Class 3 semaphorins: physiological vascular normalizing agents for anti‐cancer therapy

Serini, Guido; Bussolino, Federico; Maione, Federica; Giraudo, Enrico

doi:10.1111/joim.12017

Cited by 37 publications

(46 citation statements)

References 212 publications

(314 reference statements)

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“…S1C). The GI 50 was in a range between 5 and 36 mmol/L and increased with nucleolin levels. Coherently, N6L significantly reduced the amount of PDAC cells in S phase after 24 hours of treatment ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 97%

“…Interestingly, whereas the antiangiogenesis therapies fail to improve PDAC survival, VEGFR inhibition was capable to counteract tumor angiogenesis induced by reduction of stroma stiffness (48). There is a growing body of evidences highlighting, both in preclinical and clinical settings, the importance of tumor vessel normalization, described by Jain and colleagues (23,50). It has been demonstrated that the strong reduction of tumor hypoxia and the enhancement of vessel perfusion, accompanied by improved drug delivery, is a great advantage of using a pronormalizing agent in anticancer therapies in the clinic (23).…”

Section: àDdctmentioning

confidence: 99%

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Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature

et al. 2016

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Pancreatic cancer is a highly aggressive tumor, mostly resistant to the standard treatments. Nucleolin is overexpressed in cancers and its inhibition impairs tumor growth. Herein, we showed that nucleolin was overexpressed in human specimens of pancreatic ductal adenocarcinoma (PDAC) and that the overall survival significantly increased in patients with low levels of nucleolin. The nucleolin antagonist N6L strongly impaired the growth of primary tumors and liver metastasis in an orthotopic mouse model of PDAC (mPDAC). Similar antitumor effect of N6L has been observed in a highly angiogenic mouse model of pancreatic neuroendocrine tumor RIP-Tag2. N6L significantly inhibited both human and mouse pancreatic cell proliferation and invasion. Notably, the analysis of tumor vasculature revealed a strong increase of pericyte coverage and vessel perfusion both in mPDAC and RIP-Tag2 tumors, in parallel to an inhibition of tumor hypoxia. Nucleolin inhibition directly affected endothelial cell (EC) activation and changed a proangiogenic signature. Among the vascular activators, nucleolin inhibition significantly decreased angiopoietin-2 (Ang-2) secretion and expression in ECs, in the tumor and in the plasma of mPDAC mice. As a consequence of the observed N6L-induced tumor vessel normalization, pre-treatment with N6L efficiently improved chemotherapeutic drug delivery and increased the antitumor properties of gemcitabine in PDAC mice. In conclusion, nucleolin inhibition is a new anti-pancreatic cancer therapeutic strategy that dually blocks tumor progression and normalizes tumor vasculature, improving the delivery and efficacy of chemotherapeutic drugs. Moreover, we unveiled Ang-2 as a potential target and suitable response biomarker for N6L treatment in pancreatic cancer. Cancer Res; 76(24);

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Section: Resultsmentioning

confidence: 97%

Section: àDdctmentioning

confidence: 99%

Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature

et al. 2016

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“…Originally identified as axonal growth repulsive cues, SEMA3s are a family of cell-surface and secreted proteins capable of regulating cell-cell interactions as well as cell differentiation, morphology, and function (7). They are crucial determinants of tumor growth and metastasis through mediating tumor angiogenesis (8,9). SEMA3s are all secreted proteins and include 7 members (SEMA3A-G).…”

