Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis

Balážiová, Eva; Vymola, Petr; Hrabal, Petr; Mateu, Rosana; Zubal, Michal; Tomáš, Robert; Netuka, David; Kramář, Filip; Zemanová, Zuzana; Svobodova, Karla; Brabec, Marek; Šedo, Aleksi; Bušek, Petr

doi:10.3390/cancers13133304

Cited by 19 publications

(20 citation statements)

References 67 publications

(98 reference statements)

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“…FAP has been identi ed as an independent biomarker associated with a poor prognosis in a growing number of cancers [20][21][22][23]. The presence of proangiogenic FAP in CAFs has been reported [9,12,24] which is consistent with our ndings.…”

Section: Discussionsupporting

confidence: 91%

Tracking tumor alteration in glioma through serum fibroblast activation protein combined with image

Yang

Zhu

Xie

et al. 2023

Preprint

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Purpose Detecting tumor progression remains difficult in patients with glioma. Fibroblast activation protein (FAP) in gliomas has been showed to promote tumor progression. Glioma-circulating biomarkers have not yet been used in clinical practice. This study seeks to evaluate the feasibility of glioma detection using a serum FAP marker. Methods We adopted enzyme-linked immunoadsorbent assay (ELISA) to determine serum FAP level in 87 gliomas. The relationship between preoperative serum FAP levels and postoperative pathology, as well as molecular pathology was investigated. Serial FAP tests were performed in 33 malignant gliomas to see if they could track the disease when compared to image findings. Immunohistochemistry was performed on four gliomas using a FAP-specific antibody to confirm FAP expression in tumors. Therelationship between tumor burden as determined by volumetric analysis and serum FAP level was investigated. Results Serum FAP was significantly elevated in a large proportion of gliomas, was closely related to histopathology and molecular pathology, and longitudinally fluctuated and varied with the disease stage. The significant increase in serum FAP was associated with tumor progression and/or worsening symptoms. Conclusions Serum FAP can be used to detect the disease as a biomarker. Its detection in conjunction with MR imaging may allow for more precise and immediate diagnosis.

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Section: Discussionsupporting

confidence: 91%

Tracking tumor alteration in glioma through serum fibroblast activation protein combined with image

Yang

Zhu

Xie

et al. 2023

Preprint

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“…Many studies have demonstrated that FAP is expressed by the cancer-associated fibroblasts (CAFs) that occupy the tumor microenvironment (TME) [ 17 , 18 ], and is overexpressed in 90% of epithelial tumors, including colon and breast cancers [ 19 , 20 ]. FAP expression is associated with worse prognosis as FAP supports tumor migration [ 21 ], angiogenesis [ 22 ], metastasis via matrix remodeling in TME [ 23 ], and immunomodulatory function [ 24 ]. A study by Kesch et al [ 25 ] showed that there is a significant rise in FAP expression throughout the progression of prostate cancer, in which men with advanced CRPC have the highest number of FAP-positive lesions.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Preclinical Evaluation of Three Novel 68Ga-Labeled Bispecific PSMA/FAP-Targeting Tracers for Prostate Cancer Imaging

Verena¹,

Zhang²,

Kuo³

et al. 2023

Molecules

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Tumor heterogeneity limits the efficacy and reliability of monospecific radiopharmaceuticals in prostate cancer diagnosis and therapy. To overcome this limitation and improve lesion detection sensitivity, we developed and evaluated three bispecific radiotracers that can target both prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), which are the two key proteins overexpressed in prostate cancer. Three FAP-targeting ligands with various linker lengths were synthesized through multistep organic synthesis, and then connected to the PSMA-targeting motif. IC50(PSMA) and IC50(FAP) values of Ga-complexed bispecific ligands, Ga-AV01017, Ga-AV01030, and Ga-AV01038 were 25.2–71.6 and 1.25–2.74 nM, respectively. The uptake values in PSMA-expressing LNCaP tumor xenografts were 4.38 ± 0.55, 5.17 ± 0.51, and 4.25 ± 0.86 %ID/g for [68Ga]Ga-AV01017, [68Ga]Ga-AV01030, and [68Ga]Ga-AV01038, respectively, which were lower than the monospecific PSMA-targeting tracer [68Ga]Ga-HTK03041 (23.1 ± 6.11 %ID/g). The uptake values in FAP-expressing HEK293T:hFAP tumor xenografts were 2.99 ± 0.37, 3.69 ± 0.81, 3.64 ± 0.83 %ID/g for [68Ga]Ga-AV01017, [68Ga]Ga-AV01030, and [68Ga]Ga-AV01038, respectively, which were also lower than the monospecific FAP-targeting tracer, [68Ga]Ga-FAPI-04 (12.5 ± 2.00 %ID/g). We observed that the bispecific tracers had prolonged blood retention, in which tracers with a longer linker tend to have a higher blood uptake and lower tumor uptake. Further investigations are needed to optimize the linker selection to generate promising bispecific PSMA/FAP-targeting tracers for prostate cancer imaging.

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“…The mechanisms of high neovascularization in GBM have received great attention, including the presence of bizarre vessels and resistance to antiangiogenic therapy, which can be related to different types of angiogenesis [1][2][3][4][5][9][10][11][12][13][14][15][16][17]. It has been suggested that intussusception (intussusceptive microvascular growth) could be a mechanism of compensatory vascular growth occurring in human glioma [18,19], with advantages and inconveniences over classic sprouting angiogenesis [18].…”

Section: Introductionmentioning

confidence: 99%

Disproportion in Pericyte/Endothelial Cell Proliferation and Mechanisms of Intussusceptive Angiogenesis Participate in Bizarre Vessel Formation in Glioblastoma

Díaz‐Flores

Gutiérrez

González‐Gómez

et al. 2021

Cells

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Glioblastoma (GBM) is the most malignant tumor in the brain. In addition to the vascular pattern with thin-walled vessels and findings of sprouting angiogenesis, GBM presents a bizarre microvasculature (BM) formed by vascular clusters, vascular garlands, and glomeruloid bodies. The mechanisms in BM morphogenesis are not well known. Our objective was to assess the role of pericyte/endothelial proliferation and intussusceptive angiogenic mechanisms in the formation of the BM. For this purpose, we studied specimens of 66 GBM cases using immunochemistry and confocal microscopy. In the BM, the results showed (a) transitional forms between the BM patterns, mostly with prominent pericytes covering all the abluminal endothelial cell (EC) surface of the vessels, (b) a proliferation index high in the prominent pericytes and low in ECs (47.85 times higher in pericytes than in ECs), (c) intravascular pillars (hallmark of intussusceptive angiogenesis) formed by transcapillary interendothelial bridges, endothelial contacts of opposite vessel walls, and vessel loops, and (d) the persistence of these findings in complex glomeruloid bodies. In conclusion, disproportion in pericyte/EC proliferation and mechanisms of intussusceptive angiogenesis participate in BM formation. The contributions have morphogenic and clinical interest since pericytes and intussusceptive angiogenesis can condition antiangiogenic therapy in GBM.

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Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis

Cited by 19 publications

References 67 publications

Tracking tumor alteration in glioma through serum fibroblast activation protein combined with image

Tracking tumor alteration in glioma through serum fibroblast activation protein combined with image

Synthesis and Preclinical Evaluation of Three Novel 68Ga-Labeled Bispecific PSMA/FAP-Targeting Tracers for Prostate Cancer Imaging

Disproportion in Pericyte/Endothelial Cell Proliferation and Mechanisms of Intussusceptive Angiogenesis Participate in Bizarre Vessel Formation in Glioblastoma

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