Targeting Placental Growth Factor/Neuropilin 1 Pathway Inhibits Growth and Spread of Medulloblastoma

Snuderl, Matija; Batista, Ana; Kirkpatrick, Nathaniel D.; Almodóvar, Carmen Ruiz de; Riedemann, Lars; Walsh, Elisa C; Anolik, Rachel; Huang, Yuhui; Martin, John D.; Kamoun, Walid S.; Knevels, Ellen; Schmidt, Thomas; Farrar, Christian T.; Vakoc, Benjamin J.; Mohan, Nishant; Chung, Euiheon; Roberge, Sylvie; Peterson, Teresa; Bais, Carlos; Zhelyazkova, Boryana; Yip, Stephen; Hasselblatt, Martin; Rössig, Claudia; Niemeyer, Elisabeth; Ferrara, Napoleone; Klagsbrun, Michael; Duda, Dan G.; Fukumura, Dai; Xu, Lei; Carmeliet, Peter; Jain, Rakesh K.

doi:10.1016/j.cell.2013.01.036

Cited by 212 publications

(206 citation statements)

References 43 publications

(72 reference statements)

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“…Inhibitor of NRP1 could reduce cell proliferation and tumor growth in non-small cell lung cancer (34), medulloblastoma (35), and breast cancer (36). On the basis of these reports and our observations that NRP1 promotes cell invasion and migration in vitro, tumor metastasis in animal models, NRP1 could be a candidate molecular target for the therapy of ESCC, to which further study should be addressed.…”

Section: Discussionmentioning

confidence: 99%

Calreticulin Promotes Migration and Invasion of Esophageal Cancer Cells by Upregulating Neuropilin-1 Expression via STAT5A

Feng

Pan

et al. 2014

Clinical Cancer Research

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Purpose: We previously revealed that the calreticulin (CRT) gene is a candidate oncogene promoting cell migration and invasion and that neuropilin-1 (NRP1) is a possible effector downstream of CRT in esophageal squamous carcinoma cells. This study aims to explore the mechanisms underlying the migration and invasion of esophageal cancer cells regulated by CRT through NRP1.Experimental Design: Quantitative reverse-transcription polymerase chain reaction, Western blot analysis, chromatin immunoprecipitation, and reporter gene assays were used to investigate the relationship between CRT and NRP1. In vitro and in vivo assays were carried out to evaluate the effects of NRP1 on malignant phenotypes of ESCC cells and tumor metastasis in NOD/SCID mice. Immunohistochemistry was performed to analyze the expression of CRT and NRP1 in esophageal squamous cell carcinomas (ESCC).Results: Knockdown of CRT decreased the expression of NRP1. Inhibition of NRP1 reduced ESCC cell motility in vitro and experimental metastasis in vivo. Ectopic expression of NRP1 rescued the defects of cell migration and invasion in CRT-shRNA cells. CRT depletion inhibited STAT5A phosphorylation at the Y694 site via a CaMKII-independent pathway. Moreover, STAT5A directly regulated NRP1 transcription. Knockdown of CRT or NRP1 led to a downregulation of MMP2, MMP9, and FAK. Notably, positive correlation was found between CRT and NRP1 expression in ESCC tissues (P ¼ 5.87 Â 10 À5 ). CRT and NRP1 coexpression was significantly associated with lymph node metastasis (P ¼ 0.025). Conclusions: Our findings suggest that NRP1 is a critical downstream effector of CRT in promoting cell migration and invasion, which might contribute to the metastasis of ESCC.

