Mechanisms of lymphatic metastasis

Abstract

Malignant tumors release growth factors such as VEGF-C to induce lymphatic vessel expansion (lymphangiogenesis) in primary tumors and in draining sentinel LNs, thereby promoting LN metastasis. Surprising recent evidence suggests that lymphatic vessels do not merely represent passive channels for tumor spread, but that they may actively promote tumor cell recruitment to LNs, cancer stem cell survival, and immune modulation. New imaging approaches allow the sensitive visualization of the earliest LN metastases and the quantitative, noninvasive measurement of the function of tumor-draining lymphatic vessels, with potential applications in the development of biomarkers for prognosis and measurement of therapeutic response.

Figure 1. An important contribution of tumor and LN lymphangiogenesis to cancer metastasis.

(A) Normal lymphatic tissue drainage through lymphatic capillaries, collecting lymphatics, and LNs. (B) Lymphangiogenic factors produced by premetastatic tumors, including VEGF-C, VEGF-D, VEGF-A, and HGF, are taken up by peritumoral lymphatic capillaries and are transported via the collecting lymphatics toward the tumor-draining SLN, where they act directly on preexisting lymphatic vessels to induce LN lymphangiogenesis. Tumor-draining lymphatic vessels display an enlarged size and increased lymph flow and pulsing. (C) Once metastatic tumor cells have spread to their draining LNs, they serve as a major source of lymphangiogenic factors. These promote the remodeling and SMC rearrangement of distant (post-SLN) lymphatic vessels and lymphangiogenesis in distant LNs and promote secondary metastasis, including organ metastasis, via the thoracic duct, which connects to the venous circulation via the subclavian vein. CSC, cancer stem cell. The chemokines CCL21 and CXCL12, released by activated lymphatic endothelial cells (LECs) within SLNs, might provide a niche for cancer cells with stem cell–like properties that express the receptors CCR7 and CXCR4.

Figure 2. SLN metastases can impair lymphatic drainage and lead to rerouting of lymphatic flow.

(A) After peritumoral injection around the primary tumor, the lymphatic tracer is taken up by lymphatic capillaries and is transported via collecting lymphatics to the draining SLN, which may contain metastasized tumor cells (positive SLN) or not (negative SLN). (B) Larger metastases within the SLN can obstruct the lymphatic drainage, leading to rerouting of lymph flow toward another LN that may be metastasis free and therefore may represent a false-negative SLN, leading to incorrect cancer staging. (C) At later stages, this LN may also contain metastatic tumor cells (positive SLN).