Cancer metastasis through the lymphatic versus blood vessels

Abstract

Whether cancer cells metastasize from the primary site to the distant sites via the lymphatic vessels or the blood vessels directly into the circulation is still under intense study. In this review article, we follow the journey of cancer cells metastasizing to the sentinel lymph nodes and beyond to the distant sites. We emphasize cancer heterogeneity and microenvironment as major determinants of cancer metastasis. Multiple molecules have been found to be associated with the complicated process of metastasis. Based on the large sentinel lymph node data, it is reasonable to conclude that cancer cells may metastasize through the blood vessels in some cases but in most cases, they use the sentinel lymph nodes as the major gateway to enter the circulation to distant sites.

Keywords: Cancer metastasis; Lymphatic and blood vessels.

Fig. 1

Tumor Microenvironment and lymphatic sytemomics. Points of interplay between the developing cancer and ongoing processes within the interstitium and lymphatic system; lymphedema, lymphangiogensis, tumor-generated immune response. Potential sites of epi/endothelial-mesenchymal transition (EMT) and the reverse process (MET) in development/regeneration and neoplasia (green) are identified. These complex structural-functional interactions participate in the pathogenesis, clinical manifestations, evaluation, and prognosis as well as the treatment of cancer. Permission has been obtained from the following article: Witte, M et al. (2012) Clin Exp Mets 29: 707–712

Fig. 2

The metastatic process involves several critical steps where cancer cells leave the primary site, breach the nearby tissue, and gain entry into adjacent blood or lymphatic vessels—a phase known as intravasation. In this figure, a blood vessel is depicted. Once these cancer cells infiltrate the vascular system, their ability to halt and cling to the inner lining of the blood vessels becomes crucial, setting the stage for their subsequent exit from the bloodstream. A portion of these cells successfully bind to the walls of blood vessels and manage to move out of the bloodstream and into the surrounding tissue. In this new location, they have the potential to initiate secondary metastatic growths. For circulating cancer cells to transition in and out of the bloodstream and navigate through it, they must attach themselves to the inner surface of the blood vessel and maneuver through the endothelial wall cells. Reproduced with permission. Vasilaki D, Bakopoulou A, Tsouknidas A, Johnstone E, Michalakis K (2021) Biophysical interactions between components of the tumor microenvironment promote metastasis. Biophys Rev 13 (3):339–357. 10.1007/s12551-021-00811-y

Fig. 3

The capillary junction shows the connection between the arteriole and venule. The diameter of the capillary is about 8–10 microns. The capillary vessel consists of a single layer of flattened endothelial cells. The diameter of the post-capillary venule is about 30 micrometers, large enough for cancer cells with an average diameter up to 20 micrometers to squeeze through the post-capillary venule. The lymphatic capillary is slightly larger with a diameter varying from 10 to 80 microns. It consists of a single layer of lymphatic endothelial cells with valves to allow the flow of lymph in one direction. See Fig. 4. Reprinted with permission from Justin Seibert of Seibert Science. Science S (2024) Lymphatic System. https://youtu.be/X2hHK1BHV2E?si=ywPqXIZorj3sZj_u

Fig. 4

Movement of lymph from blood to lymphatic capillaries with valves to alllow lymph to flow only in one direction. Lymph leaves blood capillaries under osmotic pressure (white arrows). In the right lower diagram, lymph enters lymphatic capillaries under negative pressure (black arrows) and travels to the lymph nodes via the afferent lymphatic vessels and exits through the efferent lymphatic vessels. Reprinted with permission from Tactile Medical. On a daily basis, 17 liters of the 20 liters of blood at the arterio-venous capillary junctions return through the venous capillary circulatory system. About 3 liters of fluid, without the cellular components of blood, escape into the extracellular space and drain into the lymphatic vessels. This fluid, known as lymph, carries cellular debris, protein macromolecules, excess water, and toxins. Lymphedema occurs when the extracellular fluid is not adequately drained. The lymph fluid is filtered through multiple lymph nodes (about 600 in a normal person) before it finally drains into the thoracic duct on the left neck and into the subclavian vein and into the jugular vein on the right neck where it re-enters the vascular system as sterile lymph fluid (https://www.youtube.com/watch?v=I7orwMgTQ5I)

Fig. 5

Dichotomy of routes of cancer metastasis: one through the lymphatic vessels to the sentinel lymph nodes as the primary gateway and the other through the blood vessels directly to the distant sites. Permission has been obtained to reproduce this figure from Springer Nature from the cover image for the Special Issue of Clinical and Experimental Metastasis, Springer Nature, Volume 35, Number 5–6, 2018

Fig. 6

Establishment of the lymph node (LN) pre-metastatic niche. Tumor-derived factors, including vascular endothelial growth factor (VEGF-A, VEGF-C and VEGF-D), extracellular vesicles, TGF-β and lysyl oxidase (LOX), induce an immunosuppressive microenvironment by recruiting macrophages, myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Proliferation of lymphatic endothelial cells (LECs) and fibroblastic reticular cells (FRCs) drives the production of LN factors such as chemokines (CCL19; CCL21; CXCL1, 2, 5, 8, and 12); TGF-β; matrix metalloproteinases (MMPs); indoleamine-2,3-dioxygenase (IDO); and nitric oxide (NO), which induce high endothelial venule (HEV) remodeling, stimulate lymphangiogenesis, and regulate tumor cells chemoattraction at metastatic stage. Permission to use this figure from Cellular and Molecular Life Sciences, Gillot et al., 2021, falls under Creative Commons CC BY 4.0. Gillot L, Baudin L, Rouaud L, Kridelka F, Noel A (2021) The pre-metastatic niche in lymph nodes: formation and characteristics. Cell Mol Life Sci 78 (16):5987–6002. 10.1007/s00018-021-03873-z