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FältnamnIndikatorerMetadata
00007314naa a2200613 4500
001oai:DiVA.org:uu-329632
003SwePub
008170926s2017 | |||||||||||000 ||eng|
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3296322 URI
0247 a https://doi.org/10.1038/nature229772 DOI
040 a (SwePub)uu
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Olmeda, Davidu Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.4 aut
2451 0a Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine
264 c 2017-06-28
264 1b NATURE PUBLISHING GROUP,c 2017
338 a print2 rdacarrier
520 a Cutaneous melanoma is a type of cancer with an inherent potential for lymph node colonization, which is generally preceded by neolymphangiogenesis(1-3). However, sentinel lymph node removal does not necessarily extend the overall survival of patients with melanoma(4,5). Moreover, lymphatic vessels collapse and become dysfunctional as melanomas progress(6,7). Therefore, it is unclear whether (and how) lymphangiogenesis contributes to visceral metastasis. Soluble and vesicle-associated proteins secreted by tumours and/or their stroma have been proposed to condition pre-metastatic sites in patients with melanoma(8-14). Still, the identities and prognostic value of lymphangiogenic mediators remain unclear(2,14). Moreover, our understanding of lymphangiogenesis (in melanomas and other tumour types) is limited by the paucity of mouse models for live imaging of distal pre-metastatic niches(15). Injectable lymphatic tracers have been developed(7), but their limited diffusion precludes whole-body imaging at visceral sites(16). Vascular endothelial growth factor receptor 3 (VEGFR3) is an attractive 'lymphoreporter' 17 because its expression is strongly downregulated in normal adult lymphatic endothelial cells, but is activated in pathological situations such as inflammation and cancer(17,18). Here, we exploit this inducibility of VEGFR3 to engineer mouse melanoma models for whole-body imaging of metastasis generated by human cells, clinical biopsies or endogenously deregulated oncogenic pathways. This strategy revealed early induction of distal pre-metastatic niches uncoupled from lymphangiogenesis at primary lesions. Analyses of the melanoma secretome and validation in clinical specimens showed that the heparin-binding factor midkine is a systemic inducer of neo-lymphangiogenesis that defines patient prognosis. This role of midkine was linked to a paracrine activation of the mTOR pathway in lymphatic endothelial cells. These data support the use of VEGFR3 reporter mice as a 'MetAlert' discovery platform for drivers and inhibitors of metastasis.
7001 a Cerezo-Wallis, Danielau Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.4 aut
7001 a Riveiro-Falkenbach, Ericau Univ Complutense Madrid, Inst I 12, Hosp Univ Octubre 12, Med Sch,Dept Pathol, Madrid 28041, Spain.4 aut
7001 a Pennacchi, Paula C.u Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.4 aut
7001 a Contreras-Alcalde, Martau Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.4 aut
7001 a Ibarz, Nuriau Spanish Natl Canc Res Ctr CNIO, Prote Unit, Biotechnol Programme, Madrid 28029, Spain.4 aut
7001 a Cifdaloz, Metehanu Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.;Roche Innovat Ctr Munich, Roche Pharma Res & Early Dev, D-82377 Penzberg, Germany.4 aut
7001 a Catena, Xavieru Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.4 aut
7001 a Calvo, Tonantzin G.u Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.4 aut
7001 a Canon, Estelau Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.4 aut
7001 a Alonso-Curbelo, Direnau Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.;Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA.4 aut
7001 a Suarez, Javieru Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.4 aut
7001 a Osterloh, Lisau Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.4 aut
7001 a Grana, Osvaldou Spanish Natl Canc Res Ctr CNIO, Bioinformat Unit, Struct Biol & Biocomp Programme, Madrid 28029, Spain.4 aut
7001 a Mulero, Franciscau Spanish Natl Canc Res Ctr CNIO, Mol Imaging Unit, Biotechnol Programme, Madrid 28029, Spain.4 aut
7001 a Megias, Diegou Spanish Natl Canc Res Ctr CNIO, Confocal Microscopy Unit, Biotechnol Programme, Madrid 28029, Spain.4 aut
7001 a Canamero, Martau Spanish Natl Canc Res Ctr CNIO, Histopathol Unit, Biotechnol Programme, Madrid 28029, Spain.4 aut
7001 a Martinez-Torrecuadrada, Jorge L.u Spanish Natl Canc Res Ctr CNIO, Crystallog & Prot Engn Unit, Biotechnol Programme, Madrid 28029, Spain.4 aut
7001 a Mondal, Chandraniu Icahn Sch Med Mt Sinai, Tisch Canc Inst, Div Hematol & Oncol, Dept Med, New York, NY 10029 USA.4 aut
7001 a Di Martino, Julieu Icahn Sch Med Mt Sinai, Tisch Canc Inst, Div Hematol & Oncol, Dept Med, New York, NY 10029 USA.4 aut
7001 a Lora, Davidu Hosp Univ 12 Octubre, Inst I 12, CIBERESP, Madrid 28041, Spain.4 aut
7001 a Martinez-Corral, Inesu Uppsala universitet,Vaskulärbiologi,Spanish Natl Canc Res Ctr CNIO, Transgen Mice Unit, Biotechnol Programme, Madrid 28029, Spain4 aut0 (Swepub:uu)inema117
7001 a Bravo-Cordero, J. Javieru Icahn Sch Med Mt Sinai, Tisch Canc Inst, Div Hematol & Oncol, Dept Med, New York, NY 10029 USA.4 aut
7001 a Munoz, Javieru Spanish Natl Canc Res Ctr CNIO, Prote Unit, Biotechnol Programme, Madrid 28029, Spain.4 aut
7001 a Puig, Susanau Hosp Clin Barcelona, Inst Invest Biomed August Pi & Sunyer, Melanoma Unit, Dermatol Dept, E-08036 Barcelona, Spain.4 aut
7001 a Ortiz-Romero, Pablou Univ Complutense Madrid, Hosp Univ Octubre 12, Inst I 12, Dept Dermatol,Med Sch, Madrid 28041, Spain.4 aut
7001 a Rodriguez-Peralto, Jose L.u Univ Complutense Madrid, Inst I 12, Hosp Univ Octubre 12, Med Sch,Dept Pathol, Madrid 28041, Spain.4 aut
7001 a Ortega, Sagrariou Spanish Natl Canc Res Ctr CNIO, Transgen Mice Unit, Biotechnol Programme, Madrid 28029, Spain.4 aut
7001 a Soengas, Maria S.u Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.4 aut
7102 a Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.b Univ Complutense Madrid, Inst I 12, Hosp Univ Octubre 12, Med Sch,Dept Pathol, Madrid 28041, Spain.4 org
7730 t Natured : NATURE PUBLISHING GROUPg 546:7660, s. 676-680q 546:7660<676-680x 0028-0836x 1476-4687
8564 u https://europepmc.org/articles/pmc6005659?pdf=render
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-329632
8564 8u https://doi.org/10.1038/nature22977

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