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. 2021 Dec 23;14(1):48. doi: 10.3390/cancers14010048

Figure 4.

Figure 4

Liver damage activates and dysregulates liver macrophages and LSECs’ role in HCC: (A) KCs are polarized to TAMs, a M2 phenotype macrophage with proangiogenic and proinflammatory properties that act on neighboring cells. Moreover, DAMPs and MAMPs are recognized by PRR on KCs aggravating liver diseases and hepatocellular carcinoma development. Importantly, exhausted KCs are replaced by recruited circulating monocytes, which polarize to TAMs. TAMs can also be recruited through IL-4, IL-10, and CCL2 signals from circulating monocytes. Crosstalk between immune and cancer cells occurs through TGFβ-Tim3 interaction and promotes the polarization of M2 TAMs towards a pro-oncogenic phenotype that triggers tumor growth, invasion, and migration by several secreted factors such as cytokines, proangiogenic factors, and MMPs. (B) Liver damage causes LSECs capillarization, losing specific features such as fenestration and homeostatic proteins (LYVE-1 and STAB1 and 2). Subsequently, LSECs secrete several proinflammatory (IL-8 and CCL2) and adhesion molecules (VCAM-1 and ICAM-1), ECM components (laminin) and growth factors (HGF) that act as angiocrine factors favoring the capillarization process and tumor microenvironment during tumorigenesis. (C) PLVAP+ and VEGFR2+-ECs migrate to tumoral tissue contributing to tumor growth by the formation of new vessels. Moreover, TAEs promote neo-angiogenesis by upregulation of MMP2, inducing ECM remodeling. Abbreviations: CCL2, chemokine (C-C motif) ligand 2; CCR2, C-C chemokine receptor type 2; DAMPS, damage-associated molecular patterns; Heps, hepatocytes; ECs, endothelial cells; ICAM-1, intracellular adhesion molecule 1; KCs, Kupffer cells; LSECs, liver sinusoidal endothelial cells; LYVE-1, lymphatic vessel endothelial hyaluronan receptor 1 MAMPs, microbial-associated molecular patterns; PLVAP, plasmalemma vesicle associated protein; PRRs, pattern recognition receptors; STAB, stabilin; TAEs, tumor-associated endothelial cells; TAMs, tumor-associated macrophages cells; VCAM-1, vascular cell adhesion molecule 2. VEGFR2, vascular endothelial growth factor receptor 2. Created with BioRender.com.