Targeting Lysyl Oxidase Family Meditated Matrix Cross-Linking as an Anti-Stromal Therapy in Solid Tumours

Setargew, Yordanos F.; Wyllie, Kaitlin; Grant, Rhiannon D.; Chitty, Jessica L.; Cox, Thomas R.

doi:10.3390/cancers13030491

Cited by 59 publications

(55 citation statements)

References 170 publications

(254 reference statements)

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“…The present study sheds new insight into the role that the tumor ECM – established by LH2-mediated cross-links – plays in promoting HNSCC metastasis. Several studies have suggested that increased total collagen cross-links resulting from upregulation of LOX family members are associated with poor prognosis in patients with breast, lung, and oral cancers [ 28 , 42 , 48 , 50 ]. However, here we show that knockdown of LH2 alone is sufficient to blunt invasion and metastasis despite robust cellular expression of LOX and LOXL2.…”

Section: Discussionmentioning

confidence: 99%

Lysyl hydroxylase 2-induced collagen cross-link switching promotes metastasis in head and neck squamous cell carcinomas

et al. 2021

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Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and incidence rates are continuing to rise globally. HNSCC patient prognosis is closely related to the occurrence of tumor metastases, and collagen within the tumor microenvironment (TME) plays a key role in this process. Lysyl hydroxylase 2 (LH2), encoded by the Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 2 ( PLOD2 ) gene, catalyzes hydroxylation of telopeptidyl lysine (Lys) residues of fibrillar collagens which then undergo subsequent modifications to form stable intermolecular cross-links that change the biomechanical properties (i.e. quality) of the TME. While LH2-catalyzed collagen modification has been implicated in driving tumor progression and metastasis in diverse cancers, little is known about its role in HNSCC progression. Thus, using gain- and loss-of-function studies, we examined the effects of LH2 expression levels on collagen cross-linking and cell behavior in vitro and in vivo using a tractable bioluminescent imaging-based orthotopic xenograft model. We found that LH2 overexpression dramatically increases HNSCC cell migratory and invasive abilities in vitro and that LH2-driven changes in collagen cross-linking robustly induces metastasis in vivo . Specifically, the amount of LH2-mediated collagen cross-links increased significantly with PLOD2 overexpression, without affecting the total quantity of collagen cross-links. Conversely, LH2 knockdown significantly blunted HNSCC cells invasive capacity in vitro and metastatic potential in vivo . Thus, regardless of the total “quantity” of collagen crosslinks, it is the “quality” of these cross-links that is the key driver of HNSCC tumor metastatic dissemination. These data implicate LH2 as a key regulator of HNSCC tumor invasion and metastasis by modulating collagen cross-link quality and suggest that therapeutic strategies targeting LH2-mediated collagen cross-linking in the TME may be effective in controlling tumor progression and improving disease outcomes.

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Section: Discussionmentioning

confidence: 99%

Lysyl hydroxylase 2-induced collagen cross-link switching promotes metastasis in head and neck squamous cell carcinomas

et al. 2021

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“…In various tumors, overexpression of LOX induced by a hypoxic (45). Targeting LOX family-mediated matrix cross-linking as an anti-matrix therapy for solid tumors (46). Similarly, Setargew et al…”

Section: Discussionmentioning

confidence: 99%

“…De Vita et al reported: Lysyl oxidase engineered lipid nanovesicles for the treatment of triple-negative breast cancer ( 45 ). Targeting LOX family-mediated matrix cross-linking as an anti-matrix therapy for solid tumors ( 46 ). Similarly, Setargew et al found that radioactive LOX-trackable nanoparticles (LOX ab-NPs) can be used as chemotherapy carriers for combined targeted radiotherapy and chemotherapy in clinical oncology ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

