Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents

Chen, Minfeng; Lei, Xueping; Shi, Changzheng; Huang, Maohua; Li, Xiaobo; Wu, Baojian; Li, Zhengqiu; Wu, Han; Du, Bin; Hu, Jiaxing; Nie, Qiulin; Mai, Weiqian; Ma, Nan; Xu, Nanhui; Zhang, Xinyi; Fan, Chun‐Lin; Hong, Aihua; Mao, Xia; Luo, Liangping; Ma, Aijin; Li, Hongsheng; Q, Yu; Chen, Heru; Zhang, Dongmei; Ye, Wen‐Cai

doi:10.1172/jci94258

Cited by 75 publications

(55 citation statements)

References 50 publications

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“…Many of angiogenesis inhibitors targeting endothelial cells often result in drug resistance. Pericytes is identified as one of the most important factors that contribute to the drug resistance 19,37 . Several studies showed that Shh is critical for the maturation of neovessels through regulating migration and recruitment of MC 19,38 .…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel tumor angiogenesis inhibitor targeting Shh/Gli1 signaling pathway in Non-small cell lung cancer

et al. 2020

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Although angiogenesis inhibitors targeting VEGF/VEGFR2 have been applied for tumor therapy, the outcomes are still unsatisfactory. Thus, it is urgent to develop novel angiogenesis inhibitor for cancer therapy from new perspectives. Identification of novel angiogenesis inhibitor from natural products is believed to be one of most promising strategy. In this study, we showed that pristimerin, an active agent isolated from traditional Chinese herbal medicine Celastrus aculeatus Merr, was a novel tumor angiogenesis inhibitor that targeting sonic hedgehog (Shh)/glioma associated oncogene 1 (Gli1) signaling pathway in non-small cell lung cancer (NSCLC). We showed that pristimerin affected both the early-and late-stage of angiogenesis, suggesting by that pristimerin inhibited Shh-induced endothelial cells proliferation, migration, invasion as well as pericytes recruitment to the endothelial tubes, which is critical for the new blood vessel maturation. It also suppressed tube formation, vessel sprouts formation and neovascularization in chicken embryo chorioallantoic membrane (CAM). Moreover, it significantly decreased microvessel density (MVD) and pericyte coverage in NCI-H1299 xenografts, resulting in tumor growth inhibition. Further research revealed that pristimerin suppressed tumor angiogenesis by inhibiting the nucleus distribution of Gli1, leading to inactivation of Shh/Gli1 and its downstream signaling pathway. Taken together, our study showed that pristimerin was a promising novel antiangiogenic agent for the NSCLC therapy and targeting Shh/Gli1 signaling pathway was an effective approach to suppress tumor angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Identification of a novel tumor angiogenesis inhibitor targeting Shh/Gli1 signaling pathway in Non-small cell lung cancer

et al. 2020

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“…A recent study demonstrated that antiangiogenic agents, such as vascular disrupting agents (VDA), failed to affect the most peripheral vessels, which are particularly rich in pericytes, indicating that pericytes might be closely related to VDA treatment resistance. In the light of this aspect, the study demonstrated the efficacy of a derivative of vinblastine, which acts selectively towards pericytes, inducing a complete regression of multiple lines of tumor xenografts and VDA treatment resistance [142]. The inhibition of PDGF-B signaling by an anti-PDGFR antibody causes destabilization of the retinal vasculature, suggesting that pericyte recruitment and their interaction with endothelial cells play an important role in the pathological angiogenesis of ocular disease.…”

Section: Uveal Melanomamentioning

confidence: 99%

Pericytes in Microvessels: From “Mural” Function to Brain and Retina Regeneration

