Pleiotrophin Exerts Its Migration and Invasion Effect through the Neuropilin-1 Pathway

Abstract

Pleiotrophin (PTN) is a pleiotropic growth factor that exhibits angiogenic properties and is involved in tumor growth and metastasis. Although it has been shown that PTN is expressed in tumor cells, few studies have investigated its receptors and their involvement in cell migration and invasion. Neuropilin-1 (NRP-1) is a receptor for multiple growth factors that mediates cell motility and plays an important role in angiogenesis and tumor progression. Here we provide evidence for the first time that NRP-1 is crucial for biological activities of PTN. We found that PTN interacted directly with NRP-1 through its thrombospondin type-I repeat domains. Importantly, binding of PTN to NRP-1 stimulated the internalization and recycling of NRP-1 at the cell surface. Invalidation of NRP-1 by RNA interference in human carcinoma cells inhibited PTN-induced intracellular signaling of the serine-threonine kinase, mitogen-activated protein MAP kinase, and focal adhesion kinase pathways. Accordingly, NRP-1 silencing or blocking by antibody inhibited PTN-induced human umbilical vein endothelial cell migration and tumor cell invasion. These results suggest that NRP-1/PTN interaction provides a novel mechanism for controlling the response of endothelial and tumoral cells to PTN and may explain, at least in part, how PTN contributes to tumor angiogenesis and cancer progression.

NRP1 transport of cancer therapeutics mediated by tumor-penetrating peptides

“…It functions as a co-receptor for a number of extracellular ligands including some isoforms of VEGF, class 3 semaphorins, hepatic growth factor, FGF and TGF-β (see reviews of Graziani and Lacal, (24); Guo and Kooi, (25)) (26–29). Whereas class 3 semaphorins bind to the a1/a2/b1 domains of the NRP1 receptor, growth factors such as VEGF165 bind exclusively to its b1/b2 domains.…”

“…The complex of VEGF165-VEGFR2-NRP1 also has a role in the development of lymph vessels in tumors (34–36), although the interaction of VEGFC/VEGFD-VEGFR3-NRP2 has a much more essential role in their development and proliferation. In addition to the VEGF-mediated pathway, other growth factors (i.e., FGF, HGF, TGF-β) and receptors may interact with NRP1 on tumor and stroma cells (i.e., immune and endothelial cells, fibroblasts) to promote tumor aggressiveness (26–29). Independent of growth factors and their cognate receptors, TPP through interaction with NRP1 reduced tumor cell migration and metastases (discussed in next section) (37).…”

“…Through a genome-wide RNAi strategy, the interaction between the GIPC1/synectin and the cytosolic domain of NRP1 was determined to be necessary for endocytosis of the TPP-cargo (39). If the fate of NRP1, once endocytosed is similar to after binding with pleiotropin, then NRP1 is at least partially recycled to the cell surface (29). Beyond NRP1-mediated endocytosis, the intracellular pathway of TPP or the TPP-cargo is largely unknown.…”

Participation of MicroRNAs in the Treatment of Cancer with Phytochemicals

“…Pleiotrophin (PTN) can interact with neuropilin-1 receptors, stimulating downstream signaling pathways, such as PI3K and focal adhesion kinase (FAK), to facilitate cancer growth and metastasis [ 252 ]. It was suggested that miR-384 augmented by luteolin targets PTN in colorectal cancer cells [ 150 ], suggesting that luteolin suppresses colorectal cancer metastasis, in part, via the miR-384/PTN axis.…”

Arany és ezüst nanorészecskék sejtbiológiai hatásainak vizsgálata p53 deficiens rákos sejtekben és tumor metasztázis modellben

“…Ez szintén releváns lehet, ugyanis az Oszteopontinról számos alkalommal leírták már, hogy növeli a tumorsejtek proliferációs aktivitását, és elősegíti a primer tumorok áttétképzését [209]. Az ezüst és arany-ezüst nanorészecske kezelések hatására csökkent expressziót mutató Ptn gén terméke a multifunkciós biológiai szereppel rendelkező neurit növekedési faktor 1 (NEGF1, pleiotrophin), elősegíti a tumorokban az angiogenezist és serkenti a metasztázis kialakulását [210]. Az arany-ezüst nanorészecskék csökkentették a CCL7 kemokin expresszióját biztosító gén (Ccl7) kifejeződését is, amiről bebizonyosodott már, hogy a CCR3 receptor aktiválásán keresztül epitheliális-mesenchymális tranzíciót okoz a tumorsejtekben, így növelve azok metasztázis-képző hatékonyságát [211].…”