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Endothelial Cell Malignancies: New Insights From the Laboratory and Clinic


Endothelial Cell Malignancies: New Insights From the Laboratory and Clinic

Michael J Wagner et al. NPJ Precis Oncol.


Endothelial cell malignancies are rare in the Western world and range from intermediate grade hemangioendothelioma to Kaposi sarcoma to aggressive high-grade angiosarcoma that metastasize early and have a high rate of mortality. These malignancies are associated with dysregulation of normal endothelial cell signaling pathways, including the vascular endothelial growth factor, angiopoietin, and Notch pathways. Discoveries over the past two decades related to mechanisms of angiogenesis have led to the development of many drugs that intuitively would be promising therapeutic candidates for these endothelial-derived tumors. However, clinical efficacy of such drugs has been limited. New insights into the mechanisms that lead to dysregulated angiogenesis such as mutation or amplification in known angiogenesis related genes, viral infection, and chromosomal translocations have improved our understanding of the pathogenesis of endothelial malignancies and how they evade anti-angiogenesis drugs. In this review, we describe the major molecular alterations in endothelial cell malignancies and consider emerging opportunities for improving therapeutic efficacy against these rare but deadly tumors.

Conflict of interest statement

The authors declare no competing interests.


Fig. 1
Fig. 1
Clinical appearance of angiosarcoma and response to paclitaxel. Pretreatment appearance of cutaneous angiosarcoma in a patient with lymphedema of the upper extremity following treatment for breast cancer (left), and appearance after response to paclitaxel (right)
Fig. 2
Fig. 2
Key pathways in endothelial cell malignancies. Alterations in angiosarcoma (orange stars) include 1. Activating mutations in VEGFR2 (KDR), and amplification of VEGFR3 (FLT4), 2. A recurrent activating R707Q mutation in PLCG1, 3. Loss of function mutations in PTPRB, removing the inhibitory signal on Tie2, 4. Mutations in K-, H-, and N-RAS, BRAF, and MAPK1, and amplification of B- and C- RAF, and MAPK1. 5. Mice with loss of Tsc1 have constitutive activation of mTOR signaling and develop angiosarcoma. 6. C-MYC amplification is associated with radiation or lymphedema-induced angiosarcoma. The KSHV-derived LANA protein stabilizes HEY (6) leading to c-MYC transcription in KS cells, and stabilizes the Notch intracellular domain (NICD) (7), leading to increased Notch-mediated signaling. The HIV-1 protein Tat binds to alpha-5-beta-1 and alpha-v-beta-3 integrin receptors and stimulates migration and invasion. Tat also stimulates the release of preformed, extracellularly bound bFGF into a soluble form that can induce vascular cell growth and prevent apoptosis, and Tat directly interacts with VEGFR2 leading to ligand independent activation of its downstream effectors (8). Expression of the lytic phase KSHV viral G-protein coupled receptor (vGPCR) leads to activation of the MAPK and PI3K/mTOR pathways (9) which ultimately causes HIF-1a-mediated transcription of Notch-related proteins (10). Ang2 angiopoietin2, AKT protein kinase B, b-FGF basic fibroblast growth factor, BMP bone morphogenetic protein, DLL delta-like, ERK1/2 mitogen-activated protein kinase 1/2, FGFR, FAK focal adhesion kinase, FGFR fibroblast growth factor receptor, GRB2 growth factor receptor-bound protein 2, HES hairy enhancer-of-split, HEY hairy and enhancer of split related protein, HIF-1alpha hypoxia inducible factor 1 alpha subunit, LANA latency-associated nuclear antigen, MAML mastermind-like protein, MEK MAPK kinase, mTOR mammalian target of rapamycin, MYC Myc proto-oncogene, PLCG1 phospholipase C-gamma 1, PI3K phosphoinositide 3-kinase, PTPRB receptor-like protein-tyrosine phosphatase (PTP) beta, RBPJ recombinant binding protein suppressor of hairless, S6K P70-S6Kinase 1, TACE ADAM17, Tie2 TEK tyrosine kinase, endothelial, Tsc1 tuberous sclerosis 1, VEGF(R) vascular endothelial growth factor (receptor)
Fig. 3
Fig. 3
Illustration of microenvironment in endothelial malignancies. a Tissue level schematic of angiosarcoma composed of malignant endothelial cells that form non-functional channel like structures. Stromal support cells such as fibroblasts and pericytes, and immune cells such as macrophages, cytotoxic and suppressor T-cells, and non-malignant endothelial cells all interact to promote tumorigenesis and angiogenesis in the microenvironment. b A selection of autocrine and paracrine signaling networks in the microenvironment of endothelial malignancies. Pro-inflammatory cytokine interleukin-6 (IL-6) is secreted by angiosarcoma cells and is dependent on JAK/STAT and IKK-beta signaling. Interferon-gamma (IFN-gamma) is secreted by macrophages and cytotoxic T-cells, which stimulates Kaposi sarcoma (KS) tumor growth. Kaposi sarcoma herpes virus (KSHV) infection in resident fibroblasts stimulates secretion of multiple pro-angiogenic factors. Pericyte coverage is decreased compared to normal endothelium in endothelial malignancies, though the role of pericytes in directly promoting tumor growth is currently debatable. Ang2 angiopoietin2, b-FGF basic fibroblast growth factor, ECM extracellular matrix, FGFR fibroblast growth factor receptor,HIF-1alpha hypoxia inducible factor 1 alpha subunit, JAK tyrosine protein kinase, mTOR mammalian target of rapamycin, MMPs matrix metalloproteinases, MYC Myc proto-oncogene, PD1 programmed cell death protein 1, PDGF(R) platelet-derived growth factor (receptor), PDL1 programmed cell death 1 ligand, sIL6R soluble IL6 receptor, SMA smooth muscle actin, STAT signal transducer and activator of transcription, Tie2 TEK tyrosine kinase, endothelial, VEGF(R) vascular endothelial growth factor (receptor)

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    1. Fury MG, Antonescu CR, Van Zee KJ, Brennan MF, Maki RG. A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy. Cancer J. 2005;11:241–247. doi: 10.1097/00130404-200505000-00011. - DOI - PubMed
    1. Ravi V, Patel S. Vascular sarcomas. Curr. Oncol. Rep. 2013;15:347–355. doi: 10.1007/s11912-013-0328-2. - DOI - PubMed
    1. Antonescu C. Malignant vascular tumors--an update. Mod. Pathol. 2014;27((Suppl 1)):S30–S38. doi: 10.1038/modpathol.2013.176. - DOI - PubMed
    1. Cioffi A, Reichert S, Antonescu CR, Maki RG. Angiosarcomas and other sarcomas of endothelial origin. Hematol. Oncol. Clin. North Am. 2013;27:975–988. doi: 10.1016/j.hoc.2013.07.005. - DOI - PubMed
    1. Young RJ, Brown NJ, Reed MW, Hughes D, Woll PJ. Angiosarcoma. Lancet Oncol. 2010;11:983–991. doi: 10.1016/S1470-2045(10)70023-1. - DOI - PubMed

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