Colorectal cancer exosomes induce lymphatic network remodeling in lymph nodes

Abstract

The lymphatic network remodeling may guide tumor metastasis in a sentinel lymph node (SLN). Although tumor-derived exosomes have been demonstrated to modify the microenvironment in adjacent organs and initiate a premetastatic niche, their influence on the lymphatic network in SLNs has not been explained. Here, we show that CT26 cell exosomes (Exo) promote the proliferation of lymphatic endothelial cells and the formation of lymphatic network in SLN, facilitating the SLN metastasis of colorectal cancer (CRC). Uptake of Exo by macrophages promoted VEGFC secretion both in vivo and in vitro. Exo increased the frequency of F4/80 + macrophages in the SLN. Macrophage ablation by clodrosome prevented the exosomal effect on lymphatic network remodeling and SLN metastasis. Exosomal IRF-2 was highly expressed in serum exosomes isolated from CRC patients with LN metastasis relative to patients without LN metastasis and healthy controls. Mechanistically, exosomal IRF-2 induced the release of VEGFC by macrophages. An IRF-2 knockdown attenuated the lymphatic network remodeling in the SLN and suppressed the SLN metastasis. Our data suggest that exosomal IRF-2 remodels the lymphatic network in an SLN and may predict the development of CRC LN metastases.

Lymph Node Subcapsular Sinus Microenvironment-On-A-Chip Modeling Shear Flow Relevant to Lymphatic Metastasis and Immune Cell Homing

“…Limitations of this work include the omission of lymphatic flow rates as a considered variable despite it being widely hypothesized that they are substantially changed in disease contexts ( Habenicht et al., 2017 ; Hinson et al., 2017 ; Ji, 2017 ; Otto et al., 2014 ; Stacker et al., 2014 ; Sun et al., 2019 ). Given that the dependencies of WSS on SCS height and volumetric flow rate are first versus second order, respectively, we focused instead on how small changes with respect to SCS height could influence cell interactions within the SCS under the influence of fluid flow.…”

Exosomes and Their Role in Cancer Progression

“…45 In the same year, Sun et al reported that colon cancer-cell derived exosomes containing IRF-2 are taken up by the macrophages and induce VEGFC production, which then promotes lymph node metastasis through lymphatic endothelial cell proliferation and lymphatic vessel remodeling. 46…”

A Snapshot of The Tumor Microenvironment in Colorectal Cancer: The Liquid Biopsy

“…Furthermore, tumor cell dissemination is guided by the lymphatic network. IRF-2 in exosomes derived from colon cancer lines promotes the proliferation of lymphatic endothelial cells and the formation of the lymphatic network in the sentinel lymph node, increasing the frequency of F4/80+ macrophages and promoting Vascular Endothelial Growth Factor C (VEGFC) secretion [63]. Similarly, miR-221-3p, CXCR4 or podopladin have been related to lymphangiogenesis in other tumors [100,101,102].…”

“…Dotted line represents separation between primary tumor and distal metastasis. References are shown in brackets [38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63]. Created with BioRender.com.…”