Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis.

Exosomes are naturally occurring biological nanovesicles utilized by tumors to communicate signals to local and remote cells and tissues. Melanoma exosomes can incite a proangiogenic signaling program capable of remodeling tissue matrices. In this study, we show exosome-mediated conditioning of lymph nodes and define microanatomic responses that license metastasis of melanoma cells. Homing of melanoma exosomes to sentinel lymph nodes imposes synchronized molecular signals that effect melanoma cell recruitment, extracellular matrix deposition, and vascular proliferation in the lymph nodes. Our findings highlight the pathophysiologic role and mechanisms of an exosome-mediated process of microanatomic niche preparation that facilitates lymphatic metastasis by cancer cells.

[1]  Hamid Cheshmi Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers , 2011 .

[2]  D. Yip,et al.  The EphB4 receptor promotes the growth of melanoma cells expressing the ephrin‐B2 ligand , 2010, Pigment cell & melanoma research.

[3]  A. Harris,et al.  New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. , 2010, Blood.

[4]  A. Eggermont,et al.  Importance of tumor load in the sentinel node in melanoma: clinical dilemmas , 2010, Nature Reviews Clinical Oncology.

[5]  I. Fidler,et al.  AACR centennial series: the biology of cancer metastasis: historical perspective. , 2010, Cancer research.

[6]  K. Preissner,et al.  Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. , 2010, Cancer research.

[7]  Sandeep S. Joshi,et al.  Expression and function of hypoxia inducible factor-1 alpha in human melanoma under non-hypoxic conditions , 2009, Molecular Cancer.

[8]  Samuel A Wickline,et al.  Paracrine induction of endothelium by tumor exosomes , 2009, Laboratory Investigation.

[9]  A. Molinari,et al.  Microenvironmental pH Is a Key Factor for Exosome Traffic in Tumor Cells* , 2009, The Journal of Biological Chemistry.

[10]  C. Théry,et al.  Membrane vesicles as conveyors of immune responses , 2009, Nature Reviews Immunology.

[11]  Bethan Psaila,et al.  The metastatic niche: adapting the foreign soil , 2009, Nature Reviews Cancer.

[12]  Dana M. Brantley-Sieders,et al.  Low levels of tumor necrosis factor alpha increase tumor growth by inducing an endothelial phenotype of monocytes recruited to the tumor site. , 2009, Cancer research.

[13]  R. Kalluri,et al.  Tumor stroma derived biomarkers in cancer , 2009, Cancer and Metastasis Reviews.

[14]  R. Rabin,et al.  Systematic method for determining an ideal housekeeping gene for real-time PCR analysis. , 2008, Journal of biomolecular techniques : JBT.

[15]  M. Detmar,et al.  Tumor lymphangiogenesis and melanoma metastasis , 2008, Journal of cellular physiology.

[16]  Cicek Gercel-Taylor,et al.  MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. , 2008, Gynecologic oncology.

[17]  E. Rodriguez-Boulan,et al.  Itinerant exosomes: emerging roles in cell and tissue polarity. , 2008, Trends in cell biology.

[18]  A. Ruddell,et al.  Lymph node mapping in the mouse. , 2008, Journal of immunological methods.

[19]  Sanchita Bhatnagar,et al.  Exosome Function: From Tumor Immunology to Pathogen Biology , 2008, Traffic.

[20]  G. Mundy The premetastatic niche , 2008 .

[21]  Petra Schwille,et al.  Ceramide Triggers Budding of Exosome Vesicles into Multivesicular Endosomes , 2008, Science.

[22]  D. Roberts,et al.  Differential effects of ABT-510 and a CD36-binding peptide derived from the type 1 repeats of thrombospondin-1 on fatty acid uptake, nitric oxide signaling, and caspase activation in vascular cells. , 2008, Biochemical pharmacology.

[23]  G. Parmiani,et al.  Tumour-released exosomes and their implications in cancer immunity , 2008, Cell Death and Differentiation.

[24]  A. Vincent-Salomon,et al.  A “class action” against the microenvironment: do cancer cells cooperate in metastasis? , 2008, Cancer and Metastasis Reviews.

[25]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[26]  G. Parmiani,et al.  Tumor-released microvesicles as vehicles of immunosuppression. , 2007, Cancer research.

[27]  S. Rafii,et al.  Preparing the "soil": the premetastatic niche. , 2006, Cancer research.

[28]  E. Pasquale,et al.  The EphB4 Receptor-tyrosine Kinase Promotes the Migration of Melanoma Cells through Rho-mediated Actin Cytoskeleton Reorganization* , 2006, Journal of Biological Chemistry.

[29]  A. Villa,et al.  Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. , 2006, Cancer research.

[30]  M. Zöller,et al.  Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029. , 2006, Cancer research.

[31]  S. Gabrielsson,et al.  Direct exosome stimulation of peripheral humanT cells detected by ELISPOT , 2006, European journal of immunology.

[32]  A. Bosserhoff Novel biomarkers in malignant melanoma. , 2006, Clinica chimica acta; international journal of clinical chemistry.

[33]  Aled Clayton,et al.  Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids , 2006, Current protocols in cell biology.

[34]  William E. Grizzle,et al.  Murine Mammary Carcinoma Exosomes Promote Tumor Growth by Suppression of NK Cell Function1 , 2006, The Journal of Immunology.

[35]  D. Taylor,et al.  Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects , 2005, British Journal of Cancer.

[36]  Sébastien Roy,et al.  Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. , 2004, The Biochemical journal.

[37]  M. Martínez-Lorenzo,et al.  The human melanoma cell line MelJuSo secretes bioactive FasL and APO2L/TRAIL on the surface of microvesicles. Possible contribution to tumor counterattack. , 2004, Experimental cell research.

[38]  T. Godfrey,et al.  Characterization of amplifiable, circulating RNA in plasma and its potential as a tool for cancer diagnostics. , 2004, Clinical chemistry.

[39]  A. Harris,et al.  Hypoxia-inducible factors 1alpha and 2alpha are related to vascular endothelial growth factor expression and a poorer prognosis in nodular malignant melanomas of the skin. , 2003, Melanoma research.

[40]  K. Tryggvason,et al.  Laminin isoforms in tumor invasion, angiogenesis and metastasis. , 2002, Seminars in cancer biology.

[41]  Y. Nagamine,et al.  Regulation by p38 mitogen-activated protein kinase of adenylate- and uridylate-rich element-mediated urokinase-type plasminogen activator (uPA) messenger RNA stability and uPA-dependent in vitro cell invasion. , 1999, Cancer research.

[42]  J J Sixma,et al.  Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. , 1999, Blood.

[43]  K. Alitalo,et al.  Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. , 1998, The American journal of pathology.

[44]  Stefan Offermanns,et al.  Vascular System Defects and Impaired Cell Chemokinesis as a Result of Gα13 Deficiency , 1997, Science.

[45]  C. Zandonella,et al.  Urokinase receptor antagonists inhibit angiogenesis and primary tumor growth in syngeneic mice. , 1996, Cancer research.

[46]  S. Goerdt,et al.  Inducible expression of MS-1 high-molecular-weight protein by endothelial cells of continuous origin and by dendritic cells/macrophages in vivo and in vitro. , 1993, The American journal of pathology.

[47]  D. Cheresh,et al.  Human melanoma cells derived from lymphatic metastases use integrin alpha v beta 3 to adhere to lymph node vitronectin. , 1992, The Journal of clinical investigation.