Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, B-CELL-LYMPHOMA, TUMOR-GROWTH, NODE, LYMPHOTOXIN, LYMPHANGIOGENESIS, BEVACIZUMAB, RITUXIMAB, BEHAVIOR, STROMA, NICHE, Animals, Biopsy, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, Gene Expression Profiling, Human Umbilical Vein Endothelial Cells, Humans, Indoles, Lymph Nodes, Lymphoma, Lymphotoxin beta Receptor, Lymphotoxin-alpha, Mice, Mice, Transgenic, Naphthalenes, Naphthyridines, Neovascularization, Pathologic, Signal Transduction, Tumor Microenvironment, Vascular Endothelial Growth Factor C, Vascular Endothelial Growth Factor Receptor-3, Xenograft Model Antitumor Assays, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3101 Biochemistry and cell biology, 3211 Oncology and carcinogenesis

Abstract:

Tumor-induced remodeling of the microenvironment relies on the formation of blood vessels, which go beyond the regulation of metabolism, shaping a maladapted survival niche for tumor cells. In high-grade B-cell lymphoma, angiogenesis correlates with poor prognosis, but attempts to target established proangiogenic pathways within the vascular niche have been inefficient. Here, we analyzed Myc-driven B-cell lymphoma-induced angiogenesis in mice. A few lymphoma cells were sufficient to activate the angiogenic switch in lymph nodes. A unique morphology of dense microvessels emerged without obvious tip cell guidance and reliance on blood endothelial cell (BEC) proliferation. The transcriptional response of BECs was inflammation independent. Conventional HIF1α or Notch signaling routes prevalent in solid tumors were not activated. Instead, a nonconventional hypersprouting morphology was orchestrated by lymphoma-provided VEGFC and lymphotoxin (LT). Interference with VEGF receptor-3 and LTβ receptor signaling pathways abrogated lymphoma angiogenesis, thus revealing targets to block lymphomagenesis. SIGNIFICANCE: In lymphoma, transcriptomes and morphogenic patterns of the vasculature are distinct from processes in inflammation and solid tumors. Instead, LTβR and VEGFR3 signaling gain leading roles and are targets for lymphomagenesis blockade.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/80/6/1316/F1.large.jpg.