Glioblastoma endothelium drives bevacizumab‐induced infiltrative growth <i>via</i> modulation of PLXDC1

Falchetti, Maria Laura; D’Alessandris, Quintino Giorgio; Pacioni, Simone; Buccarelli, Mariachiara; Morgante, Liliana; Giannetti, Stefano; Lulli, Valentina; Martini, Maurizio; Larocca, Luigi Maria; Vakana, Eliza; Stancato, Louis F.; Ricci–Vitiani, Lucia; Pallini, Roberto

doi:10.1002/ijc.31983

Cited by 27 publications

(44 citation statements)

References 56 publications

(80 reference statements)

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“…Here, we used the antibody targeting Collapsin Response Mediator Protein 5 (CRMP5) that was recently proposed as a selective tumor marker for glioma cells [24,25]. Previously, we validated this antibody on patient-derived GSCs with mutant IDH1 [26]. Here, we used surgical specimens of low-grade glioma (WHO grade II astrocytoma and oligodendroglioma) with mutant IDH1/2 and showed a co-staining of the tumor cells with anti-IDH1 and anti-CRMP5 antibodies (Supplementary Figure S5 and Supplementary Table S2).…”

Section: Perivascular Invasion and Disruption Of Bbb In Human Specimementioning

confidence: 99%

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Brain Invasion along Perivascular Spaces by Glioma Cells: Relationship with Blood–Brain Barrier

Pacioni

D’Alessandris

Buccarelli

et al. 2019

Cancers

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The question whether perivascular glioma cells invading the brain far from the tumor bulk may disrupt the blood-brain barrier (BBB) represents a crucial issue because under this condition tumor cells would be no more protected from the reach of chemotherapeutic drugs. A recent in vivo study that used human xenolines, demonstrated that single glioma cells migrating away from the tumor bulk are sufficient to breach the BBB. Here, we used brain xenografts of patient-derived glioma stem-like cells (GSCs) to show by immunostaining that in spite of massive perivascular invasion, BBB integrity was preserved in the majority of vessels located outside the tumor bulk. Interestingly, the tumor cells that invaded the brain for the longest distances traveled along vessels with retained BBB integrity. In surgical specimens of malignant glioma, the area of brain invasion showed several vessels with preserved BBB that were surrounded by tumor cells. On transmission electron microscopy, the cell inter-junctions and basal lamina of the brain endothelium were preserved even in conditions in which the tumor cells lay adjacently to blood vessels. In conclusion, BBB integrity associates with extensive perivascular invasion of glioma cells.

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Section: Perivascular Invasion and Disruption Of Bbb In Human Specimementioning

confidence: 99%

“…Immunosuppressed athymic rats (male, 250-280 g; Charles River, Milan, Italy) were used for brain xenografts [26] (Supplementary materials and methods).…”

Section: Intracranial Xenografts Of Gfp Expressing U87mg Gsc1 and Gmentioning

confidence: 99%

Brain Invasion along Perivascular Spaces by Glioma Cells: Relationship with Blood–Brain Barrier

Pacioni

D’Alessandris

Buccarelli

et al. 2019

Cancers

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“…In glioblastoma, Bevacizumab may trigger a phenotypic change of the tumor that undergoes a gliomatosis-like growth pattern. This infiltrative shift occurs mostly along perivascular spaces and relies on the over-expression of PLXDC1 (Plexin Domain Containing 1) by tumor cells and on the restoration of the endothelial component of blood brain barrier [ 78 ]. When targeting tumor angiogenesis, we should consider that a functional tumor vasculature allows the access in the tumor mass of therapeutic drugs and cells of the immune system.…”

Section: Therapy-induced Senescence Of Tumor Vasculaturementioning

confidence: 99%

Cancer Response to Therapy-Induced Senescence: A Matter of Dose and Timing

Mongiardi

Pellegrini

Pallini

et al. 2021

Cancers

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Cellular senescence participates to fundamental processes like tissue remodeling in embryo development, wound healing and inhibition of preneoplastic cell growth. Most senescent cells display common hallmarks, among which the most characteristic is a permanent (or long lasting) arrest of cell division. However, upon senescence, different cell types acquire distinct phenotypes, which also depend on the specific inducing stimuli. Senescent cells are metabolically active and secrete a collection of growth factors, cytokines, proteases, and matrix-remodeling proteins collectively defined as senescence-associated secretory phenotype, SASP. Through SASP, senescent cells modify their microenvironment and engage in a dynamic dialog with neighbor cells. Senescence of neoplastic cells, at least temporarily, reduces tumor expansion, but SASP of senescent cancer cells as well as SASP of senescent stromal cells in the tumor microenvironment may promote the growth of more aggressive cancer subclones. Here, we will review recent data on the mechanisms and the consequences of cancer-therapy induced senescence, enlightening the potentiality and the risk of senescence inducing treatments.

