Lymphangiogenic gene expression is correlated with worse prognosis and consensus molecular subtype-4 in both primary and liver metastatic CRC. VEGFC and Nrp-2 expression may be predictive of lymph node involvement in recurrence after resection of CRLM. Nrp-2, expressed on both tumor and LECs, may have a mechanistic role in lymphatic invasion and is a potential novel target in CRC.
The lymphatic system is essential
in maintaining tissue fluid homeostasis
as well as antigen and immune cell transport to lymph nodes. Moreover,
lymphatic vasculature plays an important role in various pathological
processes, such as cancer. Fundamental to this research field are
representative in vitro models. Here we present a microfluidic lymphatic
vessel model to study lymphangiogenesis and its interaction with colon
cancer organoids using a newly developed lymphatic endothelial cell
(LEC) line. We generated immortalized human LECs by lentiviral transduction
of human telomerase (hTERT) and BMI-1 expression cassettes into primary
LECs. Immortalized LECs showed an increased growth potential, reduced
senescence, and elongated lifespan with maintenance of typical LEC
morphology and marker expression for over 12 months while remaining
nontransformed. Immortalized LECs were introduced in a microfluidic
chip, comprising a free-standing extracellular matrix, where they
formed a perfusable vessel-like structure against the extracellular
matrix. A gradient of lymphangiogenic factors over the extracellular
matrix gel induced the formation of luminated sprouts. Adding mouse
colon cancer organoids adjacent to the lymphatic vessel resulted in
a stable long-lived coculture model in which cancer cell-induced lymphangiogenesis
and cancer cell motility can be investigated. Thus, the development
of a stable immortalized lymphatic endothelial cell line in a membrane-free,
perfused microfluidic chip yields a highly standardized lymphangiogenesis
and lymphatic vessel–tumor cell coculture assay.
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