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. 2021 Mar 6;13(5):1130. doi: 10.3390/cancers13051130

Figure 1.

Figure 1

Pre-metastatic niche promotion by tumor microenvironment. Primary tumor (A) secretes soluble factors to prepare pre-metastatic niche (B). (1) Tumor cell leaves primary site, moving across extracellular matrix (ECM) and reaching blood stream (C) or lymphatic vessel (D) [2,8,13]. (2) Extravasation is mediated by vascular endothelial cell receptors and tumor cell adhesion molecules (Intercellular Cell-Adhesion Molecule (ICAM), Vascular Cell-Adhesion Molecule (VCAM)) [6]. Moreover, levels of TNFα, C-X-C chemokine Receptor type 4 (CXCR4) and Hypoxia-inducible Factor 1 (HIF-1) act in extravasation [3,6,8]. (3) Presence of VEGF, CXCL2-3-8 promotes niche vascularization [11,14]. Collagen provides scaffold for new vessels [5]. (4) In premetastatic niche, tumor-derived secreted factors recruit Kupffer cells, hepatic stellated cells and neutrophils [5]. Niche ECM is remodeled by local fibroblasts and MMPs [11]. Soluble factors TGF-β, IL2, IL10 and tumor inhibitory molecules Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and Programmed Death-ligand 1 (PD-1), promote immunosuppression [5]. (5) Tumor cells and pre-metastatic niche itself secrete factors that drive tumor cells to liver (i.e., C-C Motif Chemokine Ligand 20 (CCL20), CXCR4, Carcinoembryonic antigen (CEA), osteopontin) [3,15,16,17]. Moreover, tumor cell surface receptors condition distal organ targeting [15,16]. Created with BioRender.com (accessed on 1 May 2020).