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Section: Discussionmentioning

confidence: 99%

Calreticulin Promotes Migration and Invasion of Esophageal Cancer Cells by Upregulating Neuropilin-1 Expression via STAT5A

Feng

Pan

et al. 2014

Clinical Cancer Research

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“…In developmental angiogenesis, VEGFR1 has a negative role by trapping VEGF (71), but this model does not explain its disease-restricted proangiogenic activity (72,73). Stromal cell PlGF production, induced by contact with tumor cells, not only promotes angiogenesis in the leukemic bone marrow or medulloblastoma, but also stimulates tumor cell proliferation via Nrp1 signaling (74,75). Although it is superfluous for vascular development, VEGF-B promotes contextual enlargement of myocardial capillaries (76) or growth of coronary vessels (77).…”

Section: Pathological Angiogenesis: Distinct From Vascular Development?mentioning

confidence: 99%

Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer

Welti¹,

Loges²,

Dimmeler³

et al. 2013

J. Clin. Invest.

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543

453

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Four decades ago, angiogenesis was recognized as a therapeutic target for blocking cancer growth. Because of its importance, VEGF has been at the center stage of antiangiogenic therapy. Now, several years after FDA approval of an anti-VEGF antibody as the first antiangiogenic agent, many patients with cancer and ocular neovascularization have benefited from VEGF-targeted therapy; however, this anticancer strategy is challenged by insufficient efficacy, intrinsic refractoriness, and resistance. Here, we examine recent discoveries of new mechanisms underlying angiogenesis, discuss successes and challenges of current antiangiogenic therapy, and highlight emerging antiangiogenic paradigms.

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“…Since we and others have suggested a role for NRP-1 in endothelial or tumour cells independent of other VEGFRs, 16,32,33 we investigated whether cilengitide might modulate the response of M14-N cells to VEGF-A, using an in vitro chemotactic assay. Interestingly, cilengitide was found to inhibit the chemotactic response to VEGF-A, whereas it did not affect cell migration in response to human fibroblast conditioned medium (Fig.…”

Section: Mechanisms Involved In the Inhibitory Effects Of Cilengitidementioning

confidence: 99%

Cilengitide downmodulates invasiveness and vasculogenic mimicry of neuropilin 1 expressing melanoma cells through the inhibition of αvβ5 integrin

Ruffini

Graziani

Levati

et al. 2014

Intl Journal of Cancer

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During melanoma progression, tumour cells show increased adhesiveness to the vascular wall, invade the extracellular matrix (ECM) and frequently form functional channels similar to vascular vessels (vasculogenic mimicry). These properties are mainly mediated by the interaction of integrins with ECM components. Since we had previously identified neuropilin 1 (NRP-1), a coreceptor of vascular endothelial growth factor A (VEGF-A), as an important determinant of melanoma aggressiveness, aims of this study were to identify the specific integrins involved in the highly invasive phenotype of NRP-1 expressing cells and to investigate their role as targets to counteract melanoma progression. Melanoma aggressiveness was evaluated in vitro as cell ability to migrate through an ECM layer and to form tubule-like structures using transfected cells. Integrins relevant to these processes were identified using specific blocking antibodies. The avb5 integrin was found to be responsible for about 80% of the capability of NRP-1 expressing cells to adhere on vitronectin. In these cells avb5 expression level was twice higher than in low-invasive control cells and contributed to the ability of melanoma cells to form tubule-like structures on matrigel. Cilengitide, a potent inhibitor of am integrins activation, reduced ECM invasion, vasculogenic mimicry and secretion of VEGF-A and metalloproteinase 9 by melanoma cells. In conclusion, we demonstrated that amb5 integrin is involved in the highly aggressive phenotype of melanoma cells expressing NRP-1. Moreover, we identified a novel mechanism that contributes to the antimelanoma activity of the av integrin inhibitor cilengitide based on the inhibition of vasculogenic mimicry.

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Targeting Placental Growth Factor/Neuropilin 1 Pathway Inhibits Growth and Spread of Medulloblastoma

Cited by 212 publications

References 43 publications

Calreticulin Promotes Migration and Invasion of Esophageal Cancer Cells by Upregulating Neuropilin-1 Expression via STAT5A

Calreticulin Promotes Migration and Invasion of Esophageal Cancer Cells by Upregulating Neuropilin-1 Expression via STAT5A

Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer

Cilengitide downmodulates invasiveness and vasculogenic mimicry of neuropilin 1 expressing melanoma cells through the inhibition of αvβ5 integrin

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