Abstract 88: Metastatic lymph nodes can serve as a source of systemic metastasis
Authors: Takeda Kazu , Mori Shiro , Kodama Tetsuya 
Published: August 2018

Abstract
Cancer metastasis is a major cause of death in cancer patients and metastatic lymph nodes (MLN) are associated with poor prognosis. In the field of breast cancer research, the role of MLN has been discussed for nearly a hundred years. Halsted formulated “Halsted theory”, whereby breast cancer spread through the lymphatic system first to nearby lymph nodes and subsequently to other organs in the body. An alternative hypothesis, “Systemic theory” was put forward by Fisher who believed that breast cancer was a systemic disease, with tumors having the ability to spread to distant sites from the primary locus. Thu, MLN can hardly be the source of systemic metastasis. However, the actual role of MLN in routing cancer cells to distant organs remains incompletely characterized because of inadequate investigations in animal experiments. In the present study, we show that MLN can be the source of systemic metastasis using MXH10/Mo-lpr/lpr (MXH10/Mo/lpr) mice, which develop systemic swelling of lymph nodes up to 10 mm in diameter. Previously we developed a MLN model using MXH10/Mo/lpr by injection of tumor cells into its LN directory. In the present study, we first investigated the venous/lymphatic system around the subiliac LN (SiLN) where SiLN is one of the superficial LNs in the MXH10/Mo/lpr and the proper axially LN is the downstream LN of SiLN. The thoracoepigastric vein (TEV) runs along the lymphatic vessels between the SiLN and the PALN and connects to the inferior vena cava and subclavian vein via the SiLN and PALN. After intravenous injection of fluorescence liposomes, we demonstrated that intranodal venulas perforated the capsule of the SiLNs and anastomosed with the TEV. Next, we investigated the flow dynamics of a fluorescent solution that was injected into the SiLNs. We found that the fluorescent solution flowed into the efferent lymphatic vessels as well as the TEV. Moreover, the MLN model showed different flow dynamics compared to the control LN. Fluorescent solution tended to flow into the blood circulation more than the efferent lymphatic vessel. This finding suggested that the vasculature and lymphatic systems have a connection with the LN under specific mechanistic conditions, such as elevation of intranodal pressure by injection. This mechanical force could have facilitated the fluorescent solution to flow into the efferent lymphatic vessel along with the development of a connection between the two circulation systems in the LN. We previously reported that intranodal pressure increases in MLN during tumor cell proliferation and circulatory connection can be developed in the MLN. Therefore, tumor cells metastasized into the LN can route their metastatic pathways to the hematogenous system. Thus, the MLN has the potential to be a direct source of systemic metastasis. We anticipate that our results will facilitate the study of the progression of systemic metastasis via the MLN.
Citation Format: Kazu Takeda, Shiro Mori, Tetsuya Kodama. Metastatic lymph nodes can serve as a source of systemic metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 88.