Selective upregulation of vascular endothelial growth factor receptors neuropilin‐1 and ‐2 in human neuroblastoma

Fakhari, Mitra; Pullirsch, Dieter; Abraham, Dietmar; Paya, Kurosh; Hofbauer, Roland; Holzfeind, Paul; Hofmann, Michael; Aharinejad, Seyedhossein

doi:10.1002/cncr.10177

Cited by 86 publications

(65 citation statements)

References 20 publications

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“…Np-1 and Np-2 are up-regulated in the endothelial cells of human neuroblastomas (42), and their concomitant overexpres- sion is associated with increased vascularity and poor prognosis in non-small cell lung cancer (43). Furthermore, Np-1 promotes the angiogenic process during wound healing (44), whereas Np-2 is expressed in pancreatic endocrine islet cells and in endocrine tumors in the gastrointestinal tract (45).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Expression of Neuropilin-1 and -2 in Human Pancreatic Cancer Cells

Fukahi

Fukasawa

Neufeld

et al. 2004

Clinical Cancer Research

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Purpose: Neuropilin (Np)-1 and -2 are coreceptors for vascular endothelial growth factor (VEGF). This study was designed to assess their role in pancreatic ductal adenocarcinoma (PDAC).Experimental Design: We assessed Np-1 and Np-2 expression by real-time quantitative PCR in relation to the expression of VEGF ligands and receptors in pancreatic cancer cell lines and tissues.Results: ASPC-1, CAPAN-1, and PANC-1 pancreatic cancer cells and tumor-derived, laser-captured pancreatic cancer cells exhibited higher Np-1 and Np-2 mRNA levels than VEGF receptor-1, -2, or -3 mRNA levels. Transfection of Np-1 and Np-2 cDNAs in COS-7 cells, and treatment with tunicamycin revealed that both proteins were glycosylated. Both proteins were expressed in pancreatic cancer cell lines, in the PDAC samples, and in acinar cells adjacent to the cancer cells. The normal pancreas was devoid of Np-1 immunoreactivity, whereas Np-2 immunoreactivity was present in the endocrine islets and in some acinar cells, but not in ductal cells.Conclusions: The aberrant localization of Np-1 and Np-2 in the cancer cells in PDAC suggests that in addition to exerting proangiogenic effects, these coreceptors may contribute to novel autocrine-paracrine interactions in this malignancy.

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Section: Discussionmentioning

confidence: 99%

Aberrant Expression of Neuropilin-1 and -2 in Human Pancreatic Cancer Cells

Fukahi

Fukasawa

Neufeld

et al. 2004

Clinical Cancer Research

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“…Interestingly, VEGF was found to bind to tumour cells which did not express VEGFR-1 or VEGFR-2 [38] and it was subsequently found that these cells express NRPs. NRP-1 expression was observed in some tumours and originally thought to be exclusively expressed by the tumour endothelium but more recently NRP-1 expression was identified on tumour cells such as the MDA-MB-231 breast tumour cells, human astrocytomas, neuroblastoma, lung, pancreatic, gastric tumour cells and colon cancer cells [42][43][44][45][46][47][48][49]. Neuropilin-2 (NRP-2) can also bind VEGF, but like NRP-1 lacks a cytoplasmic signaling domain.…”

Section: Vegf Receptorsmentioning

confidence: 99%

Angiogenic and cell survival functions of Vascular Endothelial Growth Factor (VEGF)

