M. Brown1,2, F. P. Assen2, A. Leithner2, J. Abe3, H. Schachner1, G. Asfour1, Z. Horvath1, J.V. Stein3, P. Uhrin4, M. Sixt2, D. Kerjaschki1
1 Clinical Institiute of Pathology, Medical University of Vienna, 1090 Vienna, Austria;
2 Institute of Science and Technology (IST Austria), 3400 Klosterneuburg, Austria;
3 Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
4 Institute for Vascular Biology, Medical University of Vienna, 1090 Vienna, Austria
Abstract
Death of cancer patients is caused by metastases in lung, brain and other organs remote from the primary tumor site. Initially, mammary carcinoma colonize draining sentinel lymph nodes before they seed distant organ metastases and it is debated whether tumor subclones with metastatic potential enter the blood stream via lymph nodes and/or vessels within the primary tumor. Here we have established a novel mouse model to determine the ability of tumors to disseminate via the draining lymph node. Recapitulating the route of tumor cells into human sentinel lymph nodes, mammary carcinoma cells were micro-infused into the afferent lymphatic vessels of popliteal lymph nodes, which directly guided them into the subcapsular sinus. Within 3 days tumor cells had infiltrated the paracortex, attached to and intravasated into blood vessels and seeded lung metastases without the involvement of the thoracic duct. Remarkably, the lymph node stroma was exceedingly more efficient in seeding distant metastasis than the orthotopic environment of the mammary fat pad, implying a central role in the process of systemic tumor cell dissemination.