The potential for targeting extracellular LOX proteins in human malignancy

One important message from the vast literature on the LOX family is that the lysyl oxidases may induce contradictory effects depending on the tissue studied and on the pathways to which they are associated. Another message is that the same catalytic action, such as the cross-linking of collagen, may not be associated to pathological conditions, but be part of a reaction needed to repair or strengthen a tissue. A LOX (PP)-Harvey rat sarcoma viral oncogene homolog (HRAS)-nuclear factor kappa B (NFKB) pathway in gastric cancers is associated with tumor suppression, 30 but a LOX-FAK-SRC increases cell motility and cell-ECM adhesion, 35 which is necessary for local invasion and metastasis. Data from our group suggests that the inhibition of extracellular LOXL2 may hamper or enhance metastasis, depending on the tumor type treated. We are only beginning to scratch at the surface of understanding LOX family function, and further research about the usefulness of the LOX family in aneurysms and vascular defects is needed. A targeted attack on LOX family synthesis will conceivably affect its antitumoral as well as its protumoral characteristics, and, given the importance of the ECM for cellular behavior, altering LOX family function is potentially fraught with secondary effects. Using LOX as an anti-HRAS agent could slow primary tumor growth, but boost metastasis (a situation similar to that found with other targeted drugs in humans). However, as the tumor suppressor functions of LOX have been shown to be independent of its enzymatic function, selective inhibitors of LOX catalytic activity should leave any tumor suppressor function intact. However, development of such compounds is complicated by the identical nature of the LOX family active sites and by the lack of available crystal structures. Nevertheless, the overexpression of LOX early during in situ breast cancer followed by its repression during invasive carcinoma suggests that it may rewire its molecular connections over time, pushed by dynamic microenvironmental changes. 44 , 45 Thus, much more needs to be learnt about LOX function and dynamics, in both healthy and disease contexts, before effective targeting can begin. Network medicine may provide a way to tackle these problems. 46 It has been demonstrated that a systems biology simulation of epidermal growth factor receptor signaling variation in vitro will produce a combined therapy cycle that maximizes effect and minimizes the emergence of resistance. 47 The simulation predicts the rewiring of molecular networks associated with cancer proliferation, allowing for therapy that prevents resistance. However, predicting and attacking networks involved in the running of the cancer microenvironment is an unmet challenge. Knowledge may be gained by using omics approaches to understand how LOX connects to molecules produced locally and how molecules in the primary tumor interact with those in metastatic target organs. Targeting molecular networks involving LOX family members may allow for dissection and attack of their protumoral activities, while keeping side-effects and resistance at a minimum.

While it is clear from the extensive research that the LOX family are potent anticancer targets, strategies for combination therapies and for preventing resistance have not been investigated. Despite this, clinical trials in cancer patients are due to begin with the LOXL2 monoclonal antibody, and several LOX/LOXL2 drug development programs are underway, quickly approaching clinical trials in patients.

Cancer cells in a tumor proliferate amongst stromal cells and vessels supported by the interstitial extracellular matrix (ECM). The ECM is a material formed by macromolecules that gives structure and anatomy to every tissue, but during cancer it also supplies proinflammatory signals associated with invasion, intravasation, and metastasis. These biological functions seem to be related to the physical properties of the ECM; cancer-associated ECM is stiffer and denser and suffers simultaneous processes of deposition and degradation that liberate growth factors embedded in it, while trapping more stromal and circulating cancer cells. 1 , 2 Lysyl oxidase (LOX) has been proven to be a crucial mediator in remodeling of the cancer-associated ECM, metastasis, and the premetastatic niche. 3 This evidence points to the LOX family as a potential target in the prevention and treatment of metastatic disease. However, extracellular LOX has been shown to have antitumor activity in certain cancers, 4 whereas the by-product of LOX biosynthesis has antioncogenic activity. This suggests that: 1) an anti-LOX treatment for cancer must be limited to tumors where LOX enhances progression, which possibly implies the need for molecular diagnostic tools; and 2) there may be a role for LOX or LOX by-products as anticancer agents. Here we will review the current knowledge on the extracellular LOX enzymes and their potential role in cancer therapy.