Facteur de croissance nerveuse

Le facteur de croissance nerveuse ou NGF (acronyme de l'appellation anglophone Nerve growth factor) est un polypeptide de la famille des neurotrophines. Il est impliqué dans la croissance, la prolifération et la survie d'un certain nombre de neurones mais également d'autres cellules. Ce facteur de croissance a été le premier à avoir été identifié et à ce titre constitue le prototype de cette famille de facteurs. Son gène, NGF, est situé sur le chromosome 1 humain. Rôles Il intervient dans le circuit neuronal de la douleur, augmentant la sensibilité à celle-ci, en particulier dans le cadre d'une inflammation. Il active les récepteurs TRPV1 par la voie des MAPK et de la phosphoinositide 3-kinase, Découverte En 1948, alors qu'elle travaillait sous la direction de Viktor Hamburger, la neurobiologiste Rita Levi-Montalcini découvre une tumeur de souris qui stimule la croissance nerveuse quand on l'implante dans un embryon de poulet. Cet effet est attribué à une sub

ADAM17 Promotes Motility, Invasion, and Sprouting of Lymphatic Endothelial Cells

Witold Waldemar Kilarski, Renata Katarzyna Mezyk-Kopec, Melody Swartz

Tumor-associated lymphatic vessels actively participate in tumor progression and dissemination. ADAM17, a sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules, is believed to promote tumor development, facilitating both tumor cell proliferation and migration, as well as tumor angiogenesis. In this work we addressed the issue of whether ADAM17 may also promote tumor lymphangiogenesis. First, we found that ADAM17 is important for the migratory potential of immortalized human dermal lymphatic endothelial cells (LEC). When ADAM17 was stably silenced in LEC, their proliferation was not affected, but: (i) single-cell motility, (ii) cell migration through a 3D Matrigel/collagen type I matrix, and (iii) their ability to form sprouts in a 3D matrix were significantly diminished. The differences in the cell motility between ADAM17-proficient and ADAM17-silenced cells were eliminated by inhibitors of EGFR and HER2, indicating that ADAM17-mediated shedding of growth factors accounts for LEC migratory potential. Interestingly, ADAM17 depletion affected the integrin surface expression/functionality in LEC. ADAM17-silenced cells adhered to plastic, type I collagen, and fibronectin faster than their ADAM17-proficient counterparts. The difference in adhesion to fibronectin was abolished by a cyclic RGD peptide, emphasizing the involvement of integrins in the process. Using a soluble receptor array, we identified BIG-H3 among several candidate proteins involved in the phenotypic and behavioral changes of LEC upon ADAM17 silencing. In additional assays, we confirmed the increased expression of BIG-H3, as well as TGF beta 2 in ADAM17-silenced LEC. The antilym-phangiogenic effects of ADAM17 silencing in lymphatic endothelial cells suggest further relevance of ADAM17 as a potential target in cancer therapy.

Public Library Science2015

ADAM17 Silencing in Mouse Colon Carcinoma Cells: The Effect on Tumoricidal Cytokines and Angiogenesis

Renata Katarzyna Mezyk-Kopec, Melody Swartz

ADAM17 (a disintegrin and metalloprotease 17) is a major sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules and is often overexpressed in malignant cells. It is generally accepted that ADAM17 promotes tumor development via activating growth factors from the EGF family, thus facilitating autocrine stimulation of tumor cell proliferation and migration. Here we show, using MC38CEA murine colon carcinoma model, that ADAM17 also regulates tumor angiogenesis and cytokine profile. When ADAM17 was silenced in MC38CEA cells, in vivo tumor growth and in vitro cell motility were significantly diminished, but no effect was seen on in vitro cell proliferation. ADAM17-silencing was accompanied by decreased in vitro expression of vascular endothelial growth factor-A and matrix metalloprotease-9, which was consistent with the limited angiogenesis and slower growth seen in ADAM17-silenced tumors. Among the growth factors susceptible to shedding by ADAM17, neuregulin-1 was the only candidate to mediate the effects of ADAM17 on MC38CEA motility and tumor angiogenesis. Concentrations of TNF and IFN gamma, cytokines that synergistically induced proapoptotic effects on MC38CEA cells, were significantly elevated in the lysates of ADAM17-silenced tumors compared to mock transfected controls, suggesting a possible role for ADAM17 in host immune suppression. These results introduce new, complex roles of ADAM17 in tumor progression, including its impact on the anti-tumor immune response.

Public Library of Science2012

ADAM17 Promotes Motility, Invasion, and Sprouting of Lymphatic Endothelial Cells

Witold Waldemar Kilarski, Renata Katarzyna Mezyk-Kopec, Melody Swartz

Public Library Science2015