Angiogenic Signalling Pathways Altered in Gliomas: Selection Mechanisms for More Aggressive Neoplastic Subpopulations with Invasive Phenotype

Bulnes, Susana; Bengoetxea, Harkaitz; Ortuzar, Naiara; Argandoña, Enrike; García-Blanco, Álvaro; Rico‐Barrio, Irantzu; Lafuente, José Vicente

doi:10.1155/2012/597915

Cited by 25 publications

(34 citation statements)

References 83 publications

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“…MHCII‐sorted cells expressed more CCR7, CCL19, CXCL10, and IL12 than MRC1‐sorted cells (Fig A). On the contrary, MRC1‐sorted cells expressed significantly more TGFβ and VEGF‐A, together with the M2 markers mannose receptor and CD209 (Fig A) (Bulnes et al , ). Given the cytokine profile of M2 macrophages and their perivascular accumulation in late‐stage tumors, it is conceivable that presentation, localization, and bio‐availability of VEGF‐A will change during the transition from early‐ to late‐stage tumors.…”

Section: Resultsmentioning

confidence: 96%

Dynamic stroma reorganization drives blood vessel dysmorphia during glioma growth

et al. 2017

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Glioma growth and progression are characterized by abundant development of blood vessels that are highly aberrant and poorly functional, with detrimental consequences for drug delivery efficacy. The mechanisms driving this vessel dysmorphia during tumor progression are poorly understood. Using longitudinal intravital imaging in a mouse glioma model, we identify that dynamic sprouting and functional morphogenesis of a highly branched vessel network characterize the initial tumor growth, dramatically changing to vessel expansion, leakage, and loss of branching complexity in the later stages. This vascular phenotype transition was accompanied by recruitment of predominantly pro‐inflammatory M1‐like macrophages in the early stages, followed by in situ repolarization to M2‐like macrophages, which produced VEGF‐A and relocate to perivascular areas. A similar enrichment and perivascular accumulation of M2 versus M1 macrophages correlated with vessel dilation and malignancy in human glioma samples of different WHO malignancy grade. Targeting macrophages using anti‐CSF1 treatment restored normal blood vessel patterning and function. Combination treatment with chemotherapy showed survival benefit, suggesting that targeting macrophages as the key driver of blood vessel dysmorphia in glioma progression presents opportunities to improve efficacy of chemotherapeutic agents. We propose that vessel dysfunction is not simply a general feature of tumor vessel formation, but rather an emergent property resulting from a dynamic and functional reorganization of the tumor stroma and its angiogenic influences.

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Section: Resultsmentioning

confidence: 96%

Dynamic stroma reorganization drives blood vessel dysmorphia during glioma growth

et al. 2017

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“…This is intriguing when considering that the most vascularized tumors should have the higher oxygen supply and therefore less hypoxia. However, blood vessels in glioblastomas are structurally and functionally abnormal, responsible for an ineffective perfusion and leading to tumor hypoxia (9,14,23,24).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Relationship Between Hypoxia and Angiogenesis in Human Glioblastoma: A Multimodal Imaging Study

et al. 2017

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Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. This aggressiveness is in part attributed to the closely interrelated phenomena tumor hypoxia and angiogenesis, although few in vivo data exist in human brain tumors. This work aimed to study hypoxia and angiogenesis, in vivo and in situ, in patients admitted with GBM using multimodal imaging. Twenty-three GBM patients were assessed byF-fluoromisonidazole (F-FMISO) PET and conventional and perfusion MRI before surgery. The level and location of hypoxia (F-FMISO uptake, evaluated by tumor-to-blood [T/B] ratio), vascularization (cerebral blood volume [CBV]), and vascular permeability (contrast enhancement after gadolinium injection) were analyzed. The spatial relationship between tumor hypoxia and angiogenesis was assessed by an overlap analysis of the volume of F-FMISO uptake and the volumes of the high CBV regions and the contrast-enhancement regions. A significant correlation was found between hypoxia and hypervascularization, especially for their maximum values (volume of maximal tumor hypoxia vs. relative CBV: = 0.61, = 0.002) and their volumes (hypoxia vs. hypervascularization: = 0.91, < 0.001). A large proportion of the high CBVs collocated with hypoxia (81.3%) and with contrast enhancement (46.5%). These results support the hypothesis of a tight association between hypoxia and angiogenesis. Our results suggest that there is insufficient tumor oxygenation in human GBM, despite increased tumor vascularization.

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“…Angiogenesis is a complex process with the involvement of several cells, particularly GSCs and endothelial cells, and different molecular mediators [ 99 ].…”

Section: Sphingolipids In Gbm Angiogenesismentioning

confidence: 99%

The Role and Function of Sphingolipids in Glioblastoma Multiforme

Hadi

Vito

Marfia

et al. 2015

Bioactive Sphingolipids in Cancer Biology and Therapy

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Aberrations in sphingolipid metabolism and thus levels have been implicated in promoting the aggressiveness of glioblastoma multiforme, one of the most lethal cancers in humans. A major player is sphingosine-1-phosphate, that pressures GBM cells to exhibit its hallmarks, leading to increased proliferation, invasiveness, stemness, angiogenesis and death resistance, this indicating a fi ne balance and interplay between S1P function and this malignancy. To the opposite GBM are organized to maintain low their ceramide and sphingomyelin levels, which in turn lead to a loss of growth control and to a gain of death resistance. While the mechanisms of these alterations are emerging, the sphingolipid signaling pathway has been implicated in controlling GBM action and mass, and in mediating the link of malignancy. Here we describe and discuss the current understanding on how GBM cells arm themselves with the abilities of manipulating sphingolipids, especially sphingosine-1-phosphate and ceramide, and how these alterations, through differential interactions, regulate different signaling

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Angiogenic Signalling Pathways Altered in Gliomas: Selection Mechanisms for More Aggressive Neoplastic Subpopulations with Invasive Phenotype

Cited by 25 publications

References 83 publications

Dynamic stroma reorganization drives blood vessel dysmorphia during glioma growth

Dynamic stroma reorganization drives blood vessel dysmorphia during glioma growth

In Vivo Relationship Between Hypoxia and Angiogenesis in Human Glioblastoma: A Multimodal Imaging Study

The Role and Function of Sphingolipids in Glioblastoma Multiforme

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