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.

中文翻译：

---

淋巴瘤的血管生成是由非规范性的信号传导途径精心策划的。

肿瘤引起的微环境重塑依赖于血管的形成，而血管的形成超出了代谢的调节范围，从而形成了肿瘤细胞适应不良的生存环境。在高级B细胞淋巴瘤中，血管生成与不良预后相关，但是针对血管利基内已建立的促血管生成途径的尝试一直无效。在这里，我们分析了小鼠Myc驱动的B细胞淋巴瘤诱导的血管生成。一些淋巴瘤细胞足以激活淋巴结中的血管生成开关。出现了密集的微血管的独特形态，没有明显的尖端细胞引导，并且不依赖于血液内皮细胞（BEC）增殖。BEC的转录反应与炎症无关。在实体瘤中普遍存在的常规HIF-1α或Notch信号传导途径未激活。代替，淋巴瘤提供的血管内皮生长因子（VEGF）-C和淋巴毒素（LT）编排了非常规的过度萌发形态。干扰VEGF受体3和LTβ受体的信号传导途径可消除淋巴瘤的血管生成，从而揭示了阻断淋巴瘤发生的靶标。