The rationale for targeting the LOX family in cancer. Nat Rev Cancer 12, 540–552 (2012). https://doi.org/10.1038/nrc3319

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