Generation of Subcutaneous and Intrahepatic Human Hepatocellular Carcinoma Xenografts in Immunodeficient Mice

Ahmed, Sharif Uddin; Zair, Murtuza; Chen, Kui; Iu, Matthew; Feng, He; Adeyi, Oyedele; Cleary, Sean P.; Ghanekar, Anand

doi:10.3791/50544-v

Cited by 2 publications

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“…Spleen injection was performed following the previously published procedures. [ 58 ] Briefly, after anesthesia, the spleen of mouse was exteriorized by a laparotomy. For the spleen injection, 2.5 × 10 6 HT‐29 or KM12SM cells suspended in 50 µL PBS were injected into the distal tip of spleens with an insulin syringe (BD, Franklin Lakes, NJ, USA).…”

Section: Methodsmentioning

confidence: 99%

FGF19‐Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer

Chen

et al. 2023

Advanced Science

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Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver‐metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer‐associated fibroblasts (iCAFs) by activating the autocrine effect of IL‐1α via the FGFR4‐JAK2‐STAT3 pathway. FGF19‐induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL‐1β, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19‐induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.

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Section: Methodsmentioning

confidence: 99%

FGF19‐Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer

Chen

et al. 2023

Advanced Science

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“…Cultured DUSP9 KO or WT HCC cells were resuspended in Matrigel (354234; BD Biosciences). We subcutaneously injected 1 × 10 6 cells/70 µL (PP5) or 7.5 × 10 5 cells/70 μL (Huh7) into 8-12-week-old female nonobese diabetic severe combined immunodeficiency gamma (NSG) mice, as described, (17) with eight replicates per sample. Mice injected with KO and WT cells were analyzed concurrently and monitored until the largest xenograft in the cohort measured 2 cm in diameter; they were then euthanized.…”

Section: Mouse Experimentsmentioning

confidence: 99%

Dual‐Specificity Phosphatase 9 Regulates Cellular Proliferation and Predicts Recurrence After Surgery in Hepatocellular Carcinoma

et al. 2021

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Hepatocellular carcinoma (CC) is a common and deadly cancer with complex molecular pathogenesis. Little is known about dual-specificity phosphatases (DUSPs) in HCC. We investigated DUSP9 expression in human HCC, associations between DUSP9 and patient outcomes, and effects of altered DUSP9 expression on HCC biology. We studied public data sets as well as 196 patients at our institution who had HCC resections. Quantitative real-time reverse transcription polymerase chain reaction and western blot demonstrated that DUSP9 expression was increased >10-fold in HCC compared to adjacent liver and healthy controls (P = 0.005). Kaplan-Meier and multivariable regression analyses revealed that higher DUSP9 expression was associated with shorter disease-free survival (high DUSP9, 1.6; 95% confidence interval, 0.9-2.3 vs. low DUSP9, 3.4; 95% confidence interval, 1.8-5.0 years; P = 0.04) and increased risk of recurrence (hazard ratio 1.55; 95% confidence interval, 1.01-2.67; P = 0.05) after resection. DUSP9 complementary DNA (cDNA) was cloned using rapid amplification of cDNA ends, revealing two DUSP9 isoforms in human HCC cells. Studies of transcriptional regulation using promoter-luciferase reporter constructs suggested that DUSP9 transcription is regulated by E26 transformation-specific transcription factors. Proliferation of hepatic cells in vitro was enhanced by lentiviral-mediated overexpression of DUSP9. In contrast, DUSP9 knockout HCC cells generated using clustered regularly interspaced short palindromic repeats (CRISPR) demonstrated decreased HCC proliferation and doxorubicin resistance in vitro and impaired xenograft growth in vivo. RNA sequencing, gene set enrichment, and network/pathway analysis revealed that DUSP9 knockout is associated with activation of protein kinase activity and apoptosis. Conclusion: DUSP9 regulates cell proliferation and predicts recurrence after surgery in HCC. DUSP9 may represent a novel prognostic candidate and therapeutic target. Additional studies are warranted to further explore the role and regulation of DUSP9 in HCC. (Hepatology Communications 2021;0:1-19).

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Generation of Subcutaneous and Intrahepatic Human Hepatocellular Carcinoma Xenografts in Immunodeficient Mice

Cited by 2 publications

References 0 publications

FGF19‐Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer

FGF19‐Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer

Dual‐Specificity Phosphatase 9 Regulates Cellular Proliferation and Predicts Recurrence After Surgery in Hepatocellular Carcinoma

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