Effect of Non-Alcoholic Liver Disease on Recurrence Rate and Liver Regeneration after Liver Resection for Colorectal Liver Metastases

Molla, Nouran; Hassanain, Mazen; Fadel, Zahir; Boucher, Louis-Martin; Madkhali, Ahmad; Altahan, Rahaf; Alrijraji, E.A.; Simoneau, Ève; Alamri, Hussam; Salman, Ayat; Gao, Zu–Hua; Metrakos, Peter

doi:10.3747/co.24.3133

Cited by 15 publications

(14 citation statements)

References 68 publications

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“…However, several studies in humans suggest that fatty liver and liver fibrosis may enhance liver metastasis. 8,9,[182][183][184][185][186][187][188] A large prospective cohort study of 2,715 patients who underwent resection for colorectal cancer liver metastases demonstrated that liver metastasis recurrence was higher in steatotic livers. 8 Another study of 953 patients with liver metastases after curative resection of colorectal cancer showed a fourfold increase in the risk of liver metastasis in fibrotic livers.…”

Section: Inflammation Mediates the Establishment And Growth Of Liver mentioning

confidence: 99%

Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets

2019

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Hepatocellular carcinoma (HCC) is associated with chronic inflammation and fibrosis arising from different etiologies, including hepatitis B and C and alcoholic and nonalcoholic fatty liver diseases. The inflammatory cytokines tumor necrosis factor-α and interleukin-6 and their downstream targets nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 drive inflammation-associated HCC. Further, while adaptive immunity promotes immune surveillance to eradicate early HCC, adaptive immune cells, such as CD8+ T cells, Th17 cells, and B cells, can also stimulate HCC development. Thus, the role of the hepatic immune system in HCC development is a highly complex topic. This review highlights the role of cytokine signals, NF-κB, JNK, innate and adaptive immunity, and hepatic stellate cells in HCC and discusses whether these pathways could be therapeutic targets. The authors will also discuss cholangiocarcinoma and liver metastasis because biliary inflammation and tumor-associated stroma are essential for cholangiocarcinoma development and because primary tumor-derived inflammatory mediators promote the formation of a “premetastasis niche” in the liver.

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Section: Inflammation Mediates the Establishment And Growth Of Liver mentioning

confidence: 99%

Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets

2019

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“…Previous animal studies have demonstrated that high‐fat diet (HFD)‐induced NAFLD promotes the tumor growth of CRC and PDAC liver metastasis . Large prospective and retrospective human cohorts have demonstrated that cancer patients with NAFLD have increased risk of liver metastasis and for recurrence after resection of liver metastasis compared with patients without NAFLD . The increased prevalence of obesity and NAFLD will likely increase the occurrence of liver metastasis.…”

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confidence: 99%

“…However, liver macrophages as well as tumor‐associated macrophages (TAMs) could promote a pro‐metastatic niche formation in the liver, likely by polarizing to M2 macrophage, to enhance the growth of metastatic tumor cells that survived the initial tumoricidal attack. Inflammatory, fibrotic, and fatty liver microenvironment enhances liver tumor growth . Indeed, in a NAFLD condition, CD4 + T cells are depleted and tumor surveillance is impaired, which promotes hepatocellular carcinoma (HCC) growth .…”

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confidence: 99%

NOD‐like receptor C4 Inflammasome Regulates the Growth of Colon Cancer Liver Metastasis in NAFLD