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confidence: 99%

RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis

et al. 2017

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Pathological proliferation of retinal blood vessels commonly causes vision impairment in proliferative retinopathies, including retinopathy of prematurity. Dysregulated crosstalk between the vasculature and retinal neurons is increasingly recognized as a major factor contributing to the pathogenesis of vascular diseases. Class 3 semaphorins (SEMA3s), a group of neuron-secreted axonal and vascular guidance factors, suppress pathological vascular growth in retinopathy. However, the upstream transcriptional regulators that mediate the function of SEMA3s in vascular growth are poorly understood. Here we showed that retinoic acid receptor-related orphan receptor a (RORa), a nuclear receptor and transcription factor, is a novel transcriptional regulator of SEMA3E-mediated neurovascular coupling in a mouse model of oxygen-induced proliferative retinopathy. We found that genetic deficiency of RORa substantially induced Sema3e expression in retinopathy. Both RORa and SEMA3E were expressed in retinal ganglion cells. RORa directly bound to a specific ROR response element on the promoter of Sema3e and negatively regulated Sema3e promoter-driven luciferase expression. Suppression of Sema3e using adeno-associated virus 2 carrying short hairpin RNA targeting Sema3e promoted disoriented pathological neovascularization and partially abolished the inhibitory vascular effects of RORa deficiency in retinopathy. Our findings suggest that RORa is a novel transcriptional regulator of SEMA3E-mediated neurovascular coupling in pathological retinal angiogenesis.-Sun, Y., Liu, C.-H., Wang, Z., Meng, S. S., Burnim, S. B., SanGiovanni, J. P., Kamenecka, T. M., Solt, L. A., Chen, J. RORa modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis. FASEB J. 31, 4492-4502 (2017). www.fasebj.org

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“…Interestingly, we observed a strong increase in pericyte coverage in tumor vessels of treated mice (by 44% in RIP-Tag2, by 33% in HCT116 and by 31% in HPAF-II), compared with controls (Figures 2C–G). Both results indicated that OSC inhibition in cancers strongly impairs angiogenesis and induces tumor blood vessel normalization, which, in turn, could contribute to the reduction of metastasis formation2122. Remarkably, Ro 48-8071 delivery did not affect the normal vasculature of either exocrine pancreas (Supplementary Figures S2A and S2B) or normal islets (data not shown) in late-stage tumor bearing RIP-Tag2 mice, indicating that OSC inhibition results in a selective impairment of cancer angiogenesis.…”

Section: Resultsmentioning

confidence: 85%

The cholesterol biosynthesis enzyme oxidosqualene cyclase is a new target to impair tumour angiogenesis and metastasis dissemination

Maione

Oliaro‐Bosso

Meda

et al. 2015

Sci Rep

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Aberrant cholesterol homeostasis and biosynthesis has been observed in different tumour types. This paper investigates the role of the post-squalenic enzyme of cholesterol biosynthesis, oxidosqualene cyclase (OSC), in regulating tumour angiogenesis and metastasis dissemination in mouse models of cancer. We showed that Ro 48-8071, a selective inhibitor of OSC, reduced vascular density and increased pericyte coverage, with a consequent inhibition of tumour growth in a spontaneous mouse model of pancreatic tumour (RIP-Tag2) and two metastatic mouse models of human colon carcinoma (HCT116) and pancreatic adenocarcinoma (HPAF-II). Remarkably, the inhibition of OSC hampered metastasis formation in HCT116 and HPAF-II models. Ro 48-8071 induced tumour vessel normalization and enhanced the anti-tumoral and anti-metastatic effects of 5-fluorouracil (5-FU) in HCT116 mice. Ro 48-8071 exerted a strong anti-angiogenic activity by impairing endothelial cell adhesion and migration, and by blocking vessel formation in angiogenesis assays. OSC inhibition specifically interfered with the PI3K pathway. According to in vitro results, Ro 48-8071 specifically inhibited Akt phosphorylation in both cancer cells and tumour vasculature in all treated models. Thus, our results unveil a crucial role of OSC in the regulation of cancer progression and tumour angiogenesis, and indicate Ro 48-8071 as a potential novel anti-angiogenic and anti-metastatic drug.

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Class 3 semaphorins: physiological vascular normalizing agents for anti‐cancer therapy

Cited by 37 publications

References 212 publications

Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature

Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature

RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis

The cholesterol biosynthesis enzyme oxidosqualene cyclase is a new target to impair tumour angiogenesis and metastasis dissemination

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