Progression of Metastasis through Lymphatic System

Abstract

Lymph nodes are the most common sites of metastasis in cancer patients. Nodal disease status provides great prognostic power, but how lymph node metastases should be treated is under debate. Thus, it is important to understand the mechanisms by which lymph node metastases progress and how they can be targeted to provide therapeutic benefits. In this review, we focus on delineating the process of cancer cell migration to and through lymphatic vessels, survival in draining lymph nodes and further spread to other distant organs. In addition, emerging molecular targets and potential strategies to inhibit lymph node metastasis are discussed.

Keywords: anti-tumor immunity; lymph node; lymphatic vessel; metastasis.

Figure 1

Cancer cells migrate and invade lymphatic vessels. (Left) Primary tumor cancer cells release VEGF A/C to promote local lymphangiogenesis. Cancer cells also undergo EMT to increase their invasiveness. In addition, they can upregulate CCR7/8 and CXCR4/5 expression, enabling their responsiveness to the corresponding ligands, CCL1/19/21 and CXCL10/12, respectively. (Right) In response to these stimuli, cancer cells migrate to lymphatic vessels through chemotaxis. Some cancer cells express ALOX15, which catalyzes arachidonic acid to 12[S]-HETE and 15[S]-HETE. Accumulation of these metabolites causes circular defects on lymphatic endothelium, facilitating cancer cell entrance. Of note, interstitial fluid flow not only mechanically contributes to cancer cell migration to lymphatic vessels but also assists cancer cells to produce and follow autocrine chemokine gradients to lymphatic vessels.

Figure 2

Cancer cells survive in lymph nodes and spread to other organs. (Left) To adapt to the lipid-rich environment in lymph nodes, cancer cells enhance their reliance on fatty acid metabolism by upregulating CD36 and FABP5. In addition, to avoid immune destruction, cancer cells increase expression of the immunosuppressive checkpoint molecule PD-L1, while decreasing MHC I/II expression. (Middle) Midkine and VEGF-C secreted by cancer cells induce lymphangiogenesis in draining lymph nodes prior to seeding, generating a pre-metastatic niche. Similarly, cancer cells also release extracellular vesicles to interact with B cells in the cortex, promoting lymph node metastasis. Although the lymph node is filled with various immune cell populations, the microenvironment is immunosuppressive. Tolerogenic DCs, M2-like TAMs, and CD15+ TANs were enriched in metastatic lymph nodes. These cells contribute to inhibition of cytotoxic T cells. The lytic activity of NK cells is also reduced in metastatic lymph nodes. (Right) After surviving in the lymph node, cancer cells can invade the lymph node blood vasculature and further spread to distant organs. Cancer cells can also exit through the efferent lymphatic vessel.