2005

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Vascular endothelial growth factor (VEGF) was originally identified as an endothelial cell specific growth factor stimulating angiogenesis and vascular permeability. Some family members, VEGF C and D, are specifically involved in lymphangiogenesis. It now appears that VEGF also has autocrine functions acting as a survival factor for tumour cells protecting them from stresses such as hypoxia, chemotherapy and radiotherapy. The mechanisms of action of VEGF are still being investigated with emerging insights into overlapping pathways and cross-talk between other receptors such as the neuropilins which were not previously associated with angiogenesis. VEGF plays an important role in embryonic development and angiogenesis during wound healing and menstrual cycle in the healthy adult. VEGF is also important in a number of both malignant and non-malignant pathologies. As it plays a limited role in normal human physiology, VEGF is an attractive therapeutic target in diseases where VEGF plays a key role. It was originally thought that in pathological conditions such as cancer, VEGF functioned solely as an angiogenic factor, stimulating new vessel formation and increasing vascular permeability. It has since emerged it plays a multifunctional role where it can also have autocrine pro-survival effects and contribute to tumour cell chemoresistance. In this review we discuss the established role of VEGF in angiogenesis and the underlying mechanisms. We discuss its role as a survival factor and mechanisms whereby angiogenesis inhibition improves efficacy of chemotherapy regimes. Finally, we discuss the therapeutic implications of targeting angiogenesis and VEGF receptors, particularly in cancer therapy.

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“…In addition, it has been shown that when administered with a frequent, low-dose schedule, certain chemotherapeutic drugs can have potent antiendothelial cell activity (9,10). Conversely, evidence is accumulating that VEGF blockade, although traditionally presumed to exert direct activity only against the tumor endothelium, may also have direct antitumor effects against certain malignancies (11).…”

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confidence: 99%

Bevacizumab-Induced Transient Remodeling of the Vasculature in Neuroblastoma Xenografts Results in Improved Delivery and Efficacy of Systemically Administered Chemotherapy

Dickson¹,

Hamner²,

Sims³

et al. 2007

Clinical Cancer Research

399

343

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Purpose: Dysfunctional tumor vessels can be a significant barrier to effective cancer therapy.However, increasing evidence suggests that vascular endothelial growth factor (VEGF) inhibition can effect transient ''normalization''of the tumor vasculature, thereby improving tumor perfusion and, consequently, delivery of systemic chemotherapy. We sought to examine temporal changes in tumor vascular function in response to the anti-VEGF antibody, bevacizumab. Experimental Design: Established orthotopic neuroblastoma xenografts treated with bevacizumab were evaluated at serial time points for treatment-associated changes in intratumoral vascular physiology, penetration of systemically administered chemotherapy, and efficacy of combination therapy. Results: After a single bevacizumab dose, a progressive decrease in tumor microvessel density to <30% of control was observed within 7 days. Assessment of the tumor microenvironment revealed a rapid, sustained decrease in both tumor vessel permeability and tumor interstitial fluid pressure, whereas intratumoral perfusion, as assessed by contrast-enhanced ultrasonography, was improved, although this latter change abated by 1week. Intratumoral drug delivery mirrored these changes; penetration of chemotherapy was improved by as much as 81% when given 1to 3 days after bevacizumab, compared with when both drugs were given concomitantly, or 7 days apart. Finally, administering topotecan to tumor-bearing mice 3 days after bevacizumab resulted in greater tumor growth inhibition (36% of control size) than with monotherapy (88% bevacizumab, 54% topotecan) or concomitant administration of the two drugs (44%). Conclusions: Bevacizumab-mediated VEGF blockade effects alterations in tumor vessel physiology that allow improved delivery and efficacy of chemotherapy, although careful consideration of drug scheduling is required to optimize antitumor activity.

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Selective upregulation of vascular endothelial growth factor receptors neuropilin‐1 and ‐2 in human neuroblastoma

Cited by 86 publications

References 20 publications

Aberrant Expression of Neuropilin-1 and -2 in Human Pancreatic Cancer Cells

Aberrant Expression of Neuropilin-1 and -2 in Human Pancreatic Cancer Cells

Angiogenic and cell survival functions of Vascular Endothelial Growth Factor (VEGF)

Bevacizumab-Induced Transient Remodeling of the Vasculature in Neuroblastoma Xenografts Results in Improved Delivery and Efficacy of Systemically Administered Chemotherapy

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