Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases

Perryman, Lara; Gray, Steven G.

doi:10.3390/cancers14040981

Cited by 7 publications

(5 citation statements)

References 185 publications

(182 reference statements)

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“…Given the clinical similarities of fibrosis that characterizes both MESO 37 and PDAC, we hypothesized that there may also be similar pathology findings that explain the relevance of DeCAF subtypes in MESO. We found that DeCAF subtypes were associated with histological type (p = 0.001) with 93% (53/57) of epithelioid type tumors having a restCAF subtype (Fig.5d,e).…”

Section: Resultsmentioning

confidence: 99%

Determination of permissive and restraining cancer-associated fibroblast (DeCAF) subtypes

Peng,

Kharitonova,

et al. 2024

Preprint

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Cancer-associated fibroblast (CAF) subpopulations in pancreatic ductal adenocarcinoma (PDAC) have been identified using single-cell RNA-sequencing (scRNAseq) with divergent characteristics, but their clinical relevance remains unclear. We translate scRNAseq-derived CAF cell-subpopulation-specific marker genes to bulk RNAseq data, and develop a single-sample classifier, DeCAF, for the classification of clinically restraining and permissive CAF subtypes. We validate DeCAF in 19 independent bulk transcriptomic datasets across four tumor types (PDAC, mesothelioma, bladder and renal cell carcinoma). DeCAF subtypes have distinct histology features, immune landscapes, and are prognostic and predict response to therapy across cancer types. We demonstrate that DeCAF is clinically replicable and robust for the classification of CAF subtypes in patients for multiple tumor types, providing a better framework for the future development and translation of therapies against permissive CAF subtypes and preservation of restraining CAF subtypes.

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Section: Resultsmentioning

confidence: 99%

Determination of permissive and restraining cancer-associated fibroblast (DeCAF) subtypes

Peng,

Kharitonova,

et al. 2024

Preprint

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“…Moreover, in some tumors the cross-linking of collagen and elastin fibers mediated by LOX is increased. In particular, LOX expression is upregulated in many tumors, for example mesothelioma, downstream of hypoxia (HIFs) by a mechanism that is, in part, driven by TGFβ ( 22 , 85 , 86 ). An unbalanced increase in LOX expression and activity promotes an increase in ECM stiffness that induces mechanical activation of latent TGFβ and fuels the initiation of a vicious cycle that maintains an inflammatory environment and promotes tumor progression ( 83 ).…”

Section: Inflammation In Desmoplastic Matrix Remodelingmentioning

confidence: 99%

Multiple aspects of matrix stiffness in cancer progression

Mancini,

Gentile,

Pentimalli

et al. 2024

Front. Oncol.

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The biophysical and biomechanical properties of the extracellular matrix (ECM) are crucial in the processes of cell differentiation and proliferation. However, it is unclear to what extent tumor cells are influenced by biomechanical and biophysical changes of the surrounding microenvironment and how this response varies between different tumor forms, and over the course of tumor progression. The entire ensemble of genes encoding the ECM associated proteins is called matrisome. In cancer, the ECM evolves to become highly dysregulated, rigid, and fibrotic, serving both pro-tumorigenic and anti-tumorigenic roles. Tumor desmoplasia is characterized by a dramatic increase of α-smooth muscle actin expressing fibroblast and the deposition of hard ECM containing collagen, fibronectin, proteoglycans, and hyaluronic acid and is common in many solid tumors. In this review, we described the role of inflammation and inflammatory cytokines, in desmoplastic matrix remodeling, tumor state transition driven by microenvironment forces and the signaling pathways in mechanotransduction as potential targeted therapies, focusing on the impact of qualitative and quantitative variations of the ECM on the regulation of tumor development, hypothesizing the presence of matrisome drivers, acting alongside the cell-intrinsic oncogenic drivers, in some stages of neoplastic progression and in some tumor contexts, such as pancreatic carcinoma, breast cancer, lung cancer and mesothelioma.

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“…This implies that inhibitors of lysyl oxidases may turn out to be useful therapeutic agents for the treatment of many types of cancer. In addition, inhibition of lysyl oxidases may assist in the control of fibrotic diseases, such as idiopathic lung fibrosis and liver cirrhosis, and may help to reduce tumor desmoplasia [ 118 , 119 , 120 ]. The first attempt in this direction was the development of a LOXL2-targeting antibody that showed promise in pre-clinical studies [ 43 , 121 , 122 ].…”

Section: Development Of Anti-tumorigenic Therapeutics Targeting Lysyl...mentioning

confidence: 99%

Lysyl Oxidase Family Enzymes and Their Role in Tumor Progression

Liburkin-Dan

Toledano

Neufeld

2022

IJMS

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The five genes of the lysyl oxidase family encode enzymes that covalently cross-link components of the extracellular matrix, such as various types of collagen and elastin, and, thus, promote the stabilization of extracellular matrixes. Several of these genes, in particular lysyl oxidase (LOX) and lysyl oxidase like-2 (LOXL2) were identified as genes that are upregulated by hypoxia, and promote tumor cells invasion and metastasis. Here, we focus on the description of the diverse molecular mechanisms by which the various lysyl oxidases affect tumor progression. We also describe attempts that have been made, and are still on-going, that focus on the development of efficient lysyl oxidase inhibitors for the treatment of various forms of cancer, and of diseases associated with abnormal fibrosis.

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Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases

Cited by 7 publications

References 185 publications

Determination of permissive and restraining cancer-associated fibroblast (DeCAF) subtypes

Determination of permissive and restraining cancer-associated fibroblast (DeCAF) subtypes

Multiple aspects of matrix stiffness in cancer progression

Lysyl Oxidase Family Enzymes and Their Role in Tumor Progression

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