Transcriptional profiling of breast cancer‐associated lymphatic vessels reveals VCAM‐1 as regulator of lymphatic invasion and permeability

Abstract

Tumor‐associated lymphangiogenesis and lymphatic invasion of tumor cells correlate with poor outcome in many tumor types, including breast cancer. Various explanations for this correlation have been suggested in the past, including the promotion of lymphatic metastasis and an immune‐inhibitory function of lymphatic endothelial cells (LECs). However, the molecular features of tumor‐associated lymphatic vessels and their implications for tumor progression have been poorly characterized. Here, we report the first transcriptional analysis of tumor‐associated LECs directly isolated from the primary tumor in an orthotopic mouse model of triple negative breast cancer (4T1). Gene expression analysis showed a strong upregulation of inflammation‐associated genes, including endothelial adhesion molecules such as VCAM‐1, in comparison to LECs derived from control tissue. In vitro experiments demonstrated that VCAM‐1 is not involved in the adhesion of tumor cells to LECs but unexpectedly promoted lymphatic permeability by weakening of lymphatic junctions, most likely through a mechanism triggered by interactions with integrin α4 which was also induced in tumor‐associated LECs. In line with this, in vivo blockade of VCAM‐1 reduced lymphatic invasion of 4T1 cells. Taken together, our findings suggest that disruption of lymphatic junctions and increased permeability via tumor‐induced lymphatic VCAM‐1 expression may represent a new target to block lymphatic invasion and metastasis.

Tumor exposed-lymphatic endothelial cells promote primary tumor growth via IL6

“…It is likely that a cocktail of tumor-derived factors is involved in IL6 stimulation. The modulation of pro-inflammatory cytokine secretion observed in teLEC is in line with a recent study reporting a strong inflammatory gene expression signature in LEC isolated from murine mammary 4T1 tumors [ 21 ]. IL6 is released by various cells in the TME including cancer-associated fibroblasts (CAF).…”

“…These data are in line with the morphological changes (weakened intercellular junctions) observed in LEC monolayer exposed to the HaCaT cell series used here. The modulation of cell adhesion molecules in LEC exposed to tumor cells such as ICAM-1 [ 46 , 47 ] and VCAM-1 [ 21 ] can also contribute to tumor cell intravasation [ 21 , 48 ] ( Fig. 6 ).…”

“…Accordingly, we found enhanced ICAM-1 production in teLEC. The increased expression of VCAM-1 in cancer-associated lymphatic vessels has been recently reported to promote lymphatic permeability by weakening lymphatic junctions [ 21 , 49 ]. In addition to those effects on tumor cell intravasation into lymphatics, LEC have attracted substantial attention in their capacity to modulate the immune response [ 16 , 50 , 51 ] ( Fig.…”

“…LEC appear increasingly as a heterogeneous cell population in terms of molecular and structural features, which display adaptive capacities [ 19 , 20 ]. The implication of LEC plasticity in the TME and how it could be involved during cancer progression and metastatic dissemination remains poorly documented [ 21 , 22 ]. In primary tumors, peritumoral LV are often enlarged and considered as the major route for dissemination.…”

Parallels of Resistance between Angiogenesis and Lymphangiogenesis Inhibition in Cancer Therapy

“…Few studies have sought to reverse lymphatic vessel permeability in vivo. Vascular cell adhesion molecule 1 (VCAM-1) is upregulated on LECs by tumor inflammation and was shown to regulate lymphatic vessel permeability [81]. Blocking VCAM-1 in vitro and in vivo reduced tumor-mediated lymphatic permeability and lymphatic invasion, suggesting reducing tumor-induced lymphatic vessel permeability may be a feasible approach to regulate lymphatic metastasis.…”