P16.12 Proangiogenic effect of fibroblast activation protein positive stromal cells derived from human glioblastomas

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii58-ii58
Author(s):  
E Balaziova ◽  
P Vymola ◽  
P Hrabal ◽  
R Mateu ◽  
R Tomas ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Stromal Cells ◽  
Chorioallantoic Membrane ◽  
Fibroblast Activation Protein ◽  
Conditioned Media ◽  
Comparative Genomic ◽  
Polymorphism Analysis ◽  
Fibroblast Activation ◽  
Cytokine Array ◽  
Chorioallantoic Membrane Assay

Abstract BACKGROUND Increased expression of fibroblast activation protein (FAP) is characteristic for several cancer types including human glioblastomas (GBM). FAP is expressed on both cancer as well as stromal cells which were demonstrated in extracranial tumors to maintain a microenvironment permissive for tumor growth and thus to contribute to tumor progression. FAP is considered a potential diagnostic and therapeutic target and several approaches for its targeting have been recently developed. In this work, we investigated the role of FAP+ stromal cells in glioblastoma angiogenesis. MATERIAL AND METHODS Expression of FAP and other phenotypic markers was assessed by immunocytochemistry and immunohistochemistry. FAP+ stromal cells and primary microvascular endothelial cells were isolated using magnetic activated cell sorting (MACS). Genetic aberrations were assayed by comparative genomic hybridization/single-nucleotide polymorphism analysis. Angiogenesis was evaluated using a 3D spheroid-based sprouting assay and a chorioallantoic membrane assay. A cytokine array was used to analyze soluble mediators released by FAP+ stromal cells. RESULTS FAP+ stromal cells were predominantly localized around activated CD105+ endothelial cells and their quantity positively correlated with glioblastoma vascularization. FAP+ stromal cells derived from human GBMs had a mesenchymal phenotype, were non-tumorigenic and in most cases lacked cytogenetic aberrations characteristic of GBMs. Conditioned media derived from FAP+ stromal cells induced angiogenic sprouting of both macrovascular HUVEC as well as microvascular primary endothelial cells derived from human GBMs. In a chorioallantoic membrane assay, admixture of FAP+ stromal cells to glioma cells was associated with increased angiogenesis and more frequent occurrence of hemorrhages. Cytokine array revealed a significant disbalance between several proangiogenic and antiangiogenic mediators compared to normal pericytes, and an increased Angiopoietin 2/1 ratio in conditioned media from FAP+ stromal cells. CONCLUSION Our results bring new evidence that GBM associated FAP+ stromal cell promote angiogenesis by changing the balance between proangiogenic and antiangiogenic mediators and thus they may contribute to glioblastoma progression. ACKNOWLEDGEMENT Supported by Progres Q28/1LFUK and grant LM2015064 of the EATRIS-CZ and the Center for Tumor Ecology (CZ.02.1.01/0.0/0.0/16_019/0000785).

scholarly journals Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3304
Author(s):  
Eva Balaziova ◽  
Petr Vymola ◽  
Petr Hrabal ◽  
Rosana Mateu ◽  
Michal Zubal ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Stromal Cells ◽  
Chorioallantoic Membrane ◽  
Glioma Cells ◽  
Mesenchymal Cells ◽  
Fibroblast Activation Protein ◽  
Fibroblast Activation ◽  
Cytogenetic Aberrations ◽  
Wide Range ◽  
Angiopoietin 2

Fibroblast activation protein (FAP) is a membrane-bound protease that is upregulated in a wide range of tumours and viewed as a marker of tumour-promoting stroma. Previously, we demonstrated increased FAP expression in glioblastomas and described its localisation in cancer and stromal cells. In this study, we show that FAP+ stromal cells are mostly localised in the vicinity of activated CD105+ endothelial cells and their quantity positively correlates with glioblastoma vascularisation. FAP+ mesenchymal cells derived from human glioblastomas are non-tumorigenic and mostly lack the cytogenetic aberrations characteristic of glioblastomas. Conditioned media from these cells induce angiogenic sprouting and chemotaxis of endothelial cells and promote migration and growth of glioma cells. In a chorioallantoic membrane assay, co-application of FAP+ mesenchymal cells with glioma cells was associated with enhanced abnormal angiogenesis, as evidenced by an increased number of erythrocytes in vessel-like structures and higher occurrence of haemorrhages. FAP+ mesenchymal cells express proangiogenic factors, but in comparison to normal pericytes exhibit decreased levels of antiangiogenic molecules and an increased Angiopoietin 2/1 ratio. Our results show that FAP+ mesenchymal cells promote angiogenesis and glioma cell migration and growth by paracrine communication and in this manner, they may thus contribute to glioblastoma progression.

scholarly journals P04.28 Effect of fibroblast activation protein-expressing stromal cells from human glioblastomas on glioma and endothelial cells

2018 ◽  
Vol 20 (suppl_3) ◽  
pp. iii284-iii285
Author(s):  
P Busek ◽  
E Balaziova ◽  
R Mateu ◽  
P Vymola ◽  
K Vlasicova ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Stromal Cells ◽  
Fibroblast Activation Protein ◽  
Fibroblast Activation

scholarly journals P11.41 Comparison of fibroblast activation protein expression and localization in glioblastomas and brain metastases

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii52-iii52
Author(s):  
P Busek ◽  
M Zubal ◽  
B Chmielova ◽  
Z Vanickova ◽  
P Hrabal ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Brain Tissue ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Glioma Cells ◽  
Fibroblast Activation Protein ◽  
Epithelial Cancer ◽  
Fibroblast Activation

