The Hepatic Pre-Metastatic Niche

Ormseth, Benjamin; Onuma, Amblessed E.; Zhang, Hongji; Tsung, Allan

doi:10.3390/cancers14153731

Cited by 5 publications

(4 citation statements)

References 135 publications

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“…However, primary tumours can initiate metastasis before spreading from primary sites by inducing PMN formation via soluble factors [ 35 ]. Recently, PMNs have attracted considerable attention owing to their critical roles in determining metastatic efficacy [ 36 , 37 ]. Small extracellular vesicles originating from cancer cells have been extensively recognized as initiators of PMNs by delivering proteins, RNA, and DNA in various cancer types [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Gastric cancer-derived LBP promotes liver metastasis by driving intrahepatic fibrotic pre-metastatic niche formation

Xie,

Qiu,

et al. 2023

J Exp Clin Cancer Res

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Background Liver metastasis (LM) is one of the most common distant metastases of gastric cancer (GC). However, the mechanisms underlying the LM of GC (GC-LM) remain poorly understood. This study aimed to identify the tumour-secreted protein associated with GC-LM and to investigate the mechanisms by which this secreted protein remodels the liver microenvironment to promote GC-LM. Methods Data-independent acquisition mass spectrometry (DIA-MS), mRNA expression microarray, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were performed to identify and validate the GC-secreted proteins associated with GC-LM. A modified intrasplenic injection mouse model of LM was used to evaluate the progression and tumour burden of LM in vivo. Flow cytometry, immunofluorescence (IF), western blots (WB) and IHC were performed to validate the pre-metastatic niche (PMN) formation in the pre-modelling mouse models. mRNA sequencing of PMA-treated THP-1 cells with or without lipopolysaccharide binding protein (LBP) treatment was used to identify the functional target genes of LBP in macrophages. Co-immunoprecipitation (Co-IP), WB, ELISA, IF and Transwell assays were performed to explore the underlying mechanism of LBP in inducing intrahepatic PMN formation. Results LBP was identified as a critical secreted protein associated with GC-LM and correlated with a worse prognosis in patients with GC. LBP activated the TLR4/NF-κB pathway to promote TGF-β1 secretion in intrahepatic macrophages, which, in turn, activated hepatic satellite cells (HSCs) to direct intrahepatic fibrotic PMN formation. Additionally, TGF-β1 enhanced the migration and invasion of incoming metastatic GC cells in the liver. Consequently, selective targeting of the TGF-β/Smad signaling pathway with galunisertib demonstrated its efficacy in effectively preventing GC-LM in vivo. Conclusions The results of this study provide compelling evidence that serological LBP can serve as a valuable diagnostic biomarker for the early detection of GC-LM. Mechanistically, GC-derived LBP mediates the crosstalk between primary GC cells and the intrahepatic microenvironment by promoting TGF-β1 secretion in intrahepatic macrophages, which induces intrahepatic fibrotic PMN formation to promote GC-LM. Importantly, selectively targeting the TGF-β/Smad signaling pathway with galunisertib represents a promising preventive and therapeutic strategy for GC-LM.

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Section: Discussionmentioning

confidence: 99%

Gastric cancer-derived LBP promotes liver metastasis by driving intrahepatic fibrotic pre-metastatic niche formation

Xie,

Qiu,

et al. 2023

J Exp Clin Cancer Res

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“…Among other factors produced by the primary tumor that precondition the liver microenvironment to form niches of activated resident cells promoting tumor expansion, bone marrow-derived immune cells recruited to the liver, including neutrophils, fibrocytes, and myeloid-derived suppressor cells (MDSCs) also appear to play an important role [13]. Studying the diverse signaling mechanisms involved in this "premetastatic niche", released by the primary tumor to the liver, identified TGF-β, interleukin 6 (IL-6), integrin beta-like 1 (ITGBL1), glucose-regulated protein 78 (GRP78), the tissue inhibitor of metalloproteinases (TIMP-1), and a significant list of miRNA signatures transferred via exosomes [14].…”

Section: Introductionmentioning

confidence: 99%

Liver metastatic colonization by invasive cancer cells: a review of potential biomarkers with mitochondrial involvement

