Can metastatic lymph nodes be the starting point of systemic metastasis?

A simple confirmation experiment is to inject a fluorescent dye into a lymph node and watch its route of flow[1].

The fluorescent dye is injected into the subiliac lymph node (SLN) of a MHX10/Mo-lpr/lpr mouse.

After flowing out from the efferent lymphatic vessel, the fluorescent dye escapes from veins running through the surface layer of the SLN.

This flow of fluorescent dye suggests invasion of tumor cells into the blood circulation of the lymph node itself and their metastasis to distant organs via the bloodstream.

We have proposed the lymph node-mediated hematogenous metastasis theory, in which tumor cells originate from sentinel lymph nodes and metastasize to distant organs[1-3].

Based on this theory, treatment of lymph nodes at the early stage of metastasis will prevent cancer cells from spreading to distant organs.

Lymphatic drug delivery is a novel therapeutic method developed based on the above theory[4-7].

References
[1] K. Takeda, S. Mori, T. Kodama, Study of fluid dynamics reveals direct communications between lymphatic vessels and venous blood vessels at lymph nodes of mice, Journal of immunological methods, 445 (2017) 1-9.
[2] L. Shao, K. Takeda, S. Kato, S. Mori, T. Kodama, Communication between lymphatic and venous systems in mice, Journal of immunological methods, 424 (2015) 100-105.
[3] T. Kodama, S. Mori, M. Nose, Tumor cell invasion from the marginal sinus into extranodal veins during early-stage lymph node metastasis can be a starting point for hematogenous metastasis, Journal of Cancer Metastasis and Treatment, 4 (2018) 56.
[4] A. Tada, S. Horie, S. Mori, T. Kodama, Therapeutic effect of cisplatin given with a lymphatic drug delivery system on false-negative metastatic lymph nodes, Cancer science, 108 (2017) 2115-2121.
[5] T. Kodama, D. Matsuki, A. Tada, K. Takeda, S. Mori, New concept for the prevention and treatment of metastatic lymph nodes using chemotherapy administered via the lymphatic network, Scientific reports, 6 (2016) 32506.
[6] R. Fukumura, A. Sukhbaatar, R. Mishura, M. Sakamoto, S. Mori, T. Kodama, Study of the physicochemical properties of drugs suitable for administration using a lymphatic drug delivery system, Cancer science, (2021).
[7] H. Fujii, S. Horie, A. Sukhbaatar, R. Mishra, M. Sakamoto, S. Mori, T. Kodama, Treatment of false-negative metastatic lymph nodes by a lymphatic drug delivery system with 5-fluorouracil, Cancer Med, 8 (2019) 2241-2251.