Mechanisms of Tumor-Induced Lymphovascular Niche Formation in Draining Lymph Nodes

Abstract

Summary: Enlargement of the lymphatic vascular network in tumor-draining lymph nodes (LNs) often precedes LN metastasis, likely providing a lymphovascular niche for tumor cells. We investigated morphological and molecular changes associated with the lymphatic remodeling process, using the 4T1 breast cancer and B16F10 melanoma models. Lymphatic expansion in tumor-draining LNs is mediated by sprouting and proliferation of lymphatic endothelial cells (LECs) as early as 4 days after tumor implantation. RNA sequencing revealed an altered transcriptional profile of LECs from tumor-draining compared to naive LNs with similar changes in both tumor models. Integrin αIIb is upregulated in LECs of tumor-draining LNs and mediates LEC adhesion to fibrinogen in vitro. LEC-associated fibrinogen was also detected in LNs in vivo, suggesting a role of integrin αIIb in lymphatic remodeling. Together, our results identify specific responses of LN LECs to tumor stimuli and provide insights into the mechanisms of lymphovascular niche formation in tumor-draining LNs. : Commerford et al. characterize the morphological and molecular changes that occur in lymphatic endothelial cells (LECs) in tumor-draining lymph nodes (LNs) in two distinct tumor models. They show an upregulation of integrin αIIb in LN LECs and find that integrin αIIb mediates LEC adhesion to fibrinogen. Keywords: breast cancer, skin cancer, tumor promotion and progression, cell adhesion, cell matrix interactions, endothelial cell functions, lymph node lymphangiogenesis, gene expression profiling