Abstract
Therapies targeting tumor vasculature would improve the treatment of lung metastasis, although the early changes in vascular structure are incompletely understood. Here, we show that obstructive metastatic foci in lung arterioles decrease the pulmonary vascular network. To generate a mouse model of lung metastasis activation, luciferase-expressing tumor cells were inoculated into the subiliac lymph node (SiLN) of an MXH10/Mo-lpr/lpr mouse, and metastatic tumor cells in the lungs were activated by SiLN resection. Activation of metastases was monitored by in vivo bioluminescence imaging. Pulmonary blood vessel characteristics were analyzed using ex vivo micro-computed tomography. The enhanced permeability and retention (EPR) effect in neovasculature after tumor cell activation was evaluated from the accumulation of intravenously injected indocyanine green (ICG) liposomes. Metastatic foci in lung arterioles were investigated histologically. Micro-computed tomography revealed decreases in pulmonary blood vessel length, volume and number of branching nodes during the early stage of metastasis caused by metastatic foci. ICG liposome accumulation by the EPR effect was not detected. Histology identified metastatic foci in lung arterioles. The lack of an EPR effect after the formation of metastatic foci in lung arterioles makes conventional systemic chemotherapy ineffective for lung metastasis. Thus, alternative therapeutic methods of drug delivery are needed.
Highlights
Therapies targeting tumor vasculature would improve the treatment of lung metastasis, the early changes in vascular structure are incompletely understood
Pulmonary blood vessel density was markedly lower in mice in which the subiliac lymph node (SiLN) was inoculated with tumor cells and resected (Fig. 1J,L) but higher in mice in which the inoculated SiLN was not resected (Fig. 1I,K)
We described the pathomorphology of lung metastasis in a mouse model in which tumor cells in the lung were activated by the resection of a tumor-bearing SiLN
Summary
Therapies targeting tumor vasculature would improve the treatment of lung metastasis, the early changes in vascular structure are incompletely understood. Micro-computed tomography revealed decreases in pulmonary blood vessel length, volume and number of branching nodes during the early stage of metastasis caused by metastatic foci. The lack of an EPR effect after the formation of metastatic foci in lung arterioles makes conventional systemic chemotherapy ineffective for lung metastasis. Our research group has established a mouse model of lung metastasis using MXH10/Mo-lpr/lpr (MXH10/ Mo/lpr) mice[13,14,15], which involves the inoculation of tumor cells into a subiliac lymph node (SiLN) followed by resection of the tumor-containing SiLN at different time intervals[16,17,18,19]. The process of activation of tumor cells in the lung may not be related to neoangiogenesis
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