Fatty change of the liver microenvironment influences the metastatic potential of colorectal cancer

Abstract

Summary Fatty liver is the most common cause of liver disease, and its prevalence has been increasing globally. Colorectal cancer (CRC) accounts for approximately 10% of all cancers and metastasizes most commonly to the liver. Paget's ‘Seed and Soil’ theory of metastasis proposed that the secondary growth of cancer cells is dependent on the distal organ microenvironment. This implies that the risk of metastasis may change due to changes in the microenvironment of target organs. However, the association between steatosis, fatty change in the liver microenvironment, and liver metastasis has not been clarified. Here, we induced fatty liver conditions in BALB/c mice using a choline‐deficient high‐fat diet with 0.1% methionine (CDAHFD) and then injected the CT26 cells to produce experimental metastasis. The number of metastatic tumours was significantly increased in mice with severe fatty liver as compared to control mice. The average size of metastatic tumours was smaller in mice with moderate fatty liver than in control mice. The stromal components, including cancer‐associated fibroblasts, tumour‐associated macrophages and tumour‐infiltrating lymphocytes, were also examined. Metastatic tumours in fatty liver showed invasive growth patterns without a fibrotic capsule. Compared to control groups, the polarization of macrophages and subtypes of tumour‐infiltrating lymphocytes differed depending on the extent of fatty liver progression. These results indicated that fatty changes in the liver influenced liver metastasis of CRC. Although moderate fatty changes suppress the growth of metastatic tumours in the liver, a severe fatty microenvironment may promote invasion and metastasis through alteration of the tumour microenvironment (TME).

Lipid metabolism in cancer: New perspectives and emerging mechanisms

“…Diet-induced obesity was a requirement for this effect, with obesity-resistant mice not experiencing increased metastatic tumor growth with HFD feeding (Bousquenaud et al, 2018). Using the CR26 colorectal cancer cell line, feeding BALB/c mice with a choline-deficient HFD stimulated fatty liver development and increased liver metastases (Masaki et al, 2020).…”

Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives, and recent mechanistic insights

“…Masaki S. Int J Exp Pathol 2020 15 Fatty liver conditions were induced in BALB/c mice. CT26 cells were injected into the liver.…”

“…In addition, attempts have been made to develop technologies for predicting HGPs using medical imaging and machinelearning algorithms [7][8][9][10] . Novel animal models for liver metastasis exhibiting features of the different HGPs are a particularly valuable development [11][12][13][14][15][16][17] . These models will allow us to: 1) perform functional validation of HGP-specific signalling pathways described in the clinical samples of liver metastases, 2) identify non-invasive surrogate markers for the different HGPs and 3) test the efficacy of new therapeutic strategies based on the HGPs.…”

Whole-liver enhanced CT radiomics analysis to predict metachronous liver metastases after rectal cancer surgery

“…In addition, the effect of fatty liver on LM of CRC has been widely concerned in recent years [ 9 ], but no unified conclusion has been reached. Some studies believed that the fatty liver microenvironment was conducive to tumor progression [ 10 ], while others thought that moderate fat changes could inhibit the growth of LM [ 11 ]. This finding may be attributed to the influence of liver microenvironment changes induced by diffuse liver injury on the planting of metastatic cells in the liver.…”