Endothelial Tie1-mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis.

The endothelial tyrosine kinase receptor Tie1 remains poorly characterized, largely owing to its orphan receptor status. Global Tie1 inactivation causes late embryonic lethality, thereby reflecting its importance during development. Tie1 also plays pivotal roles during pathologies such as atherosclerosis and tumorigenesis.

Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation.

Neuropilin-1 (NRP1) regulates developmental and pathological angiogenesis, arteriogenesis, and vascular permeability, acting as a coreceptor for semaphorin 3A (Sema3A) and the 165-amino acid isoform of vascular endothelial growth factor A (VEGF-A165). NRP1 is also the receptor for the CendR peptides, a class of cell- and tissue-penetrating peptides with a specific R-x-x-R carboxyl-terminal motif. Because the cytoplasmic domain of NRP1 lacks catalytic activity, NRP1 is mainly thought to act through the recruitment and binding to other receptors.

Evidence for new homotypic and heterotypic interactions between transmembrane helices of proteins involved in receptor tyrosine kinase and neuropilin signaling.

Signaling in eukaryotic cells frequently relies on dynamic interactions of single-pass membrane receptors involving their transmembrane (TM) domains. To search for new such interactions, we have developed a bacterial two-hybrid system to screen for both homotypic and heterotypic interactions between TM helices. We have explored the dimerization of TM domains from 16 proteins involved in both receptor tyrosine kinase and neuropilin signaling.

Rhodocetin-αβ-induced neuropilin-1-cMet association triggers restructuring of matrix contacts in endothelial cells.

Objective: The snake venom component rhodocetin-αβ (RCαβ) stimulates endothelial cell motility in an α2β1 integrin-independent manner. We aimed to elucidate its cellular and molecular mechanisms.

Methods And Results: We identified neuropilin-1 (Nrp1) as a novel target of RCαβ by protein-chemical methods.

De novo design of a tumor-penetrating peptide.

Poor penetration of antitumor drugs into the extravascular tumor tissue is often a major factor limiting the efficacy of cancer treatments. Our group has recently described a strategy to enhance tumor penetration of chemotherapeutic drugs through use of iRGD peptide (CRGDK/RGPDC). This peptide comprises two sequence motifs: RGD, which binds to αvβ3/5 integrins on tumor endothelia and tumor cells, and a cryptic CendR motif (R/KXXR/K-OH).

Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma.

Antiangiogenic therapy can produce transient tumor regression in glioblastoma (GBM), but no prolongation in patient survival has been achieved. We have constructed a nanosystem targeted to tumor vasculature that incorporates three elements: (i) a tumor-homing peptide that specifically delivers its payload to the mitochondria of tumor endothelial cells and tumor cells, (ii) conjugation of this homing peptide with a proapoptotic peptide that acts on mitochondria, and (iii) multivalent presentation on iron oxide nanoparticles, which enhances the proapoptotic activity. The iron oxide component of the nanoparticles enabled imaging of GBM tumors in mice.

Specific penetration and accumulation of a homing peptide within atherosclerotic plaques of apolipoprotein E-deficient mice.

The ability to selectively deliver compounds into atherosclerotic plaques would greatly benefit the detection and treatment of atherosclerotic disease. We describe such a delivery system based on a 9-amino acid cyclic peptide, LyP-1. LyP-1 was originally identified as a tumor-homing peptide that specifically recognizes tumor cells, tumor lymphatics, and tumor-associated macrophages.

First evidence of RNA interference mechanism induced in human: getting closer to a cure?

Knocking down a human gene by RNA silencing has been the focus of a number of laboratories since the discovery of the RNAi mechanism more than 10 years ago. In their remarkable work, M. Davis and collaborators show for the first time the induction of an RNAi pathway in humans following systemic administration of nanoparticles.

The good, the bad and the ugly: a neuropilin-2 story from normal to tumor-associated lymphangiogenesis.

VEGF-C is a crucial player in lymphangiogenesis. Besides VEGFR-2 and VEGFR-3, it also binds NRP2. NRP2 enhances VEGF-C/VEGFR-3 effects in developmental lymphangiogenesis, but its role in adult and tumoral lymphangiogenesis is not known.

Transmembrane domain interactions control biological functions of neuropilin-1.

Neuropilin-1 (NRP1) is a transmembrane receptor playing a pivotal role in the control of semaphorins and VEGF signaling pathways. The exact mechanism controlling semaphorin receptor complex formation is unknown. A structural analysis and modeling of NRP1 revealed a putative dimerization GxxxG motif potentially important for NRP1 dimerization and oligomerization.