Abstract
Simple SummaryTo improve efficacy of solid cancer treatment, efforts have shifted towards targeting both the cancer cells and the surrounding tumour tissue they grow in. The lysyl oxidase (LOX) family of enzymes underpin the fibrotic remodeling of the tumour microenvironment to promote both cancer growth, spread throughout the body and modulate response to therapies. This review examines how the lysyl oxidase family is involved in tumour development, how they can be targeted, and their potential as diagnostic and prognostic biomarkers in solid tumours.The lysyl oxidase (LOX) family of enzymes are a major driver in the biogenesis of desmoplastic matrix at the primary tumour and secondary metastatic sites. With the increasing interest in and development of anti-stromal therapies aimed at improving clinical outcomes of cancer patients, the Lox family has emerged as a potentially powerful clinical target. This review examines how lysyl oxidase family dysregulation in solid cancers contributes to disease progression and poor patient outcomes, as well as an evaluation of the preclinical landscape of LOX family targeting therapeutics. We also discuss the suitability of the LOX family as a diagnostic and/or prognostic marker in solid tumours.
Highlights
Introduction to the MatrixThe extracellular matrix (ECM) provides a supporting scaffold for cells to differentiate, communicate and grow within and plays an important function in maintaining tissue homeostasis [1,2]
transforming growth factorβ (TGF-β) regulation of lysyl oxidase (LOX) family member expression appears to occur though PI3K/Akt signaling pathways downstream of the TGF-β receptor (Figure 3), with TGF-β causing an increase in Akt phosphorylation and subsequently LOX family expression in cardiac fibroblasts in 2D cultures [82,87], whilst inhibition of PI3K has been shown to decrease LOX expression in colorectal adenocarcinoma SW620 cells [82]
The complexities of correlating LOX family expression and tumour staging are typified in prostate cancer, where high LOX expression has been correlated with advanced tumour stage; low LOX expression was associated with decreased overall survival [128]
Summary
The extracellular matrix (ECM) provides a supporting scaffold for cells to differentiate, communicate and grow within and plays an important function in maintaining tissue homeostasis [1,2]. This is achieved by a complex interplay between the fibrous proteins (such as collagens), glycoproteins, proteoglycans, and the bound organic (e.g., growth factors, cytokines) and inorganic (e.g., water, divalent cations) molecules of which the ECM is comprised [1]. In particular the fibrillar collagens, are important in conferring the biomechanical properties of the matrix These mechano-activating properties in turn help to regulate, among other things, cell migration and proliferation [6,9]. The reprogramming of fibroblasts to cancer associated fibroblasts (CAFs) leads to desmoplasia, in which the ECM is remodeled by degradation of the existing, structured “normal” ECM and replaced by excessive, disordered “tumour” ECM that feeds into disease progression [10]
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