Format

Send to

Choose Destination
Nature. 2017 Jun 28;546(7660):676-680. doi: 10.1038/nature22977.

Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine.

Author information

1
Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
2
Department of Pathology, Medical School, Universidad Complutense, Instituto i+12, Hospital Universitario 12 de Octubre, Madrid 28041, Spain.
3
Proteomics Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
4
Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
5
Molecular Imaging Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
6
Confocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
7
Histopathology Unit, Biotechnology Programme,Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
8
Crystallography and Protein Engineering Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
9
Department of Medicine, Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
10
CIBERESP, Instituto i+12, Hospital Universitario 12 de Octubre, Madrid 28041, Spain.
11
Transgenic Mice Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
12
Melanoma Unit, Dermatology Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques d'August Pi i Sunyer, 08036 Barcelona, Spain.
13
Department of Dermatology, Medical School, Universidad Complutense, Instituto i+12, Hospital Universitario 12 de Octubre, Madrid 28041, Spain.

Abstract

Cutaneous melanoma is a type of cancer with an inherent potential for lymph node colonization, which is generally preceded by neolymphangiogenesis. However, sentinel lymph node removal does not necessarily extend the overall survival of patients with melanoma. Moreover, lymphatic vessels collapse and become dysfunctional as melanomas progress. 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. Still, the identities and prognostic value of lymphangiogenic mediators remain unclear. 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. Injectable lymphatic tracers have been developed, but their limited diffusion precludes whole-body imaging at visceral sites. Vascular endothelial growth factor receptor 3 (VEGFR3) is an attractive 'lymphoreporter' because its expression is strongly downregulated in normal adult lymphatic endothelial cells, but is activated in pathological situations such as inflammation and cancer. 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.

PMID:
28658220
PMCID:
PMC6005659
DOI:
10.1038/nature22977
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center