
==== Front
Transl Oncol
Transl Oncol
Translational Oncology
1936-5233
Neoplasia Press

S1936-5233(23)00163-8
10.1016/j.tranon.2023.101777
101777
Commentary
LOX rises as a potential survival biomarker: A commentary on “Identification of LOX as a candidate prognostic biomarker in Glioblastoma multiforme” by Liu et al.
Silva-Pavez Eduardo b
Urra Hery hery.urra@uss.cl
ab⁎
a Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
b Facultad de Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián, Bellavista, Santiago, Chile
⁎ Corresponding author at: Facultad Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián. Lota 2465, Providencia, Santiago, Chile. hery.urra@uss.cl
02 9 2023
6 2024
02 9 2023
44 10177716 8 2023
30 8 2023
© 2023 The Authors. Published by Elsevier Inc.
2023

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords

Glioblastoma
LOX
Prognostic biomarker
Extracellular matrix
Bioinformatics
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pmcGlioblastoma (GB) is one of the most aggressive and deadly forms of brain cancer. Originating from astrocytes, GB is categorized as a Grade IV astrocytoma, distinguishing it as the most malignant of the gliomas. Despite advances in neuro-oncology and related fields, the prognosis for GB remains abysmal, with a median survival rate of roughly 12–15 months post-diagnosis and a five-year survival rate of less than 10% [1]. The aggressive nature of GB is attributed to its rapid proliferation, diffuse infiltration into normal brain tissues, and resistance to conventional therapies, making it a significant challenge to treat. Surgical resection is limited by the infiltrative nature of these tumors, which prevents complete removal. While valuable, adjuvant therapies like radiation and chemotherapy provide only marginal increases in overall survival due to the tumor's adaptive resistance mechanisms [2].

Biomarkers play a pivotal role in the evolving landscape of GB diagnosis, prognosis, stratification, and therapeutic decision-making. The best-known biomarker in GB is the Methylguanine-DNA Methyltransferase (MGMT) promoter methylation status, which predicts sensitivity to temozolomide treatment, the cornerstone of GB therapy. Similarly, IDH1/2 mutations, EGFR amplification, TERT promoter mutations, and PTEN deletion are also present in GB and often correlate with a worse prognosis. These molecular biomarkers have allowed for the novel classification of brain tumors, including GB, categorizing patients in terms of clinical prognosis and molecular markers [3]. As research advances, the identification and validation of new biomarkers continue to grow, providing a new understanding of GB heterogeneity. These are also the foundations for personalized medicine approaches, optimizing treatment efficacy and potentially improving patient outcomes.

In their recent study, Liu and colleagues dissect novel molecular markers of GB that dictate patient survival, a subject of increasing importance due to the pressing need to deeply understand the molecular and genetics of GB (Fig. 1) [4]. By identifying differentially expressed genes (DEGs) between GB and normal brain tissue, researchers aim to uncover the pathways and mechanisms involved in GB malignancy. Using a plethora of GB expression datasets, followed by multi-step methods and comprehensive bioinformatic approaches, authors identify, validate, and explore the implications of differentially expressed genes in GB in patient survival. The systematic workflow, starting from initial data acquisition and differential expression analysis, followed by pathway enrichment, PPI network establishment, and ending with in-depth survival and target gene analysis, allows them to postulate that lysyl oxidase (LOX) is a protein differentially expressed in GB that functions as a prognostic, survival, and stratification biomarker [4].Fig. 1 LOX is upregulated in GB compared to normal brain tissue, suggesting its potential as a candidate prognostic biomarker. Ten essential genes, including LOX, were identified as significantly upregulated in GB. Altered hub genes correlated with shorter survival among patients. Notably, LOX expression was explicitly tied to patient survival. Bioinformatic approaches revealed a positive correlation between LOX expression levels and malignancy and differentiation degrees of glioma and GB cells (Created with BioRender.com).

Fig. 1

LOX is a pivotal enzyme involved in the cross-linking and stabilization of collagen and elastin fibers in the extracellular matrix. Beyond its conventional role in tissue remodeling, recent studies have unveiled its significance in cancer biology by facilitating a stiffened tumor microenvironment, promoting tumor progression, angiogenesis, invasion, and metastasis [5]. After a significant period, it was eventually recognized that LOX is just a single member within a larger group of enzymes called the LOX family. This family encompasses four other members: LOXL1, LOXL2, LOXL3, and LOXL4. The LOX family of proteins is associated with promoting tumor progression across multiple cancer types. For instance, the overexpression of LOX or LOXL2 facilitates breast cancer invasiveness and progression. Additionally, LOX has been linked with the progression of colorectal, cervical, and lung cancers, while LOXL2 affects colorectal and gastric tumors. Further research pointed to LOXL3′s involvement in melanoma and breast cancer progression and LOXL4′s role in gastric cancer and hepatocellular carcinoma growth and spread [6].

