Role of fibrillin-2 in the control of TGF-β activation in tumor angiogenesis and connective tissue disorders

Loon, Karlijn van; Yemelyanenko, Julia; Margadant, Coert; Huijbers, Elisabeth J. M.

doi:10.1016/j.bbcan.2020.188354

Cited by 28 publications

(25 citation statements)

References 157 publications

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“…In addition, SFRP2-directed ultrasound imaging clearly shows specific signal in the tumor vasculature, while normal vessels are not visualized [6]. Proteins such as SFRP2, that seem to be specifically (over)expressed in the tumor vasculature, show great promise as therapeutic targets in the fight against cancer [7][8][9]. To enhance insight in oncogenic role of SFRP2, we performed a literature study about SFRP2 in Wnt signaling and tumor angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Secreted frizzled-related protein 2: a key player in noncanonical Wnt signaling and tumor angiogenesis

Loon

Huijbers

2020

Cancer Metastasis Rev

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Secreted frizzled-related proteins (SFRP) are glycoproteins containing a so-called frizzled-like cysteine-rich domain. This domain enables them to bind to Wnt ligands or frizzled (FzD) receptors, making potent regulators of Wnt signaling. As Wnt signaling is often altered in cancer, it is not surprising that Wnt regulators such as SFRP proteins are often differentially expressed in the tumor microenvironment, both in a metastatic and non-metastatic setting. Indeed, SFRP2 is shown to be specifically upregulated in the tumor vasculature of several types of cancer. Several studies investigated the functional role of SFRP2 in the tumor vasculature, showing that SFRP2 binds to FzD receptors on the surface of tumor endothelial cells. This activates downstream Wnt signaling and which is, thereby, stimulating angiogenesis. Interestingly, not the well-known canonical Wnt signaling pathway, but the noncanonical Wnt/Ca2+ pathway seems to be a key player in this event. In tumor models, the pro-angiogenic effect of SFRP2 could be counteracted by antibodies targeting SFRP2, without the occurrence of toxicity. Since tumor angiogenesis is an important process in tumorigenesis and metastasis formation, specific tumor endothelial markers such as SFRP2 show great promise as targets for anti-cancer therapies. This review discusses the role of SFRP2 in noncanonical Wnt signaling and tumor angiogenesis, and highlights its potential as anti-angiogenic therapeutic target in cancer.

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Section: Introductionmentioning

confidence: 99%

Secreted frizzled-related protein 2: a key player in noncanonical Wnt signaling and tumor angiogenesis

Loon

Huijbers

2020

Cancer Metastasis Rev

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“…Previous studies have shown that methylation or silencing of FBN2 in tumor cells may play an important role in carcinogenesis, invasion, and metastasis (67). However, recent research suggested the opposite, wherein FBN2 stimulates tumor angiogenesis by influencing TGF-β sequestration by microfibrils, leading to a locally higher active TGF-β concentration in the tumor microenvironment which is involved in tumor progression, metastasis, EMT, and tumor angiogenesis (68). In lung cancer, cholangiocarcinoma, and metastatic colorectal cancer, FBN2 has been found to be associated with EMT, cell migration, and metastasis (69)(70)(71).…”

Section: Discussionmentioning

confidence: 99%

Identification of key genes in cutaneous squamous cell carcinoma: a transcriptome sequencing and bioinformatics profiling study

