TGF‐β signaling in liver metastasis

Marvin, Dieuwke L.; Heijboer, Rosan; Dijke, Peter ten; Ritsma, Laila

doi:10.1002/ctm2.160

Cited by 28 publications

(29 citation statements)

References 134 publications

(249 reference statements)

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“…Hepatic steatosis can cause extracellular matrix (ECM) remodeling and reorganization, which create a fibrotic niche for CRLM and is important in tumor promotion and growth ( 40 ). Transforming growth factor β (TGF-β), which participants in pathogenesis of hepatic steatosis, is pivotal in maintaining liver homeostasis and have a leading role in CRLM ( 41 ). In addition to TGF-β, other cytokines, such as IL-1, IL-6, and TNF-α, contribute significantly to the pathophysiology of hepatic steatosis through stimulation of hepatic inflammation, and can in turn promote CRLM ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Steatosis Predicts Higher Incidence of Recurrence in Colorectal Cancer Liver Metastasis Patients

et al. 2021

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Purpose: Colorectal liver metastasis (CRLM) is the major cause of death due to colorectal cancer. Although great efforts have been made in treatment of CRLM, about 60–70% of patients will develop hepatic recurrence. Hepatic steatosis was reported to provide fertile soil for metastasis. However, whether hepatic steatosis predicts higher incidence of CRLM recurrence is not clear. Therefore, we aimed to determine the role of hepatic steatosis in CRLM recurrence in the present study.Methods: Consecutive CRLM patients undergoing curative treatment were retrospectively enrolled and CT liver-spleen attenuation ratio was used to detect the presence of hepatic steatosis. In patients with hepatic steatosis, we also detected the presence of fibrosis. Besides, a systematic literature search was performed to do meta-analysis to further analyze the association between hepatic steatosis and CRLM recurrence.Results: A total of 195 eligible patients were included in our center. Patients with hepatic steatosis had a significantly worse overall (P = 0.0049) and hepatic recurrence-free survival (RFS) (P = 0.0012). Univariate and multivariate analysis confirmed its essential role in prediction of RFS. Besides, hepatic fibrosis is associated with worse overall RFS (P = 0.039) and hepatic RFS (P = 0.048). In meta-analysis, we included other four studies, with a total of 1,370 patients in the case group, and 3,735 patients in the control group. The odds ratio was 1.98 (95% CI: 1.25–3.14, P = 0.004), indicating that patients with steatosis had a significantly higher incidence of CRLM recurrence.Conclusion: In summary, patients with hepatic steatosis had a significantly worse overall and hepatic RFS and it's associated with higher incidence of CRLM recurrence.

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Section: Discussionmentioning

confidence: 99%

Hepatic Steatosis Predicts Higher Incidence of Recurrence in Colorectal Cancer Liver Metastasis Patients

et al. 2021

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“…Interestingly, it was previously suggested that TGF-β1 can be secreted by hepatocytes and macrophages, in turn activating HSCs ( 40 ). Accumulating evidence indicated that TGF-β1 mainly transduces signals through Smad ( 41 , 42 ). We have also reported that Smad assisted β-catenin transport to the nucleus of HSCs, initiating fibrosis gene expression ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

“…HSCs are the main sources of ECM, and their activation has been considered as a key event in liver fibrosis ( 40 ). In this process, cytokines released from injured hepatocytes initiates HSC activation ( 41 ). In the present study, hepatocyte-HSC interaction was stimulated using a co-culture system, as previously reported ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

