Lymphangiogenesis and metastasis—A closer look at the neuropilin/semaphorin3 axis

Migliozzi, Matthew; Mucka, Patrick; Bielenberg, Diane R.

doi:10.1016/j.mvr.2014.07.006

Cited by 15 publications

(11 citation statements)

References 110 publications

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“…Fluid (and cells) are taken up into lymphatic capillaries, and fluid propulsion is channeled down lymphatic collecting ducts (containing valves) toward lymph nodes (LN). Fluid may be filtered through several LNs; but, ultimately, all lymphatic fluid is emptied back into the venous system [48]. …”

Section: Lymphangiogenesis and Metastasismentioning

confidence: 99%

“…Direct angiogenesis inhibitors act directly on the endothelial cell, but may have off-target effects on tumor cells as well. These inhibitors include endostatin, angiostatin, thalidomide, TNP470, and Semaphorin 3F [48]. Direct angiogenesis inhibitors typically block EC proliferation or motility regardless of the stimulator.…”

Section: Anti-angiogenesis Therapy and Metastasismentioning

confidence: 99%

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The Contribution of Angiogenesis to the Process of Metastasis

Bielenberg

Zetter²

2015

The Cancer Journal

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429

296

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The role of angiogenesis in tumor growth has been studied continuously for over 45 years. It is now appreciated that angiogenesis is also essential for the dissemination and establishment of tumor metastases. In this review, we focus on the role of angiogenesis as a necessity for the escape of tumor cells into the bloodstream and for the establishment of metastatic colonies in secondary sites. We also discuss the role of tumor lymphangiogenesis as a means of dissemination of lymphatic metastases. Appropriate combination therapies may be used in the future to both prevent and treat metastatic disease through the rational use of anti-angiogenic and anti-lymphangiogenic therapies in ways that are informed by the current and future work in the field.

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Section: Lymphangiogenesis and Metastasismentioning

confidence: 99%

Section: Anti-angiogenesis Therapy and Metastasismentioning

confidence: 99%

The Contribution of Angiogenesis to the Process of Metastasis

Bielenberg

Zetter²

2015

The Cancer Journal

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429

296

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“…Lymphatic capillaries are blind-ended vessels that drain fluid from the interstitial space. They are lined by thin-walled lymphatic endothelial cells lacking basal lamina and lacking pericyte coverage (3). Initial lymphatics drain into larger collecting vessels covered on the abluminal side with a basement membrane and smooth muscle cells.…”

Section: Routes Of Cancer Disseminationmentioning

confidence: 99%

The role of EMT and MET in cancer dissemination

Banyard

Bielenberg

2015

Connective Tissue Research

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216

196

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Metastatic cancer cells are lethal. Understanding the molecular mechanisms that bolster the conversion from benign to malignant progression is key to treating these heterogeneous and resistant neoplasms. The epithelial-mesenchymal transition (EMT) is a conserved cellular program that alters cell shape, adhesion, and movement. The shift to a more mesenchymal-like phenotype can promote tumor cell intravasation of surrounding blood vessels and emigration to a new organ, yet may not be necessary for extravasation or colonization into that environment. Lymphatic dissemination, on the other hand, may not require EMT. This review presents emerging data on the modes by which tumor cells promote EMT/MET via microRNA and prepare the pre-metastatic niche via exosomes.

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“…Lymphangiography showed pooled dye and retrograde lymph flow in inflamed ears compared to unchallenged ears (Supplemental Figure S1B). 32 Immunoblot analysis of C57BL/6J mice ear proteins after DTH showed nearly twofold increased expression of Nrp2 by day 1 and nearly threefold by days 5 to 7 ( Figure 1C). Moreover, Nrp2 expression (b-galactosidase activity) was up-regulated in inflamed endothelium in Nrp2 þ/LacZ mice ( Figure 1D).…”

Section: Resultsmentioning

confidence: 94%

“…SEMA3F-transfected tumors served as positive controls for immunostaining (Supplemental Figure S1F). 32 Additionally, exogenous SEMA3F protein inhibited vascular permeability in the skin in VEGFA-induced Miles assays in WT mice (Figure 2, C and D). At equal doses, SEMA3F protein was as effective as bevacizumab, a VEGFA-neutralizing antibody, in blocking vascular permeability.…”

Section: Nrp2 Regulates Vascular Permeability and Edemamentioning

confidence: 89%

Inflammation and Lymphedema Are Exacerbated and Prolonged by Neuropilin 2 Deficiency

Mucka

Levonyak

Geretti

et al. 2016

The American Journal of Pathology

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The vasculature influences the progression and resolution of tissue inflammation. Capillaries express vascular endothelial growth factor (VEGF) receptors, including neuropilins (NRPs), which regulate interstitial fluid flow. NRP2, a receptor of VEGFA and semaphorin (SEMA) 3F ligands, is expressed in the vascular and lymphatic endothelia. Previous studies have demonstrated that blocking VEGF receptor 2 attenuates VEGFA-induced vascular permeability. The inhibition of NRP2 was hypothesized to decrease vascular permeability as well. Unexpectedly, massive tissue swelling and edema were observed in Nrp2 À/À mice compared with wild-type littermates after delayed-type hypersensitivity reactions. Vascular permeability was twofold greater in inflamed blood vessels in Nrp2-deficient mice compared to those in Nrp2-intact littermates. The addition of exogenous SEMA3F protein inhibited vascular permeability in Balb/cJ mice, suggesting that the loss of endogenous Sema3F activity in the Nrp2-deficient mice was responsible for the enhanced vessel leakage. Functional lymphatic capillaries are necessary for draining excess fluid after inflammation; however, Nrp2-mutant mice lacked superficial lymphatic capillaries, leading to 2.5-fold greater fluid retention and severe lymphedema after inflammation. In conclusion, Nrp2 deficiency increased blood vessel permeability and decreased lymphatic vessel drainage during inflammation, highlighting the importance of the NRP2/SEMA3F pathway in the modulation of tissue swelling and resolution of postinflammatory edema. (Am J Pathol 2016 http://dx

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Lymphangiogenesis and metastasis—A closer look at the neuropilin/semaphorin3 axis

Cited by 15 publications

References 110 publications

The Contribution of Angiogenesis to the Process of Metastasis

The Contribution of Angiogenesis to the Process of Metastasis

The role of EMT and MET in cancer dissemination

Inflammation and Lymphedema Are Exacerbated and Prolonged by Neuropilin 2 Deficiency

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