Zou¹,

Xu²,

Deng³

et al. 2021

Ann Transl Med

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Background: Long-term exposure to ultraviolet (UV) radiation can cause cutaneous squamous cell carcinoma (cSCC), which is one of the most common malignant cancers worldwide. Actinic keratosis (AK) is generally considered a precancerous lesion of cSCC. However, the pathogenesis and oncogenic processes of AK and cSCC remain elusive, especially in the context of photodamage.Methods: In this study, transcriptome sequencing was performed on AK, cSCC, normal sun-exposed skin (NES) tissues, and normal non-sun-exposed skin (NNS) from 24 individuals. Bioinformatics analysis to identify the differentially expressed genes (DEGs) of 4 groups, and potential key genes of cSCC were validated by real-time quantitative reverse transcription PCR (qRT-PCR).Results: A total of 46,930 genes were differentially expressed in the 4 groups, including 127 genes that were differentially expressed between NES and NNS, 420 DEGs in AK compared to NES, 1,658 DEGs in cSCC compared to NES, and 1,389 DEGs in cSCC compared to AK. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that the DEGs are involved in multiple pathways, including extracellular matrix (ECM)-receptor interaction, immune, inflammatory, microbial infection, and other related pathways. Finally, 5 new genes (HEPHL1, FBN2, SULF1, SULF2, and TCN1) were confirmed significantly upregulated in cSCC.Conclusions: Using transcriptome sequencing and integrated bioinformatical analysis, we have identified key DEGs and pathways in cSCC, which could improve our understanding of the cause and underlying molecular events of AK and cSCC. HEPHL1, FBN2, SULF1, SULF2, and TCN1 may be novel potential biomarkers and therapeutic targets of cSCC.

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“…It is well known that mutation of FBN2 leads to dominant heritable connective tissue disorders [64]. Importantly, a recent review article has gained insight on fibrillin-2 as a critical mediator that binds to transforming growth factor-beta (TGF-β) during extracellular matrix formation [65]. The TLR9/ TGF-β1/PDGF-β pathway was excessively activated in peripheral mononuclear cells isolated from LN patients [66].…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of genome-wide association study identifies FBN2 as a novel locus associated with systemic lupus erythematosus in Thai population

et al. 2020

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Background: Differences in the expression of variants across ethnic groups in the systemic lupus erythematosus (SLE) patients have been well documented. However, the genetic architecture in the Thai population has not been thoroughly examined. In this study, we carried out genome-wide association study (GWAS) in the Thai population. Methods: Two GWAS cohorts were independently collected and genotyped: discovery dataset (487 SLE cases and 1606 healthy controls) and replication dataset (405 SLE cases and 1590 unrelated disease controls). Data were imputed to the density of the 1000 Genomes Project Phase 3. Association studies were performed based on different genetic models, and pathway enrichment analysis was further examined. In addition, the performance of disease risk estimation for individuals in Thai GWAS was assessed based on the polygenic risk score (PRS) model trained by other Asian populations. Results: Previous findings on SLE susceptible alleles were well replicated in the two GWAS. The SNPs on HLA class II (rs9270970, A>G, OR = 1.82, p value = 3.61E−26), STAT4 (rs7582694, C>G, OR = 1.57, p value = 8.21E−16), GTF2I (rs73366469, A>G, OR = 1.73, p value = 2.42E−11), and FAM167A-BLK allele (rs13277113, A>G, OR = 0.68, p value = 1.58E−09) were significantly associated with SLE in Thai population. Meta-analysis of the two GWAS identified a novel locus at the FBN2 that was specifically associated with SLE in the Thai population (rs74989671, A>G, OR = 1.54, p value = 1.61E−08). Functional analysis showed that rs74989671 resided in a peak of H3K36me3 derived from CD14+ monocytes and H3K4me1 from T lymphocytes. In addition, we showed that the PRS model trained from the Chinese population could be applied in individuals of Thai ancestry, with the area under the receiver-operator curve

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Role of fibrillin-2 in the control of TGF-β activation in tumor angiogenesis and connective tissue disorders

Cited by 28 publications

References 157 publications

Secreted frizzled-related protein 2: a key player in noncanonical Wnt signaling and tumor angiogenesis

Secreted frizzled-related protein 2: a key player in noncanonical Wnt signaling and tumor angiogenesis

Identification of key genes in cutaneous squamous cell carcinoma: a transcriptome sequencing and bioinformatics profiling study

Meta-analysis of genome-wide association study identifies FBN2 as a novel locus associated with systemic lupus erythematosus in Thai population

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