Regulation of Fibroblast Activation Protein by Transforming Growth Factor Beta-1 in Glioblastoma Microenvironment

Kr̆epela, E; Vaníčková, Zdislava; Hrabal, Petr; Zubal, Michal; Chmielova, Barbora; Balážiová, Eva; Vymola, Petr; Matrasova, Ivana; Bušek, Petr; Šedo, Aleksi

doi:10.3390/ijms22031046

Cited by 22 publications

(18 citation statements)

References 67 publications

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“…In our previous work, we reported an upregulation of FAP in GBMs and identified a subpopulation of FAP + stromal cells which expressed mesenchymal markers and were typically localised around blood vessels [8,45]. In the present study, we show that the blood vessels surrounded by FAP + stromal cells are comprised of activated CD105 + endothelial cells and moreover, the quantity of FAP + stromal cells positively correlates with vascularisation and GBM progression.…”

Section: Discussionsupporting

confidence: 72%

Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis

Balážiová

Vymola

Hrabal

et al. 2021

Cancers

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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.

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Section: Discussionsupporting

confidence: 72%

Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis

Balážiová

Vymola

Hrabal

et al. 2021

Cancers

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“…In gliomas, one study in U-87MG glioma cells ( 160 ) reported both GRPR and NMBR mRNA were present; however, GRP mRNA was not found, leading the authors to suggest that the GRP effect on growth of this glioma cell line was likely mediated by a paracrine mechanism. This result is somewhat surprising, both because autocrine growth, a mechanism of activation, is present in so many other tumors and also because in gliomas, autocrine mechanisms are reported for a number of other glioma growth factors, including the G-protein coupled receptor CCR5 [with its ligand CCL5 (RANTES) present in glioma cells] ( 289 ), TGFbeta1 ( 290 ), bone morphogenetic proteins (BMP4) ( 291 ), PDGF ( 292 ), and dopamine ( 293 ). In contrast, in neuroblastomas, numerous studies support an autocrine role for Bn-related peptides in BnR activation.…”

Section: Discussion/conclusionmentioning

confidence: 99%

Bombesin Receptor Family Activation and CNS/Neural Tumors: Review of Evidence Supporting Possible Role for Novel Targeted Therapy

et al. 2021

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G-protein-coupled receptors (GPCRs) are increasingly being considered as possible therapeutic targets in cancers. Activation of GPCR on tumors can have prominent growth effects, and GPCRs are frequently over-/ectopically expressed on tumors and thus can be used for targeted therapy. CNS/neural tumors are receiving increasing attention using this approach. Gliomas are the most frequent primary malignant brain/CNS tumor with glioblastoma having a 10-year survival <1%; neuroblastomas are the most common extracranial solid tumor in children with long-term survival<40%, and medulloblastomas are less common, but one subgroup has a 5-year survival <60%. Thus, there is an increased need for more effective treatments of these tumors. The Bombesin-receptor family (BnRs) is one of the GPCRs that are most frequently over/ectopically expressed by common tumors and is receiving particular attention as a possible therapeutic target in several tumors, particularly in prostate, breast, and lung cancer. We review in this paper evidence suggesting why a similar approach in some CNS/neural tumors (gliomas, neuroblastomas, medulloblastomas) should also be considered.

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“…Melanoma-associated fibroblasts have thus been described as negative immuno-modulators, through the secretion of MMPs decreasing tumor cell lysis by natural killer (NK) cells ( 51 ). The ECM composition can be modified by the protease activity of FAP, which is expressed by tumor and stromal cells in many human carcinomas and sarcomas ( 43 , 52 , 53 ). Consistent with these observations, FAP High SMA + CAFs have been identified in aggressive carcinomas to exhibit immunosuppressive activities ( 43 , 44 ).…”

Section: Heterogeneity Of Cafs/mscsmentioning

confidence: 99%

Deciphering Tumor Niches: Lessons From Solid and Hematological Malignancies

Mancini¹,

Balabanian²,

Corre³

et al. 2021

Front. Immunol.

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Knowledge about the hematopoietic niche has evolved considerably in recent years, in particular through in vitro analyzes, mouse models and the use of xenografts. Its complexity in the human bone marrow, in particular in a context of hematological malignancy, is more difficult to decipher by these strategies and could benefit from the knowledge acquired on the niches of solid tumors. Indeed, some common features can be suspected, since the bone marrow is a frequent site of solid tumor metastases. Recent research on solid tumors has provided very interesting information on the interactions between tumoral cells and their microenvironment, composed notably of mesenchymal, endothelial and immune cells. This review thus focuses on recent discoveries on tumor niches that could help in understanding hematopoietic niches, with special attention to 4 particular points: i) the heterogeneity of carcinoma/cancer-associated fibroblasts (CAFs) and mesenchymal stem/stromal cells (MSCs), ii) niche cytokines and chemokines, iii) the energy/oxidative metabolism and communication, especially mitochondrial transfer, and iv) the vascular niche through angiogenesis and endothelial plasticity. This review highlights actors and/or pathways of the microenvironment broadly involved in cancer processes. This opens avenues for innovative therapeutic opportunities targeting not only cancer stem cells but also their regulatory tumor niche(s), in order to improve current antitumor therapies.

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Regulation of Fibroblast Activation Protein by Transforming Growth Factor Beta-1 in Glioblastoma Microenvironment

Cited by 22 publications

References 67 publications

Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis

Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis

Bombesin Receptor Family Activation and CNS/Neural Tumors: Review of Evidence Supporting Possible Role for Novel Targeted Therapy

Deciphering Tumor Niches: Lessons From Solid and Hematological Malignancies

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