At the molecular level, hypoxic conditions in rapidly expanding tumors lead to an upregulation of LOX and LOXL2. This increase enhances the deposition of collagen fibers in the tumor environment, forming thick bundles indicative of desmoplasia, a condition linked to tumor cell invasion. The overexpression of LOX's stiffens the extracellular matrix, enhancing tumor cell invasiveness and metastasis by boosting integrin clustering and PI3K signaling induced by the increased cross-linking of collagen. LOX overexpression also affects TGF-β1 and EGF receptor signaling pathways, promoting tumor growth. Interestingly, LOX in the circulation modifies distant sites' extracellular matrix, aiding metastasizing tumor cell colonization. The by-product hydrogen peroxide from LOX activates the FAK/src pathway, further enhancing metastasis. Additionally, LOX promote angiogenesis by stimulating VEGF and PDGF production. LOX also influences tumor invasion by impacting the epithelial-to-mesenchymal transition (EMT). LOXL2 interacts with actin-binding proteins, prompting cytoskeletal reorganization to boost tumor cell invasion. Furthermore, LOXL3 possesses deacetylase activity affecting Stat3′s function. Intriguingly, LOX can re-enter cells, impacting gene expression and EMT via various signaling pathways while regulating E-cadherin.

In the context of brain tumors, LOX facilitates glioma migration, invasion, and angiogenesis. LOX overexpression or gene variants heighten glioma risk and reduce survival rates [7]. Glioma patients with elevated LOX levels display increased immune cell infiltration and elevated immune checkpoint levels. Their association with numerous chemotherapy drugs suggests LOX's strong potential as a predictive marker for prognosis, chemotherapy, and immunotherapy in glioma patients [8]. Interestingly, Liu and colleagues evidenced that the expression level of LOX was positively correlated with the malignant degree of glioma and differentiation of GB cells. A similar report indicates that among hub genes, LOX stands out as a significant player in glioma progression suggesting its potential as a therapeutic target for GB [9]. LOX, SERPINH1, and many isoforms of collagen (COLA1–4), are upregulated in GB samples compared to adjacent tissue at mRNA and protein levels [9].

Notably, Liu and colleagues described through gene ontology enrichment analysis that most DEGs are integral to GB extracellular matrix (ECM) and membrane structures. These DEGs are involved in processes such as the organization of the extracellular structure, cell-substrate adhesion, and the regulation of cell morphogenesis [4]. Most of the hubs mentioned are either present in or regulate the composition of the extracellular matrix. This suggests that the architecture and composition of the ECM play a role in determining patient prognosis and survival [4]. Recently, a gene signature related to ECM organization in GB was detailed, serving as a potential novel prognostic or diagnostic biomarker tool. In this context, LOXL1, a member of the LOX family, stands out as an integral component of this gene signature [10]. Future research employing the ten hub genes described by Liu and colleagues as a gene signature could illuminate new insights into glioma prognosis and might identify potential therapeutic signatures. Although Liu and colleagues primarily base their findings on bioinformatics utilizing GB databases [4], another similar bioinformatic exploration exists [9].

Several reports underscore the potential role of individual hub genes in GB progression. Systematic analyses using these hub genes as gene signatures to forecast patient survival would be interesting. Furthermore, given the multifaceted effects of LOX family of proteins at the cellular level, a deeper investigation into the context of GB might reveal novel molecular mechanisms driving tumor progression.

Along with other hub genes, LOX is pivotal in advancing GB. To consider these as potential therapeutic targets, further studies are essential to ascertain if inhibiting their activity could decelerate or even halt the disease's progression. The current data suggest that elevated levels of LOX and specific hub genes can function as diagnostic or prognostic indicators. The efficacy of these prognostic markers might be amplified if hub genes are analyzed as part of a signature, unveiling the intricate pathways or interactions through which LOX and other hub genes operate. Upcoming research should probe whether LOX and select hub genes are correlated with resistance to standard treatments, such as Temozolomide and radiotherapy. Such insights could be instrumental in guiding treatment decisions and spearheading the development of innovative therapeutic strategies, especially in precision and personalized medicine. It remains vital to interpret these projections prudently, as extensive studies, both in vitro and in vivo, are needed to ascertain LOX's role and potential applicability in GB progression. In conclusion, it is imperative to undertake rigorous and in-depth scientific exploration to wholly decipher its contribution to oncogenesis and to investigate its prospective therapeutic use.

CRediT authorship contribution statement

Eduardo Silva-Pavez: Writing – original draft. Hery Urra: Conceptualization, Writing – original draft.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding

This research was funded by ANID/FONDECYT #11180825 (HU), ANID/FONDECYT Postdoctoral Grant #3220604 (ESP) and ANID/FONDAP/15150012 (HU)
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