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The Role and Significance of Hepatic Environmental Cells in Tumor Metastatic Colonization to Liver
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摘要: 肿瘤转移是引起肿瘤患者死亡的主要原因，是临床上面临的重要挑战。肿瘤转移是个多步骤的复杂过程，肿瘤细胞历经离开原发部位，内渗进入血管，随血液远行，从血管外渗到远处器官，最终在靶器官定植（colonization） 而生长成为转移性癌灶。肿瘤转移具有一定的靶器官亲嗜倾向，肝脏是肿瘤的常见转移部位，对肝脏有亲嗜倾向的肿瘤包括眼葡萄膜黑色素瘤、结直肠癌、胰腺癌等。肝脏解剖结构造成的血流动力学特点（例如压力小、血流慢）常常使得肿瘤细胞在肝脏易于瘀滞而利于定植，但肿瘤是否能在肝脏成功定植主要取决于肿瘤细胞与肝脏微环境（特别是肝固有细胞成分）的相互作用。肝脏微环境的固有细胞主要包括肝细胞、肝血窦内皮细胞（liver sinusoidal endothelial cells, LSECs）、肝星状细胞（hepatic stellate cells, HSCs）、枯否细胞（Kupffer cells, KCs） 等。本文将讨论肝脏的固有细胞在肿瘤肝定植转移中的作用及意义。Abstract: Metastasis, a main cause of death in tumor patients, is a complicated process that involves multiple steps, presenting a major clinical challenge. Tumor cells break the physical boundaries of a primary tumor, intravasate into the lumina of blood vessels, travel around through blood circulation, extravasate into distant organs, colonize the host organs, and eventually develop into the foci of metastatic cancer. The metastasis of tumor cells exhibits organ-tropism, i.e., tumor cells preferentially spread to specific organs. Liver is a common site for metastasis. The pattern of metastasis in uveal melanoma, colorectal carcinoma, and pancreatic ductal adenocarcinoma shows organ-tropism for liver. The anatomical structure of liver determines its hemodynamic characteristics, e.g., low pressure and slow blood flow, which tend to facilitate the stasis and colonization of tumor cells in the liver. Besides the hemodynamic features, the metastatic colonization of liver depends largely on the interaction between tumor cells and the hepatic microenvironment (especially liver-resident cellular components). Resident cells of the hepatic microenvironment include hepatocytes, liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KCs), etc. Herein, we discussed the role and significance of liver-resident cells in the metastatic colonization of tumor in the liver.
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图 1 肝固有细胞对肿瘤细胞肝定植转移的作用
Figure 1. The contribution of liver-resident cells to the metastatic colonization of tumor cells in liver
IL: interleukin; CXCL: C-X-C motif chemokine ligand; CXCR: C-X-C motif chemokine receptor; CD: cluster of differentiation; MHC: major histocompatibility complex; CKB: creatine kinase, brain-type; SAA: serum amyloid A; FGF: fibroblast growth factor; TGF: transforming growth factor; NF-κB: noncanonical nuclear factor-kappa B; VEGF-C: vascular endothelial growth factor C; HSC: hepatic stellate cell; LSEC: liver sinusoidal endothelial cells; YTHDF3: YTH N6-methyladenosine RNA binding protein F3; SMAD2: mothers against decapentaplegic homolog 2; STAT3: signal transducer and activator of transcription 3; TNF: tumor necrosis factor.
表 1 肝微环境细胞、肿瘤细胞与定植肝转移的关键分子及其可能机制
Table 1. Hepatic cell components, key molecules, and the putative mechanisms involved in liver metastasis
Cellular
component
in liverTumor Key molecules Mechanisms References LSEC CRC FAPα; FGFBP1 Tumor cell–derived FGFBP1 induces FAPα expression by enhancing the paracrine FGF2/FGFR1/ERK1/-2/EGR1 signaling pathway in HSC. FAPα promotes CXCL5 secretion in HSC, which activates CXCR2 to promote the EMT of tumor cells and the recruitment of myeloid-derived suppressor cells. [17] LSEC HCC IL-23 Cancer cells induce LSEC intracellular gap formation via proinflammatory paracrine of TNF-α. TNF-α triggered depolymerization of F-actin and induce MMP9, ICAM1, and CXCL expression in LSEC. [12] KC PDAC MIF Uptake of PDAC-derived exosomes containing MIF by Kupffer cells causes fibrotic microenvironment via upregulation of TGF-β secretion and fibronectin production by HSC, enhancing the recruitment of bone marrow-derived macrophages. [22] KC CRC Angiotensin Ⅱ Angiotensin Ⅱ-AT1a signaling enhances TGF-β1 expression in Kupffer cells. The formation of liver metastasis is correlated with collagen deposition in the metastatic area, which is dependent on AT1a signaling. [24] KC CRC MiR-135a-5p KCs phagocytose exosomes containing highly expressed miR-135a-5p from the blood circulation into the liver. Exosomal miR-135a-5p initiates the LATS2-YAP-MMP7 axis to promote the occurrence of CRC liver metastasis. [25] KC GC MiR-151a-3p MiR-151a-3p carried by sEVs targets YTHDF3 to decrease the transcriptional inhibitory activity of SP3 by reducing SUMO1 translation in a m6A-dependent manner, contributing to TGF-β1 transactivation in KC. TGF-β1 