Lymphoma angiogenesis is orchestrated by noncanonical signaling pathways


  • M. Gloger
  • L. Menzel
  • M. Grau
  • A.C. Vion
  • I. Anagnostopoulos
  • M. Zapukhlyak
  • K. Gerlach
  • T. Kammertöns
  • T. Hehlgans
  • M. Zschummel
  • G. Lenz
  • H. Gerhardt
  • U.E. Höpken
  • A. Rehm


  • Cancer Research


  • Cancer Res 80 (6): 1316-1329


  • 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 pro-angiogenic 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 reliant on blood endothelial cell (BEC) proliferation. The transcriptional response of BECs was inflammation-independent. Conventional HIF-1α or Notch signaling routes prevalent in solid tumors were not activated. Instead, a nonconventional hypersprouting morphology was orchestrated by lymphoma-provided vascular endothelial growth factor (VEGF)-C and lymphotoxin (LT). Interference with VEGF receptor-3 and LTβ receptor signaling pathways abrogated lymphoma angiogenesis, thus revealing targets to block lymphomagenesis.