Caporarello

D’Angeli

Cambria

et al. 2019

IJMS

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Pericytes are branched cells located in the wall of capillary blood vessels that are found throughout the body, embedded within the microvascular basement membrane and wrapping endothelial cells, with which they establish a strong physical contact. Pericytes regulate angiogenesis, vessel stabilization, and contribute to the formation of both the blood-brain and blood-retina barriers by Angiopoietin-1/Tie-2, platelet derived growth factor (PDGF) and transforming growth factor (TGF) signaling pathways, regulating pericyte-endothelial cell communication. Human pericytes that have been cultured for a long period give rise to multilineage progenitor cells and exhibit mesenchymal stem cell (MSC) features. We focused our attention on the roles of pericytes in brain and ocular diseases. In particular, pericyte involvement in brain ischemia, brain tumors, diabetic retinopathy, and uveal melanoma is described. Several molecules, such as adenosine and nitric oxide, are responsible for pericyte shrinkage during ischemia-reperfusion. Anti-inflammatory molecules, such as IL-10, TGFβ, and MHC-II, which are increased in glioblastoma-activated pericytes, are responsible for tumor growth. As regards the eye, pericytes play a role not only in ocular vessel stabilization, but also as a stem cell niche that contributes to regenerative processes in diabetic retinopathy. Moreover, pericytes participate in melanoma cell extravasation and the genetic ablation of the PDGF receptor reduces the number of pericytes and aberrant tumor microvessel formation with important implications for therapy efficacy. Thanks to their MSC features, pericytes could be considered excellent candidates to promote nervous tissue repair and for regenerative medicine.

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Section: Mechanisms Of Drug Resistancementioning

confidence: 99%

“…They also increase the mobility of cancer cells and their metastatic ability which explain the observed rapid occurrence of metastases after antivascular therapy and therefore a possible target for drug discovery [184,203]. More recently, another new mechanism was discussed as a potential targetable driver of resistance based on the pericyte coverage of tumor vessels [204,205]. In this perspective, Chen et al [204] used a prodrug approach to selectively target the tumor pericytes of the peripheral blood vessels via abrogation of their cytoskeleton and observed complete regression of tumors as a surrogate therapy to overcome resistance to these agents.…”

Section: Mechanisms Of Drug Resistancementioning

confidence: 99%

“…More recently, another new mechanism was discussed as a potential targetable driver of resistance based on the pericyte coverage of tumor vessels [204,205]. In this perspective, Chen et al [204] used a prodrug approach to selectively target the tumor pericytes of the peripheral blood vessels via abrogation of their cytoskeleton and observed complete regression of tumors as a surrogate therapy to overcome resistance to these agents. However, along these lines and in light of this growing body of evidence, it seems that cancer cells adapt to any developed therapy in "real-time" conditions which needs more smart combined therapies.…”

Section: Mechanisms Of Drug Resistancementioning

confidence: 99%

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Starvation tactics using natural compounds for advanced cancers: pharmacodynamics, clinical efficacy, and predictive biomarkers

2018

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The high mortality associated with oncological diseases is mostly due to tumors in advanced stages, and their management is a major challenge in modern oncology. Angiogenesis is a defined hallmark of cancer and predisposes to metastatic invasion and dissemination and is therefore an important druggable target for cancer drug discovery. Recently, because of drug resistance and poor prognosis, new anticancer drugs from natural sources targeting tumor vessels have attracted more attention and have been used in several randomized and controlled clinical trials as therapeutic options. Here, we outline and discuss potential natural compounds as salvage treatment for advanced cancers from recent and ongoing clinical trials and real‐world studies. We also discuss predictive biomarkers for patients' selection to optimize the use of these potential anticancer drugs.

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Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents

Cited by 75 publications

References 50 publications

Identification of a novel tumor angiogenesis inhibitor targeting Shh/Gli1 signaling pathway in Non-small cell lung cancer

Identification of a novel tumor angiogenesis inhibitor targeting Shh/Gli1 signaling pathway in Non-small cell lung cancer

Pericytes in Microvessels: From “Mural” Function to Brain and Retina Regeneration

Starvation tactics using natural compounds for advanced cancers: pharmacodynamics, clinical efficacy, and predictive biomarkers

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