Ohashi¹,

Wang

Yang

et al. 2019

Hepatology

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Nonalcoholic fatty liver disease (NAFLD) enhances the growth and recurrence of colorectal cancer (CRC) liver metastasis. With the rising prevalence of NAFLD, a better understanding of the molecular mechanism underlying NAFLD‐associated liver metastasis is crucial. Tumor‐associated macrophages (TAMs) constitute a large portion of the tumor microenvironment that promotes tumor growth. NOD‐like receptor C4 (NLRC4), a component of an inflammasome complex, plays a role in macrophage activation and interleukin (IL)‐1β processing. We aimed to investigate whether NLRC4‐mediated TAM polarization contributes to metastatic liver tumor growth in NAFLD. Wild‐type and NLRC4‐/‐ mice were fed low‐fat or high‐fat diet for 6 weeks followed by splenic injection of mouse CRC MC38 cells. The tumors were analyzed 2 weeks after CRC cell injection. High‐fat diet–induced NAFLD significantly increased the number and size of CRC liver metastasis. TAMs and CD206‐expressing M2 macrophages accumulated markedly in tumors in the presence of NAFLD. NAFLD up‐regulated the expression of IL‐1β, NLRC4, and M2 markers in tumors. In NAFLD, but not normal livers, deletion of NLRC4 decreased liver tumor growth accompanied by decreased M2 TAMs and IL‐1β expression in tumors. Wild‐type mice showed increased vascularity and vascular endothelial growth factor (VEGF) expression in tumors with NAFLD, but these were reduced in NLRC4‐/‐ mice. When IL‐1 signaling was blocked by recombinant IL‐1 receptor antagonist, liver tumor formation and M2‐type macrophages were reduced, suggesting that IL‐1 signaling contributes to M2 polarization and tumor growth in NAFLD. Finally, we found that TAMs, but not liver macrophages, produced more IL‐1β and VEGF following palmitate challenge. Conclusion: In NAFLD, NLRC4 contributes to M2 polarization, IL‐1β, and VEGF production in TAMs, which promote metastatic liver tumor growth.

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“…After hepatectomy, the incidences of mortality and morbidity are dependent on the volume and function of the residual liver[ 17 - 20 ]. Previous reports have demonstrated that steatosis impaired liver regeneration and caused liver dysfunction after hepatectomy[ 11 , 12 ]. NASH has been proposed to cause liver failure rather than steatosis because NASH presents with not only steatosis but also fibrosis, inflammation, and insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Steatosis is a risk factor for postoperative liver failure[ 11 , 12 ]. A number of clinical studies revealed that steatosis caused severe mortality and morbidity after liver resection compared with normal liver following liver resection[ 11 , 12 ]. In experimental models, hepatectomy of fatty livers resulted in suppressed liver regeneration and survival rates[ 13 - 16 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of safety for hepatectomy in a novel mouse model with nonalcoholic-steatohepatitis

Ozawa

Tamura

Owada

et al. 2018

WJG

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AIMTo investigate whether the liver resection volume in a newly developed nonalcoholic steatohepatitis (NASH) model influences surgical outcome.METHODSFor establishment of a NASH model, mice were fed a high-fat diet for 4 wk, administered CCl4 for the last 2 wk, and administered T0901317 for the last 5 d. We divided these mice into two groups: A 30% partial hepatectomy (PH) of NASH liver group and a 70% PH of NASH liver group. In addition, a 70% PH of normal liver group served as the control. Each group was evaluated for survival rate, regeneration, apoptosis, necrosis and DNA expression after PH.RESULTSIn the 70% PH of NASH group, the survival rate was significantly decreased compared with that in the control and 30% PH of NASH groups (P < 0.01). 10 of 32 mice in the NASH 70% PH group died within 48 h after PH. Serum aspartate aminotransferase (AST) levels and total bilirubin (T-Bil) in the NASH 70% PH group were significantly higher than the levels in the other two groups (AST: P < 0.05, T-Bil: P < 0.01). In both PH of NASH groups, signaling proteins involved in regeneration were expressed at lower levels than those in the control group (P < 0.01). The 70% PH of NASH group also exhibited a lower number of Ki-67-positive cells and higher rates of apoptosis and necrosis than the NASH 30% PH group (P < 0.01). In addition, DNA microarray assays showed differences in gene expression associated with cell cycle arrest and apoptosis.CONCLUSIONThe function of the residual liver is impaired in fatty liver compared to normal liver. A larger residual volume is required to maintain liver functions in mice with NASH.

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Effect of Non-Alcoholic Liver Disease on Recurrence Rate and Liver Regeneration after Liver Resection for Colorectal Liver Metastases

Abstract: Background Resection of metastases is the only potential cure for patients with liver metastasis from colorectal

Cited by 15 publications

References 68 publications

Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets

Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets

NOD‐like receptor C4 Inflammasome Regulates the Growth of Colon Cancer Liver Metastasis in NAFLD

Evaluation of safety for hepatectomy in a novel mouse model with nonalcoholic-steatohepatitis

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