Modifications of the extracellular matrix by the production of growth factors, by the activation of pathogenic signalling pathways and by tissue remodelling are known to be crucial in fibrotic disease and in promoting tumour growth and metastasis. Now, Barry-Hamilton and colleagues report in Nature Medicine the role of lysyl oxidase-like 2 (LOXL2) — an enzyme known to modify the extracellular matrix and to promote the cross-linking of fibrillar collagen I — in the creation and the maintenance of the pathological microenvironment of cancer and fibrotic disease, highlighting the therapeutic potential of inhibiting this enzyme.

First, they analysed human biopsy specimens of tumours and fibrotic lung and liver tissues and found an increased expression of LOXL2 mRNA and protein levels in diseased tissue compared with healthy tissue. Furthermore, upregulation of LOXL2 correlated with tumour severity. Next, they generated a LOXL2-specific monoclonal antibody called AB0023, and in vitro characterization found that it inhibited the morphological changes associated with LOXL2 induction, such as remodelling of the actin cytoskeleton.

AB0023 treatment in mice with primary breast cancer or metastatic bone cancer xenografts decreased tumour volume, which was associated with a reduced production of cross-linked fibrillar collagen; a decreased number of activated fibroblasts (the connective tissue cells that synthesize the extracellular matrix and collagen) and tumour-associated endothelial cells; and lowered microvessel density. Together, these findings suggest that LOXL2 inhibition blocks the formation of a pathological tumour microenvironment. Furthermore, AB0023 lowered the levels of transforming growth factor-β and of growth factors such as vascular endothelial growth factor, chemokine ligand 12 and connective tissue growth factor, which are all thought to contribute to disease progression. In addition, higher amounts of autophagy-associated protein beclin 1 were detected in tumour cells from AB0023-treated mice, indicating that suppression of growth factors and fibroblast activation results in the necrosis of tumour cells. In fact, AB0023 reduced tumour cell burden in the metastatic xenograft model, and ex vivo imaging and histological investigations showed a considerable treatment effect on metastasis.

In mice with liver and lung fibrosis, AB0023 administration increased survival by reducing fibrosis, reducing the number of activated fibroblasts and reducing the levels of disease mediators. Indeed, in an aggressive lung fibrosis model, AB0023 treatment improved lung tissue damage and cross-linked fibrillar collagen abundance, which the authors suggest is indicative that the treatment reversed fibrosis and stimulated lung repair.

Finally, AB0023 was well tolerated in various safety studies in mice, rats and cynomolgus monkeys. It also performed better than β-aminopropionitrile, a previously studied small-molecule competitive inhibitor of LOXL2, as it was more specific, more effective in reducing tumour volume and altered the microenvironment. Together, these experiments show that inhibition of LOXL2 with compounds such as AB0023 might have broad applicability in cancer and in fibrotic diseases by reducing the number of disease-activated fibroblasts and disease-associated growth factors.