Glioblastoma-derived Tumor Cells Induce Vasculogenic Mimicry through Flk-1 Protein Activation

Francescone, Ralph; Scully, Steve; Bentley, Brooke; Yan, Wei; Taylor, Sherry L.; Oh, Dennis; Moral, Luis; Shao, Rong

doi:10.1074/jbc.m111.334540

Cited by 134 publications

(136 citation statements)

References 60 publications

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“…Recent studies show that subsets of glioma and melanoma cells (especially stem-like tumor cells) are able to switch on certain EC markers and transdifferentiate into vascular ECs (61)(62)(63)(64)(65). Such tumor-derived ECs participate in vascularization to ensure a steady supply of oxygen and nutrients for tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Epithelial-to-mesenchymal transition confers pericyte properties on cancer cells

Shenoy¹,

Jin²,

Luo³

et al. 2016

Journal of Clinical Investigation

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. relation and complete linkage as the distance metric and clustering method, respectively. The output data were loaded into Java Tree View software to generate heatmaps (66).Statistics. Statistical differences between different experimental groups were determined by Student's t test (2 tailed). The reported values represent the mean ± SD as indicated in the figures. A P value less than 0.05 was considered statistically significant. No samples were excluded from the analysis.Study approval. All animal experimental procedures were approved by the University of Florida IACUC.

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Section: Discussionmentioning

confidence: 99%

Epithelial-to-mesenchymal transition confers pericyte properties on cancer cells

Shenoy¹,

Jin²,

Luo³

et al. 2016

Journal of Clinical Investigation

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“…RNA-sequencing analysis of patient tissue combined with histology and in situ hybridization (Ivy Glioblastoma Atlas Project; SI Appendix, Fig. S1) show that brain tumor-initiating cells (BTICs) are found predominantly in the bulk of cellular tumors, although their presence in vascular structures and perivascular niches has also been highlighted in recent research (9)(10)(11)(12)(13). This distribution pattern suggests that direct delivery to BTICs in the tumor bulk is likely to be more advantageous than systemic delivery approaches, which rely on BBB penetration to maximize the therapeutic benefits of RNAi targeting BTICs.…”

mentioning

confidence: 99%

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Khan

Suvà

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

104

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Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood-brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTICtargeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.siRNA | lipopolymeric nanoparticle | glioblastoma transcription factor | brain tumor-initiating cells | convection-enhanced delivery G lioblastoma (GBM) is one of the most challenging tumors to treat (1, 2). Despite decades of research and maximal clinical combination therapy encompassing surgical resection, chemotherapy, and radiation, the median life expectancy of patients has not been extended beyond 2 y after diagnosis (2). Increasing evidence suggests that the genetic, epigenetic, and signaling heterogeneity of GBM underlies the ineffectiveness of currently available therapeutics (1, 2). Additionally, therapeutic schemes devised to challenge brain tumor cells are frequently thwarted by insufficient delivery caused by pharmacokinetics, the blood-brain barrier (BBB), and an altered tumor microenvironment in which tumor-derived signaling recruits immunomodulatory cells and induces extracellular matrix remodeling to build safe harbors of tumorigenic niches (3-5). These obstacles call for tailored therapeutic strategies to counter tumor heterogeneity and overcome roadblocks in delivery. RNAi targeting drivers of tumorigenesis shows strong potential to supplement the development of traditional small-molecule pharmaceutics (6). However, delivery remains a key obstacle for efficient RNAi against tumor drivers (5,7,8). RNA-sequencing analysis of patient tissue combined with histology and in situ hybridization (Ivy Glioblastoma Atlas Pro...

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“…In desmoplastic areas of treated tumors, we often observed cytoplasmic CD31 expression in nonendothelial cells. This phenomenon has been documented before and has been linked to the phenomenon of vasculogenic mimicry (27,28). Third, the current trial was not designed to assess the duration of the sorafenibinduced decreased antibody uptake.…”

Section: Discussionmentioning

confidence: 95%

Tyrosine Kinase Inhibitor Sorafenib Decreases ¹¹¹In-Girentuximab Uptake in Patients with Clear Cell Renal Cell Carcinoma

Muselaers¹,

Stillebroer

Desar³

et al. 2014

J Nucl Med

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Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of metastatic clear cell renal cell carcinoma (RCC). Although TKIs have demonstrated good clinical efficacy, the lack of complete responses, the chronic nature of the treatment, and the side effects are clear disadvantages. An interesting new approach in the treatment of clear cell RCC is antibody-mediated therapy with the chimeric anti-carbonic anhydrase IX (CAIX) antibody girentuximab (cG250). As the results of several girentuximab trials become available, the question arises of whether TKI treatment can be combined with girentuximabbased therapy. In this study, we assessed the effect of the widely used TKI sorafenib on the tumor-targeting potential of 111 In-labeled girentuximab. Methods: 111 In-girentuximab imaging was performed on 15 patients suspected of having a renal malignancy, with surgery being part of their treatment plan. Of these, 10 patients were treated in a neoadjuvant setting with sorafenib (400 mg orally twice daily). Five patients received treatment during 1 wk, and 5 patients received treatment during 4 wk. In both sorafenib-treated groups, baseline and posttreatment tumor targeting of 111 In-girentuximab were compared. Surgery was performed 3 d after the last image acquisition. Five additional patients were included as a control group and had only a single 111 In-girentuximab injection and scintigraphy without any treatment. Distribution of 111 In-girentuximab was determined scintigraphically ex vivo in a 1-cm lamella of the resected tumorous kidney. Expression of CAIX and of the vascular marker CD31 was determined immunohistochemically on specimens of both tumor and normal kidney tissue. Results: Treatment with sorafenib resulted in a marked decrease of 111 In-girentuximab uptake in the tumor in clear cell RCC patients, especially in the group treated for 4 wk (mean change in both sorafenib-treated groups, 238.4%; range, 19.1% to 279.4%). Immunohistochemical analysis showed markedly reduced CD31 expression and vessel density in the sorafenib-treated groups but no differences in CAIX expression between the sorafenib-treated groups and the nontreated patients. Conclusion: Treatment with sorafenib resulted in a treatment duration-dependent significantly decreased uptake of 111 In-girentumab in clear cell RCC lesions. These results indicate that the efficacy of antibody-mediated treatment or diagnosis modalities is hampered by TKI treatment.

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Glioblastoma-derived Tumor Cells Induce Vasculogenic Mimicry through Flk-1 Protein Activation

Cited by 134 publications

References 60 publications

Epithelial-to-mesenchymal transition confers pericyte properties on cancer cells

Epithelial-to-mesenchymal transition confers pericyte properties on cancer cells

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Tyrosine Kinase Inhibitor Sorafenib Decreases ¹¹¹In-Girentuximab Uptake in Patients with Clear Cell Renal Cell Carcinoma

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Glioblastoma-derived Tumor Cells Induce Vasculogenic Mimicry through Flk-1 Protein Activation

Cited by 134 publications

References 60 publications

Epithelial-to-mesenchymal transition confers pericyte properties on cancer cells

Epithelial-to-mesenchymal transition confers pericyte properties on cancer cells

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Tyrosine Kinase Inhibitor Sorafenib Decreases 111In-Girentuximab Uptake in Patients with Clear Cell Renal Cell Carcinoma

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Product

Resources

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Tyrosine Kinase Inhibitor Sorafenib Decreases ¹¹¹In-Girentuximab Uptake in Patients with Clear Cell Renal Cell Carcinoma