Use of a Lymphatic Drug Delivery System and Sonoporation to Target Malignant Metastatic Breast Cancer Cells Proliferating in the Marginal Sinuses

Shigeki Kato,Shiro Mori,Maya Sakamoto,Tetsuya Kodama,Yuko Shirai

doi:10.1038/s41598-019-49386-5

Shigeki Kato, Shiro Mori + Show 3 more

Open Access

https://doi.org/10.1038/s41598-019-49386-5

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Abstract

Lymph node (LN) metastasis through the lymphatic network is a major route for cancer dissemination. Tumor cells reach the marginal sinuses of LNs via afferent lymphatic vessels (LVs) and form metastatic lesions that lead to distant metastasis. Thus, targeting of metastatic cells in the marginal sinuses could improve cancer treatment outcomes. Here, we investigated whether lymphatic administration of a drug combined with sonoporation could be used to treat a LN containing proliferating murine FM3A breast cancer cells, which are highly invasive, in its marginal sinus. First, we used contrast-enhanced high-frequency ultrasound and histopathology to analyze the structure of LVs in MXH10/Mo-lpr/lpr mice, which exhibit systemic lymphadenopathy. We found that contrast agent injected into the subiliac LN flowed into the marginal sinus of the proper axillary LN (PALN) and reached the cortex. Next, we examined the anti-tumor effects of our proposed technique. We found that a strong anti-tumor effect was achieved by lymphatic administration of doxorubicin and sonoporation. Furthermore, our proposed method prevented tumor cells in the marginal sinus from invading the parenchyma of the PALN and resulted in tumor necrosis. We conclude that lymphatic administration of a drug combined with sonoporation could exert a curative effect in LNs containing metastatic cells in their marginal sinuses.

Highlights

When the ALs passed through the field of view, increasing echogenicity was detected in the lymphatic vessels (LVs) but not in the thoracoepigastric vein (TEV)
We report that lymphatic drug administration combined with sonoporation resulted in enhanced anti-tumor effects against breast cancer cells proliferating in the marginal sinus of the proper axillary LN (PALN)
Selective lymphatic administration was achieved by the injection of a solution into one of the swollen Lymph node (LN) of the MXH10/Mo/lpr mouse, which is a unique animal model system (Fig. 1A, B)

Summary

Introduction

In our previous research evaluating the effects of lymphatic drug delivery and sonoporation, the mouse model of LN metastasis was generated using KM-Luc/GFP cells, which have low invasive growth characteristics and form tumor regions with well-defined borders in or near the marginal sinuses. No previous study has evaluated whether this treatment strategy would be effective against highly invasive tumor cells that show a tendency to proliferate along the marginal and lymphatic sinuses of metastatic LNs. no previous study has evaluated whether this treatment strategy would be effective against highly invasive tumor cells that show a tendency to proliferate along the marginal and lymphatic sinuses of metastatic LNs To this end, the main aim of the present study was to demonstrate that lymphatic drug administration combined with sonoporation could be an effective therapy for invasive tumor cells in the marginal sinuses of LNs. a tumor-bearing LN model was developed in MXH10/Mo/lpr mice using a murine breast cancer cell line (FM3A-Luc cells) stably expressing the luciferase firefly gene. We investigated the anti-tumor effects of lymphatic drug administration combined with sonoporation against intranodal tumor cells, which had grown and proliferated in the marginal sinuses

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