subsequently activates the SMAD2/3 pathway and enhances the stem cell-like properties of incoming GC cells. [27] KC CRC ANGPTL1 Exosomal ANGPTL1 attenuates CRC liver metastasis and impedes vascular leakiness by downregulating MMP9 level in KC through inhibiting the JAK2-STAT3 signaling pathway. [28] HSC CRC HSPC111 Exosomal HSPC111 alteres lipid metabolism of CAFs by phosphorylating ATP-citrate lyase (ACLY), which upregulates the level of acetyl-CoA. The accumulation of acetyl-CoA further promotes CXCL5 expression and secretion by increasing H3K27 acetylation in CAFs. Moreover, CXCL5-CXCR2 axis reinforces exosomal HSPC111 excretion from CRC cells and promotes liver metastasis. [35] HSC CRC MiR-181a-5p FUS mediates packaging of miR-181a-5p into CRC EVs, which in-turn persistently activates HSC by targeting SOCS3 and activating the IL6/STAT3 signaling pathway. Activated HSC can secrete the chemokine CCL20 and further activate a CCL20/CCR6/ERK1/2/Elk-1/miR-181a-5p positive feedback loop, resulting in the reprogramming of the TME and the formation of pre-metastatic niches in CRLM. [36] HSC UM TGF-β1 UM cells secrete TGF-β1 which induces quiescent HSC into aHSCs which secretes collagen type Ⅰ. Such a remodeling of extracellular matrix, in turn, activates DDR1, strengthening survival through upregulating STAT3-dependent Mcl-1 expression, enhancing stemness via upregulating STAT3-dependent SOX2, and promoting clonogenicity in cancer cells. [37] Hepatocyte PDAC IL-6 Depending on the release of IL-6 into the circulation by non-malignant cells, hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver by activating STAT3 signaling and production of SAA, leading to increased susceptibility of the liver to metastatic seeding and outgrowth. [44] Hepatocyte CRC MiR-122; MMPs Delivery of nano-formulation miR-122 into hepatocytes is associated with 1) an increased CD8+/CD4+ T-cell ratio and decreased infiltration of MDSCs; 2) downregulation of key genes involved in metastatic and cancer inflammation pathways, including several proinflammatory factors, matrix metalloproteinases, and other extracellular matrix degradation enzymes. [48] Hepatocyte CRC GREM1; ISLR Stromal GREM1 inhibits BMP signaling, while ISLR acts in the opposite way. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduces CRC tumoroid growth and promotes Lgr5+ intestinal stem cell differentiation. AAV8-mediated delivery of Islr to hepatocytes increases BMP signaling and improves survival. [49] LSEC: liver sinusoidal endothelial cell; CRC: colorectal cancer; FAPα: fibroblast activation protein alpha; FGFBP1: fibroblast growth factor binding protein 1; FGF: fibroblast growth factor; FGFR: fibroblast growth factor receptor; ERK: extracellular signal-regulated kinase; EGR: early growth response; EMT: epithelial-mesenchymal transition; HCC: hepatocellular carcinoma; IL: interleukin; TNF: tumor necrosis factor; NF-κB: noncanonical nuclear factor-kappa B; MMP: matrix metalloproteinase; ICAM: intracellular adhesion molecule; KC: Kupffer cell; MIF: migration inhibitory factor; TGF: transforming growth facto; HSC: hepatic stellate cell; AT1a: angiotensin Ⅱ subtype receptor 1a; LATS: large tumor suppressor; YAP: yes-associated protein; TRAF: TNF receptor-associated factors; GC: gastric cancer; sEVs: small extracellular vesicles; SUMO: small ubiquitin-related modifier; ANGPTL1: angiopoietin like 1; JAK: Janus kinase; HSPC111: hypothetical protein HSPC111; ACLY: ATP-citrate lyase; CXCL: C-X-C motif chemokine ligand; CXCR: C-X-C motif chemokine receptor; FUS: fused in Sarcoma; SOCS: suppressor of cytokine signaling; CCL: C-C motif chemokine ligand; CCR: C-C motif chemokine receptor; ERK: extracellular regulated MAP kinase; Elk-1: ETS transcription factor ELK1; TME: tumour microenvironment; CRLM: liver metastasis of colorectal cancer; UM: uveal melanoma; DDR1: discoidin domain receptor tyrosine kinase 1; SOX2: sex-determining region Y-box 2; PDAC: pancreatic ductal adenocarcinoma; SAA: serum amyloid A; CD: cluster of differentiation; MDSCs: myeloid-derived suppressor cells; GREM1: gremlin 1; ISLR: immunoglobulin superfamily containing leucine rich repeat; BMP: bone morphogenetic protein; Lgr5: leucine rich repeat containing G protein coupled receptor; AAV8: adeno-associated virus 8; YTHDF3: YTH N6-methyladenosine RNA binding protein F3; SMAD2: mothers against decapentaplegic homolog 2; STAT3: signal transducer and activator of transcription 3. 
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