Pouliquen

2024

Explor Dig Dis

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The liver, characterized by a unique metabolic and immunosuppressive environment, is also the organ to which invasive malignant cells of many different cancer types most frequently metastasize. The reasons for this organ-specific metastatic process have been investigated for decades. This review first provides an overview of recent breakthroughs in this field, introducing intercellular communication between circulating tumor cells and the heterogeneous cell populations of the liver, and modifications to the extracellular matrix (ECM). Subsequently, to improve the understanding of the molecular mechanisms involved in the metastasis of colorectal cancer to the liver, the second leading cause of cancer-related mortality, the recent literature on this question was analyzed. Among the various parameters involved, the mechanisms behind the activation of hepatic stellate cells, proteins inducing ECM remodeling, specific genomic features of liver metastases, metabolic rewiring, and characteristics of stromal-enriched microenvironments were discussed. To provide more insights into the molecular determinants of liver metastatic colonization, important findings reported on a set of mitochondrial proteins were addressed, the relative abundance of which changed in the liver during the progression stage of an aggressive experimental model of peritoneal malignant mesothelioma in immunocompetent rats. Based on previous studies cross-comparing the liver proteomes from curcumin-treated tumor-bearing rats/untreated tumor-bearing rats/normal rats, data from the literature were reviewed for 25 mitochondrial proteins of interest. Their role in lipid metabolism, heme biosynthesis, the electron transport chain, small molecule transport, mitochondrial dynamics, the tricarboxylic acid cycle, and protection against oxidative stress were analyzed in the context of both cancer and non-malignant liver diseases.

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“…Primary tumor can create a favorable microenvironment for subsequent tumor cell colonization before reaching the secondary organ and tissue site, that is termed the pre-metastatic niche (PMN) [2] . A increasing number of studies have shown that cancer liver metastasis depends on the formation of PMN and pro-metastatic microenvironment [3] .…”

Section: Introductionmentioning

confidence: 99%

FABP7-mediated lipid-laden macrophages drive liver metastasis through metabolic reprogramming of tumor cells and CD8+ T cells

Liang,

Xu,

Peng

et al. 2023

Preprint

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Abnormal metabolic process is involved in sequential steps of the pre-metastatic cascade and overt metastasis at the distant organ. However, the mechanisms underlying lipid metabolic reprogramming in macrophages regulates the formation of pre-metastic niche (PMN) during liver metastasis remain unknown. Here, we found that fatty acid binding protein 7 (FABP7) was up-regulated in the liver macrophages leading to lipid droplet accumulation in PMN of colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). This was partially mediated by hypoxia inducible factor-1 alpha (HIF-1α)-induced FABP7 expression that subsequently facilitated diacylglycerol acyltransferase 1 (DGAT1) activity in liver macrophages. FABP7-mediated lipid droplet induced protumoral M2-type macrophages in liver PMN, creating a highly immunosuppressive tumor microenvironment (TME). Knockout or pharmacologic inhibition of FABP7 reduced liver metastasis of CRC and PDAC, respectively. Mechanistically, lipid-laden macrophages induced by FABP7 transported their lipids to tumor cells and CD8+ T cells via exosomes, leading to heightened tumor cell proliferation and CD8+ T cell dysfunction through different metabolic reprogramming. Besides, FABP7 induced macrophages secreting pleiotrophin (PTN) to promote the proliferation of metastatic tumor cells by activating the PI3K-AKT signaling pathway. Collectively, our findings uncover a novel mechanism of FABP7-mediated lipid droplets in macrophage in liver PMN formation and metastasis, and suggest a prognostic and therapeutic potential of targeting FABP7 for liver metastasis.

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The Hepatic Pre-Metastatic Niche

Cited by 5 publications

References 135 publications

Gastric cancer-derived LBP promotes liver metastasis by driving intrahepatic fibrotic pre-metastatic niche formation

Gastric cancer-derived LBP promotes liver metastasis by driving intrahepatic fibrotic pre-metastatic niche formation

Liver metastatic colonization by invasive cancer cells: a review of potential biomarkers with mitochondrial involvement

FABP7-mediated lipid-laden macrophages drive liver metastasis through metabolic reprogramming of tumor cells and CD8+ T cells

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