Expression of LOX Suggests Poor Prognosis in Gastric Cancer

et al. 2021

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Background: Lysyl oxidase (LOX) is a key enzyme for the cross-linking of collagen and elastin in the extracellular matrix. This study evaluated the prognostic role of LOX in gastric cancer (GC) by analyzing the data of The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset.Methods: The Wilcoxon rank-sum test was used to calculate the expression difference of LOX gene in gastric cancer and normal tissues. Western blot and immunohistochemical staining were used to evaluate the expression level of LOX protein in gastric cancer. Kaplan-Meier analysis was used to calculate the survival difference between the high expression group and the low expression group in gastric cancer. The relationship between statistical clinicopathological characteristics and LOX gene expression was analyzed by Wilcoxon or Kruskal-Wallis test and logistic regression. Univariate and multivariate Cox regression analysis was used to find independent risk factors affecting the prognosis of GC patients. Gene set enrichment analysis (GSEA) was used to screen the possible mechanisms of LOX and GC. The CIBERSORT calculation method was used to evaluate the distribution of tumor-infiltrating immune cell (TIC) abundance.Results: LOX is highly expressed in gastric cancer tissues and is significantly related to poor overall survival. Wilcoxon or Kruskal-Wallis test and Logistic regression analysis showed, LOX overexpression is significantly correlated with T-stage progression in gastric cancer. Multivariate Cox regression analysis on TCGA and GEO data found that LOX (all p < 0.05) is an independent factor for poor GC prognosis. GSEA showed that high LOX expression is related to ECM receptor interaction, cancer, Hedgehog, TGF-beta, JAK-STAT, MAPK, Wnt, and mTOR signaling pathways. The expression level of LOX affects the immune activity of the tumor microenvironment in gastric cancer.Conclusion: High expression of LOX is a potential molecular indicator for poor prognosis of gastric cancer.

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“…The LOX family can be classi ed into two groups based on the structure of their N-terminal domains: LOX and LOXL1 have a propeptide at their N-terminal, whereas LOXL2, LOXL3, and LOXL4 have four scavenger receptor cysteine-rich domains [19]. The LOX family gene subtypes (LOX, LOXL1-4) are all amine oxidases and contain a highly conserved C-terminal binding domain that forms a special lysine tyrosylquinone cofactor-moiety after binding to the copper ion cofactor [20]. These family genes are critical enzymes that regulate the crosslinking of elastin and collagen to have a regulatory role in ECM assembly [21], while the dysregulation of ECM may disrupt the function or structure of the arterial wall, and may be a risk factor in the pathogenesis of aSAH [14,22].…”

Section: Discussionmentioning

confidence: 99%

Lysyl oxidase family genes polymorphisms and risk of aneurysmal subarachnoid hemorrhage: A case control study

Dong¹,

Luo²,

Li³

et al. 2021

Preprint

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Introduction: aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease caused by intracranial aneurysm (IA) rupture. Lysyl oxidase (LOX) family genes (LOX-like [LOXL] 1–4) have roles in collagen cross-linking in the extracellular matrix and may be associated with IA rupture. We aimed to explore the association between LOX polymorphisms and the risk of aSAH. Methods This case-control study included two cohorts: 133 and 115 single ruptured and unruptured IA patients, and 65 and 71 multiple ruptured and unruptured IAs patients, respectively. Genotyping of 27 single nucleotide polymorphisms (SNPs) in LOX was performed. Logistic regression analysis was performed to calculate the odds ratios (OR) and 95% confidence intervals (CI) of the SNPs of LOX and risk of aSAH. Results LOX rs180044 and LOXL4 rs3793692 were positively associated with the risk of single IA rupture in the recessive model (OR = 5.66, 2.06; 95% CI = 1.22–26.24, 1.11–3.82, respectively) and LOX rs10519694 demonstrated a protective effect on single IA rupture (dominant model: OR = 0.42, 95% CI = 0.21–0.83; recessive model: OR = 0.16, 95% CI = 0.04–0.65; additive model: OR = 0.46, 95% CI = 0.28–0.78). LOXL1 rs2165241, LOXL2 rs1063582, and LOXL3 rs17010021 demonstrated risk effects on multiple IAs rupture. LOXL3 rs17010022 showed a protective effect on multiple IAs rupture (dominant model: OR = 0.41, 95% CI = 0.21–0.82; additive model: OR = 0.51, 95% CI = 0.30–0.85). Discussion LOX and LOXL4 may be susceptible to single IA rupture, whereas LOXL1-3 may have a role in susceptibility to multiple IAs rupture in the Chinese population, suggesting LOX family genes may associated with aSAH.

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Targeting Lysyl Oxidase Family Meditated Matrix Cross-Linking as an Anti-Stromal Therapy in Solid Tumours

Cited by 59 publications

References 170 publications

Lysyl hydroxylase 2-induced collagen cross-link switching promotes metastasis in head and neck squamous cell carcinomas

Lysyl hydroxylase 2-induced collagen cross-link switching promotes metastasis in head and neck squamous cell carcinomas

Expression of LOX Suggests Poor Prognosis in Gastric Cancer

Lysyl oxidase family genes polymorphisms and risk of aneurysmal subarachnoid hemorrhage: A case control study

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