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“…Finally, the fact that a mutant that was deleted in both the Eph and the Plxdc1/2 interaction motif, RRV-YFP gH∆21-27-AELAAN, was still able to replicate on rhesus monkey fibroblasts, as evidenced by the fact that we were able to grow a virus stock on these cells, and was still infectious to a certain degree on a number of cell lines ( Similarly, Plxdc1 was first described in a screen for novel tumor endothelial members (25) and expression of both Plxdc1 and Plxdc2 is elevated in the endothelium of solid tumors (25,26,42,43). Plxdc1 expression has been described as prognostic marker and modulating factor for various human cancers (42)(43)(44)(45)(46). Given the overlap between the required changes e.g.…”

Section: Ebv and Hcmv A Clear Correlation Between Receptor Usage Dementioning

confidence: 99%

Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV)

Großkopf

Schlagowski

Ensser

et al. 2020

Preprint

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10The rhesus monkey rhadinovirus (RRV), a γ2-herpesvirus of rhesus macaques, shares many biological 11 features with the human pathogenic Kaposi's sarcoma-associated herpesvirus (KSHV). Both viruses, 12 as well as the more distantly related Epstein-Barr virus, engage cellular receptors from the Eph family 13 of receptor tyrosine kinases (Ephs). However, the importance of the Eph interaction for RRV entry 14 varies between cell types suggesting the existence of Eph-independent entry pathways. We 15 therefore aimed to identify additional cellular receptors for RRV by affinity enrichment and mass 16 spectrometry. We identified an additional receptor family, the Plexin domain containing proteins 1 17 and 2 (Plxdc1/2) that bind the RRV gH/gL glycoprotein complex. In vitro, blocking assays with soluble 18Plxdc2 decoy receptor reduced RRV infection by approx. 60%, while overexpression of Plxdc1 and 2 19 dramatically enhanced RRV susceptibility in otherwise marginally permissive Raji cells. While the 20 Plxdc2 interaction is conserved between two RRV strains, 26-95 and 17577, Plxdc1 specifically 21 interacts with RRV 26-95 gH. The Plxdc interaction is mediated by a short motif at the N-terminus of 22 RRV gH that is partially conserved between isolate 26-95 and isolate 17577, but absent in KSHV gH. 23Mutation of this motif abrogated the interaction with Plxdc1/2 in in vitro assays and reduced RRV 24 infection in a cell-type specific manner. Taken together, our findings characterize Plxdc1/2 as novel 25 interaction partners and entry receptors for RRV and support the concept of the N-terminal domain 26 of the gammaherpesviral gH/gL complex as a multifunctional receptor-binding domain. 27 vivo studies. Two major RRV sequence groups have been identified (4), which are represented by two 33 cloned isolates, RRV 26-95 (5) and RRV 17577 (6). Analogous to KSHV infection, primary RRV infection 34 is asymptomatic in healthy hosts and leads to life-long persistence, most likely in the B cell 35 compartment (7). KSHV is associated with a solid tumor of endothelial origin, Kaposi's sarcoma (KS), 36 and two B cell malignancies, primary effusion lymphoma (PEL) and the plasmablastic variant of 37 multicentric Castleman's disease (MCD), most prominently in the context of human 38 immunodeficiency virus (HIV) infection and in immunocompromised individuals. Similarly, simian 39 immunodeficiency virus (SIV)-positive rhesus macaques developed B cell lymphomas upon 40 experimental infection with RRV strain 17577 (8, 9) and several studies correlated RRV infection with 41 lymphomagenesis in SIV/SHIV-infected animals (10, 11). While RRV is not consistently associated 42 with solid malignancies, RRV has been identified in retroperitoneal fibromatosis tissue (9, 12), similar 43 to retroperitoneal fibromatosis herpesvirus (RFHV)(11). Another shared characteristic of KSHV and 44 RRV is the receptor usage on a range of cell types. Both viruses engage members of the Eph family of 45 receptor tyrosine kinases (Ephs) through their glycoprotein (g)H...

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Glioblastoma endothelium drives bevacizumab‐induced infiltrative growth via modulation of PLXDC1

Cited by 27 publications

References 56 publications

Brain Invasion along Perivascular Spaces by Glioma Cells: Relationship with Blood–Brain Barrier

Brain Invasion along Perivascular Spaces by Glioma Cells: Relationship with Blood–Brain Barrier

Cancer Response to Therapy-Induced Senescence: A Matter of Dose and Timing

Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV)

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