Abstract BACKGROUND Fibroblast activation protein (FAP) is a transmembrane serine protease that is frequently upregulated in the tumor microenvironment. In several cases, FAP protein itself and/or FAP expressing stromal cells have been shown to contribute to cancer progression and to be associated with more aggressive cancer behaviour and shorter patient survival. The aim of this study was to determine FAP expression in glioblastomas and brain metastases and to identify the cell types that express FAP in the microenvironment of these malignancies. MATERIAL AND METHODS FAP enzymatic activity and protein concentration were determined in samples from patients with brain metastases, glioblastomas and pharmacoresistant epilepsy (control non-tumorous brain tissue) by an enzymatic assay using a specific fluorogenic substrate and ELISA, respectively. Immunohistochemical labelling with antibodies against FAP and markers of astroglia, epithelial cancer cells and mesenchymal stromal cells was performed to characterize FAP expressing cells. RESULTS FAP was significantly upregulated in the majority of glioblastomas and brain metastases in comparison to non-tumorous brain tissue. In glioblastomas, FAP was localized perivascularly and in mesenchymal cells, and in part of the tumors also in the glioma cells. In brain metastases, FAP positivity was abundantly present in the stroma and predominantly co-localised with markers of mesenchymal stromal cells (TE-7, SMA, PDGFRbeta, NG2), but there was no overlap between FAP and markers of epithelial cancer cells (EpCAM, pancytokeratin). CONCLUSION FAP is upregulated in the microenvironment of human glioblastomas and brain metastases compared to non-tumorous brain tissue. In glioblastomas, FAP is expressed in part of the glioma cells, in pericytes and mesenchymal stromal cells, whereas no positivity in cancer cells and more abundant FAP+ stroma was detected in brain metastases. The selective expression of FAP in these brain tumors may be useful for the visualization and possibly therapeutic targeting of their tumor microenvironment. GRANT SUPPORT Ministry of Health of the Czech Republic, grant No. 15-31379A, Progres Q28/LF1, 2015064 LM EATRIS and the project,Center for Tumor Ecology - Research of the Cancer Microenvironment Supporting Cancer Growth and Spread” (reg. n. CZ.02.1.01/0.0/0.0/16_019/0000785) supported by the Operational Programme Research, Development and Education.

scholarly journals Fibroblast activation protein α identifies mesenchymal stromal cells from human bone marrow

2008 ◽  
Vol 142 (5) ◽  
pp. 827-830 ◽  
Author(s):  
Sohyun Bae ◽  
Chae Woon Park ◽  
Hye Kyung Son ◽  
Hye Kyung Ju ◽  
Donggi Paik ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Fibroblast Activation Protein ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Fibroblast Activation

scholarly journals Secretion of interleukin-1 by acute myeloblastic leukemia cells in vitro induces endothelial cells to secrete colony stimulating factors

Blood ◽  
1987 ◽  
Vol 70 (4) ◽  
pp. 1218-1221 ◽  
Author(s):  
JD Griffin ◽  
A Rambaldi ◽  
E Vellenga ◽  
DC Young ◽  
D Ostapovicz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Stromal Cells ◽  
Interleukin 1 ◽  
Constitutive Expression ◽  
Conditioned Media ◽  
Acute Myeloblastic Leukemia ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

The interaction of acute myeloblastic leukemia (AML) cells with stromal cells was investigated by adding AML-conditioned media to cultures of human endothelial cells. This conditioned media contained factors that induced expression of both the granulocyte macrophage colony- stimulating factor (GM-CSF) and granulocyte CSF (G-CSF) genes and release of colony stimulating activity from endothelial cells. The conditioned media contained interleukin-1 (IL-1) bioactivity and the endothelial cell stimulatory activity was partially neutralized by anti- IL-1 antiserum. Constitutive expression of the IL-1-beta gene was detected in ten of 17 AML cases analyzed. These results suggest that the unregulated secretion of IL-1 by AML cells can induce stromal cells in vitro to overproduce CSFs. This could contribute to the unrestricted growth of AML cells.

scholarly journals Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia

2013 ◽  
Vol 210 (6) ◽  
pp. 1125-1135 ◽  
Author(s):  
Eric Tran ◽  
Dhanalakshmi Chinnasamy ◽  
Zhiya Yu ◽  
Richard A. Morgan ◽  
Chyi-Chia Richard Lee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Fibroblast Activation Protein ◽  
Marrow Stromal Cells ◽  
Target Antigen ◽  
Antitumor Effects ◽  
Stromal Fibroblasts ◽  
Fibroblast Activation

Fibroblast activation protein (FAP) is a candidate universal target antigen because it has been reported to be selectively expressed in nearly all solid tumors by a subset of immunosuppressive tumor stromal fibroblasts. We verified that 18/18 human tumors of various histologies contained pronounced stromal elements staining strongly for FAP, and hypothesized that targeting tumor stroma with FAP-reactive T cells would inhibit tumor growth in cancer-bearing hosts. T cells genetically engineered with FAP-reactive chimeric antigen receptors (CARs) specifically degranulated and produced effector cytokines upon stimulation with FAP or FAP-expressing cell lines. However, adoptive transfer of FAP-reactive T cells into mice bearing a variety of subcutaneous tumors mediated limited antitumor effects and induced significant cachexia and lethal bone toxicities in two mouse strains. We found that FAP was robustly expressed on PDGFR-α+, Sca-1+ multipotent bone marrow stromal cells (BMSCs) in mice, as well as on well-characterized, clinical-grade multipotent human BMSCs. Accordingly, both mouse and human multipotent BMSCs were recognized by FAP-reactive T cells. The lethal bone toxicity and cachexia observed after cell-based immunotherapy targeting FAP cautions against its use as a universal target. Moreover, the expression of FAP by multipotent BMSCs may point toward the cellular origins of tumor stromal fibroblasts.

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