Lysyl Oxidase-Like Protein 2 Promotes Tumor Lymphangiogenesis and Lymph Node Metastasis in Breast Cancer

Wang, Qianqian; Xu, Shuai; Tian, Yue; Ju, Anji; Hou, Qiaoyun; Liu, Jie; Fu, Yan; Luo, Yongzhang

doi:10.1016/j.neo.2019.03.003

Cited by 39 publications

(34 citation statements)

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“…However, the equilibrium of the basement membrane structures and vessels requires enzymatic activity [ 34 ]. LOXL2 is also a vital prolymphangiogenic molecule and affects the function of lymphatic endothelial cells (LEC), both in vitro and in vivo [ 35 ]. The lymphangiogenesis process is critical for breast cancer malignancy and is associated with reduced survival of breast cancer patients [ 35 ].…”

Section: Loxl2 and Cancermentioning

confidence: 99%

LOXL2 Inhibitors and Breast Cancer Progression

et al. 2021

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LOX (lysyl oxidase) and lysyl oxidase like-1-4 (LOXL 1-4) are amine oxidases, which catalyze cross-linking reactions of elastin and collagen in the connective tissue. These amine oxidases also allow the cross-link of collagen and elastin in the extracellular matrix of tumors, facilitating the process of cell migration and the formation of metastases. LOXL2 is of particular interest in cancer biology as it is highly expressed in some tumors. This protein also promotes oncogenic transformation and affects the proliferation of breast cancer cells. LOX and LOXL2 inhibition have thus been suggested as a promising strategy to prevent metastasis and invasion of breast cancer. BAPN (β-aminopropionitrile) was the first compound described as a LOX inhibitor and was obtained from a natural source. However, novel synthetic compounds that act as LOX/LOXL2 selective inhibitors or as dual LOX/LOX-L inhibitors have been recently developed. In this review, we describe LOX enzymes and their role in promoting cancer development and metastases, with a special focus on LOXL2 and breast cancer progression. Moreover, the recent advances in the development of LOXL2 inhibitors are also addressed. Overall, this work contextualizes and explores the importance of LOXL2 inhibition as a promising novel complementary and effective therapeutic approach for breast cancer treatment.

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Section: Loxl2 and Cancermentioning

confidence: 99%

LOXL2 Inhibitors and Breast Cancer Progression

et al. 2021

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“…LOX family proteins are involved in several biological processes including tumour suppression, cell motility, cell transduction and cell adhesion. Dysregulation of LOX activity has been linked to pathological conditions such as cancer and fibrosis in lungs and liver [89][90][91][92][93]. TG is an enzyme responsible for cross-linking proteins such as collagen and fibronectin between glutamine and lysine residues or a primary amino group in a calcium-dependent manner.…”

Section: Cross-linking Of Ecmmentioning

confidence: 99%

Regulation of cellular senescence by extracellular matrix during chronic fibrotic diseases

et al. 2020

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The extracellular matrix (ECM) is a complex network of macromolecules surrounding cells providing structural support and stability to tissues. The understanding of the ECM and the diverse roles it plays in development, homoeostasis and injury have greatly advanced in the last three decades. The ECM is crucial for maintaining tissue homoeostasis but also many pathological conditions arise from aberrant matrix remodelling during ageing. Ageing is characterised as functional decline of tissue over time ultimately leading to tissue dysfunction, and is a risk factor in many diseases including cardiovascular disease, diabetes, cancer, dementia, glaucoma, chronic obstructive pulmonary disease (COPD) and fibrosis. ECM changes are recognised as a major driver of aberrant cell responses. Mesenchymal cells in aged tissue show signs of growth arrest and resistance to apoptosis, which are indicative of cellular senescence. It was recently postulated that cellular senescence contributes to the pathogenesis of chronic fibrotic diseases in the heart, kidney, liver and lung. Senescent cells negatively impact tissue regeneration while creating a pro-inflammatory environment as part of the senescence-associated secretory phenotype (SASP) favouring disease progression. In this review, we explore and summarise the current knowledge around how aberrant ECM potentially influences the senescent phenotype in chronic fibrotic diseases. Lastly, we will explore the possibility for interventions in the ECM–senescence regulatory pathways for therapeutic potential in chronic fibrotic diseases.

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“…These are not taken into account in our circuit as they do not represent a significant change to the original core circuit with its assumed self-activation positive feedback loop of ZEB. We also do not take into account other mechanisms whereby LOXL2 (or other Lysyl Oxidases) can enhance tumor aggressiveness; these certainly include angiogenesis [ 61 ], pre-metastasis niche formation [ 62 ], drug resistance [ 63 ] and the growth of lymphatic vessels [ 64 ] at least partially due to upregulation of VEGF. These effects would need to be included in any attempt to comprehensively treat the role of LOXL2 in cancer progression and the overall efficacy of inhibitory drugs.…”

Section: Discussionmentioning

confidence: 99%

A Theoretical Approach to Coupling the Epithelial-Mesenchymal Transition (EMT) to Extracellular Matrix (ECM) Stiffness via LOXL2

Deng

Chakraborty

Jolly

et al. 2021

Cancers

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The epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, being responsible in many cases for the onset of the metastatic cascade and being integral in the ability of cells to resist drug treatment. Most studies of EMT focus on its induction via chemical signals such as TGF-β or Notch ligands, but it has become increasingly clear that biomechanical features of the microenvironment such as extracellular matrix (ECM) stiffness can be equally important. Here, we introduce a coupled feedback loop connecting stiffness to the EMT transcription factor ZEB1, which acts via increasing the secretion of LOXL2 that leads to increased cross-linking of collagen fibers in the ECM. This increased cross-linking can effectively increase ECM stiffness and increase ZEB1 levels, thus setting a positive feedback loop between ZEB1 and ECM stiffness. To investigate the impact of this non-cell-autonomous effect, we introduce a computational approach capable of connecting LOXL2 concentration to increased stiffness and thereby to higher ZEB1 levels. Our results indicate that this positive feedback loop, once activated, can effectively lock the cells in a mesenchymal state. The spatial-temporal heterogeneity of the LOXL2 concentration and thus the mechanical stiffness also has direct implications for migrating cells that attempt to escape the primary tumor.

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Lysyl Oxidase-Like Protein 2 Promotes Tumor Lymphangiogenesis and Lymph Node Metastasis in Breast Cancer

Cited by 39 publications

References 50 publications

LOXL2 Inhibitors and Breast Cancer Progression

LOXL2 Inhibitors and Breast Cancer Progression

Regulation of cellular senescence by extracellular matrix during chronic fibrotic diseases

A Theoretical Approach to Coupling the Epithelial-Mesenchymal Transition (EMT) to Extracellular Matrix (ECM) Stiffness via LOXL2

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