Lymph Nodes and Cancer Metastasis: New Perspectives on the Role of Intranodal Lymphatic Sinuses

Abstract

The lymphatic system is essential for transporting interstitial fluid, soluble antigen, and immune cells from peripheral tissues to lymph nodes (LNs). Functional integrity of LNs is dependent on intact lymphatics and effective lymph drainage. Molecular mechanisms that facilitate interactions between tumor cells and lymphatic endothelial cells (LECs) during tumor progression still remain to be identified. The cellular and molecular structures of LNs are optimized to trigger a rapid and efficient immune response, and to participate in the process of tumor metastasis by stimulating lymphangiogenesis and establishing a premetastatic niche in LNs. Several molecules, e.g., S1P, CCR7-CCL19/CCL21, CXCL12/CXCR4, IL-7, IFN-γ, TGF-β, and integrin α4β1 play an important role in controlling the activity of LN stromal cells including LECs, fibroblastic reticular cells (FRCs) and follicular dendritic cells (DCs). The functional stromal cells are critical for reconstruction and remodeling of the LN that creates a unique microenvironment of tumor cells and LECs for cancer metastasis. LN metastasis is a major determinant for the prognosis of most human cancers and clinical management. Ongoing work to elucidate the function and molecular regulation of LN lymphatic sinuses will provide insight into cancer development mechanisms and improve therapeutic approaches for human malignancy.

Validation of Gene Profiles for Analysis of Regional Lymphatic Metastases in Head and Neck Squamous Cell Carcinoma

“…It presents a great challenge to develop more effective therapeutic strategies to prevent metastases and recurrence. For the purpose of uncovering the CSCs and immune suppression-related genetic alterations underlying metastasis in HNSCC, we chose 15 of the CSCs and immune suppression-related genes that have been reported in the primary expression of HNSCC before (Kosan and Kunz, 2002;Grosse-Gehling et al, 2013;Nor et al, 2014;Prakasam et al, 2014;Yang et al, 2014;Hartomo et al, 2015;Wu et al, 2015;Ji, 2016;Ren et al, 2016) performed RT-PCR to examine the expression levels of in cancer tissues, lymph nodes, and the matched normal tissues from the same patients with synchronous nodal metastases.…”

Lymphatic Transport and Lymph Node Location of Microspheres Subcutaneously Injected in the Vicinity of Tumors in a Rabbit Model of Breast Cancer

“…MS. It was speculated that the tumor-associated lymphatics and draining LNs are key modulators of tumor cell migration and invasion by mechanisms that remain unclear (41). Furthermore, the cells migrating to the LN could have an effect on lymphatic permeability in case of inflammatory conditions (42).…”

Circulating tumor cells and the metastatic process: the complexity of malignancy

“…Accordingly, another mechanism of tumor EMT-independent metastasis, namely tumor-induced lymphangiogenesis, has been proposed [95] . Briefly, mesenchymal cancer cells, which are able to produce and release lymphangiogenic factors, such as vascular endothelial growth factor C and D (VEGF-C and VEGF-D), promote an increase of lymphatic vessel density in the peri-and intratumoral area, so that epithelial cells are able to colonize lymphatic system and lymph nodes can facilitate their entry into the systemic circulation [96][97][98][99][100] . It has been demonstrated that an increase in lymph vessel density, due to tumor-induced lymphangiogenesis, is correlated with a high amount of lymph node metastasis, VEGF-C expression and worse disease-free/overall survival in BC patients [101] .…”