The pre-metastatic niche in lymph nodes: formation and characteristics

Abstract

Lymph node metastasis is a crucial prognostic parameter in many different types of cancers and a gateway for further dissemination to distant organs. Prior to metastatic dissemination, the primary tumor prepares for the remodeling of the draining (sentinel) lymph node by secreting soluble factors or releasing extracellular vesicles that are transported by lymphatic vessels. These important changes occur before the appearance of the first metastatic cell and create what is known as a pre-metastatic niche giving rise to the subsequent survival and growth of metastatic cells. In this review, the lymph node structure, matrix composition and the emerging heterogeneity of cells forming it are described. Current knowledge of the major cellular and molecular processes associated with nodal pre-metastatic niche formation, including lymphangiogenesis, extracellular matrix remodeling, and immunosuppressive cell enlisting in lymph nodes are additionally summarized. Finally, future directions that research could possibly take and the clinical impact are discussed.

Periostin in lymph node pre-metastatic niches governs lymphatic endothelial cell functions and metastatic colonization

“…POSTN is an ECM protein, which plays a key role in tissue remodeling by interacting with various ECM proteins such as collagen, fibronectin and integrins [ 15 ]. POSTN is highly expressed in primary tumors and has been reported to be upregulated in lung and liver PM niche [ 21 , 22 ].…”

“…The recruitment of specific cell types [ 11 ] and the remodeling of the extracellular matrix (ECM) are therefore seen as crucial events in PM elaboration. PM niches have been well described for lung, liver and bone [ 12 – 14 ], but far less for LNs [ 15 ]. Lymphatic vasculature remodeling (lymphangiogenesis) is a key step in the formation of a LN PM niche and is primarily driven by vascular endothelial growth factors (VEGF-A and VEGF-C) [ 16 , 17 ].…”

“…ECM degradation and deposition, which are often associated with tissue remodeling are poorly documented in LN PM [ 15 ]. One ECM component, periostin (POSTN) plays a key role by interacting with other components such as fibronectin, tenascin-c (TNC) and collagen types I, IV and V [ 19 ].…”

Lymphatic Vessel Regression and Its Therapeutic Applications: Learning From Principles of Blood Vessel Regression

“…As described by Yamakawa et al (2018) , tumor cells can induce lymphangiogenesis from local lymph nodes through pro-lymphangiogenic signaling, effectively creating a highway for lymphatic metastasis. For an expert review on the pre-metastatic niche and tumor signaling in regional lymph nodes, readers are referred to the review by Gillot et al (2021) . Through the secretion of VEGF-C and VEGF-D, tumors of the breast, lung, colon, prostate, and cervix promote the formation of tumor lymphatic networks that serve as routes for metastasis ( Detmar and Hirakawa, 2002 ; Kesler et al, 2013 ).…”

The Lymph Node Microenvironment May Invigorate Cancer Cells With Enhanced Metastatic Capacities

“…Recent studies have demonstrated that in the tumor-involved lymph nodes, a range of immune-suppressive cells and biological factors would be recruited or activated, which facilitated the survival and growth of metastatic tumor cells. The mechanisms include the decrease of CD8+ T cells, myeloid-derived suppressor cell (MDSC) expansion, and upregulation of regulatory T cells ( 24 – 27 ). However, the exact alterations of metastatic tumor cells from primary tumor cells remained unclear.…”