AI Article Synopsis
- The study investigates how liver metastases contribute to the spread of colon cancer to the lungs, focusing on the role of VEGF-C.
- Researchers created organoids that overexpress VEGF-C and reimplanted them into mice, finding that this led to increased lymphatic vessel growth and lung metastasis.
- The findings suggest that targeting the VEGF-C and NOTCH pathways could potentially hinder the progression of colorectal cancer by limiting metastasis.
Article Abstract
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.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724081 | PMC |
| http://dx.doi.org/10.1038/s41416-024-02892-4 | DOI Listing |
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