HBV induces liver fibrosis via the TGF‑β1/miR‑21‑5p pathway

Chen

et al. 2020

Exp Ther Med

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MicroRNA (miR)-21-5p is a newly discovered factor that mediates TGF-β1 signaling. The present study was designed to investigate the role of TGF-β1/miR-21-5p in hepatitis B virus (HBV)-induced liver fibrosis. HBV-infected sodium taurocholate co -t ra nspor ting polypeptide (NTCP)-transfected Huh7.5.1 cells were co-cultured with LX2 cells to simulate HBV infection in the present study. A total of 29 patients with chronic HBV infection were enrolled. Cells were transfected with miR-21-5p mimic or inhibitor with or without TGF-β1 stimulation. The demographic, biochemical and virological data from the 29 patients were analyzed and liver tissues were collected. miR-21-5p levels and the mRNA and protein expression of α-smooth muscle actin (SMA), collagen type 1 α 1 (CoL1A1), tissue inhibitor of metalloproteinase (TIMP)-1 and Smad from liver cells or tissues were detected by quantitative PCR analysis and western blotting, respectively. Cell viability was observed, and the liver fibrosis score was evaluated. The association between miR-21-5p and liver fibrosis was evaluated by correlation analysis. HBV infection upregulated TGF-β1/miR-21-5p mRNA expression in NTCP-Huh7.5.1 cells compared with mock infection (P<0.05). TGF-β1 incubation significantly increased miR-21-5p levels, as well as the mRNA and protein expression of α-SMA, CoL1A1 and TIMP-1, and reduced Smad7 expression in LX2 cells compared with the normal group, and these effects were counteracted by miR-21-5p inhibitor (P<0.05). miR-21-5p overexpression also contributed to TGF-β1-induced α-SMA, CoL1A1 and TIMP-1 expression in LX2 cells (P<0.05). Co-culture with HBV-infected NTCP-Huh7.5.1 cells upregulated TGF-β1/miR-21-5p activity and CoL1A1 expression in LX2 cells compared with normal control, which were significantly reduced by miR-21-5p inhibitor (P<0.05). miR-21-5p levels were significantly correlated with the liver fibrosis score (r=0.888; P<0.05). These data demonstrated that HBV induced liver fibrosis via the TGF-β1/miR-21-5p pathway and suggested that miR-21-5p may be an effective anti-fibrosis target.

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“…Secretion of CXCL12 from activated HSCs enhances metastatic colonization by binding to CXCR4 on cancer cells and thereby promoting survival and proliferation (Luker & Luker, 2006 ; Shi et al , 2020 ; Zielińska & Katanaev, 2020 ). Additionally, enhanced extracellular matrix deposition from activated HSCs induces a fibrotic liver environment that enhances metastatic growth (Fig 3C ) (Marvin et al , 2020 ). This fibrosis is a physical barrier to anti‐tumorigenic immune cells (Tsuchida & Friedman, 2017 ).…”

Section: Interaction With Specialized Tissue‐resident Cellsmentioning

confidence: 98%

Feed‐forward loops between metastatic cancer cells and their microenvironment—the stage of escalation

2022

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Breast cancer is the most frequent cancer among women, and metastases in distant organs are the leading cause of the cancerrelated deaths. While survival of early-stage breast cancer patients has increased dramatically, the 5-year survival rate of metastatic patients has barely improved in the last 20 years. Metastases can arise up to decades after primary tumor resection, hinting at microenvironmental factors influencing the sudden outgrowth of disseminated tumor cells (DTCs). This review summarizes how the environment of the most common metastatic sites (lung, liver, bone, brain) is influenced by the primary tumor and by the varying dormancy of DTCs, with a special focus on how established metastases persist and grow in distant organs due to feed-forward loops (FFLs). We discuss in detail the importance of FFL of cancer cells with their microenvironment including the secretome, interaction with specialized tissue-specific cells, nutrients/metabolites, and that novel therapies should target not only the cancer cells but also the tumor microenvironment, which are thick as thieves.

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TGF‐β signaling in liver metastasis

Cited by 28 publications

References 134 publications

Hepatic Steatosis Predicts Higher Incidence of Recurrence in Colorectal Cancer Liver Metastasis Patients

Hepatic Steatosis Predicts Higher Incidence of Recurrence in Colorectal Cancer Liver Metastasis Patients

HBV induces liver fibrosis via the TGF‑β1/miR‑21‑5p pathway

Feed‐forward loops between metastatic cancer cells and their microenvironment—the stage of escalation

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