TY - JOUR
T1 - VEGF-C propagates ‘onward’ colorectal cancer metastasis from liver to lung
T2 - Cellular and Molecular Biology
AU - Poghosyan, Susanna
AU - Frenkel, Nicola
AU - van den Bent, Lotte
AU - Raats, Danielle
AU - Spaapen, Tessa
AU - Laoukili, Jamila
AU - Borel Rinkes, Inne
AU - Kranenburg, Onno
AU - Hagendoorn, Jeroen
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2025/1
Y1 - 2025/1
N2 - Background: The formation of lung metastasis as part of the progression of colon cancer is a poorly understood process. Theoretically, liver metastases could seed lung metastases. Methods: To assess the contribution of the liver lymphatic vasculature to metastatic spread to the lungs, we generated murine liver-metastasis-derived organoids overexpressing vascular endothelial growth factor (VEGF)-C. The organoids were reimplanted into the mouse liver for tumour generation and onward metastasis. Results: Liver metastases from patients with concomitant lung metastases showed higher expression of VEGF-C, lymphatic vessel hyperplasia, and tumour cell invasion into lymphatic vessels when compared to those without lung metastases. Reimplantation of VEGF-C overexpressing organoids into the mouse liver showed that VEGF-C caused peritumoral lymphatic vessel hyperplasia, lymphatic tumour cell invasion, and lung metastasis formation. This change in metastatic organotropism was accompanied by reduced expression of WNT-driven adult stem cell markers, and increased expression of fetal stem cell markers and NOTCH pathway genes. Further NOTCH pathway inhibition with γ-secretase inhibitor (DAPT) in vivo results in a slight reduction in lung metastases and a decrease in lymphatic hyperplasia and invasion in VEGF-C-overexpressing tumours. Conclusion: Collectively, these data indicate that VEGF-C can drive onward metastasis from the liver to the lung and suggest that targeting VEGF-C/NOTCH pathways may impair the progression of colorectal cancer.
AB - Background: The formation of lung metastasis as part of the progression of colon cancer is a poorly understood process. Theoretically, liver metastases could seed lung metastases. Methods: To assess the contribution of the liver lymphatic vasculature to metastatic spread to the lungs, we generated murine liver-metastasis-derived organoids overexpressing vascular endothelial growth factor (VEGF)-C. The organoids were reimplanted into the mouse liver for tumour generation and onward metastasis. Results: Liver metastases from patients with concomitant lung metastases showed higher expression of VEGF-C, lymphatic vessel hyperplasia, and tumour cell invasion into lymphatic vessels when compared to those without lung metastases. Reimplantation of VEGF-C overexpressing organoids into the mouse liver showed that VEGF-C caused peritumoral lymphatic vessel hyperplasia, lymphatic tumour cell invasion, and lung metastasis formation. This change in metastatic organotropism was accompanied by reduced expression of WNT-driven adult stem cell markers, and increased expression of fetal stem cell markers and NOTCH pathway genes. Further NOTCH pathway inhibition with γ-secretase inhibitor (DAPT) in vivo results in a slight reduction in lung metastases and a decrease in lymphatic hyperplasia and invasion in VEGF-C-overexpressing tumours. Conclusion: Collectively, these data indicate that VEGF-C can drive onward metastasis from the liver to the lung and suggest that targeting VEGF-C/NOTCH pathways may impair the progression of colorectal cancer.
UR - http://www.scopus.com/inward/record.url?scp=85208791707&partnerID=8YFLogxK
U2 - 10.1038/s41416-024-02892-4
DO - 10.1038/s41416-024-02892-4
M3 - Article
C2 - 39521880
AN - SCOPUS:85208791707
SN - 0007-0920
VL - 132
SP - 69
EP - 80
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 1
M1 - 810
ER -