Hepatic lipids promote liver metastasis

Abstract

Obesity predisposes to cancer and a virtual universality of nonalcoholic fatty liver disease (NAFLD). However, the impact of hepatic steatosis on liver metastasis is enigmatic. We find that while control mice were relatively resistant to hepatic metastasis, those which were lipodystrophic or obese, with NAFLD, had a dramatic increase in breast cancer and melanoma liver metastases. NAFLD promotes liver metastasis by reciprocal activation initiated by tumor-induced triglyceride lipolysis in juxtaposed hepatocytes. The lipolytic products are transferred to cancer cells via fatty acid transporter protein 1, where they are metabolized by mitochondrial oxidation to promote tumor growth. The histology of human liver metastasis indicated the same occurs in humans. Furthermore, comparison of isolates of normal and fatty liver established that steatotic lipids had enhanced tumor-stimulating capacity. Normalization of glucose metabolism by metformin did not reduce steatosis-induced metastasis, establishing the process is not mediated by the metabolic syndrome. Alternatively, eradication of NAFLD in lipodystrophic mice by adipose tissue transplantation reduced breast cancer metastasis to that of control mice, indicating the steatosis-induced predisposition is reversible.

The Metabolic Mechanisms of Breast Cancer Metastasis

“…NETosis is an important neutrophil function that can promote liver metastasis of breast cancer and different pro-metastatic neutrophil populations are highly metabolically adaptable, which facilitates the formation of liver metastases ( 145 ). The products of pathologically deposited lipids can promote metastasis and nonalcoholic fatty liver disease (NAFLD) activates tumor-induced triglyceride lipolysis in juxtaposed hepatocytes, thereby promoting breast-to-liver metastasis ( 146 ). In addition to genetic tendency, metastatic cells that inhabit the brain are adaptive to crosstalk with many different brain residential cells ( 112 , 147 ).…”

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

“…In animal study, high fat diet-induced steatosis profoundly increase liver metastasis in a splenic injection model of experimental liver metastasis using syngeneic MC38 colon cancer cells ( 38 ). Referring to potential mechanisms that contribute to CRLM, Li et al ( 39 ) found that mice with hepatic steatosis have a marked predisposition to liver metastasis, which is unusual in non-steatotic mice. The mechanism is that lipolytic products are transferred to cancer cells via fatty acid transporter protein 1, and promote cancer cells growth by mitochondrial oxidation ( 39 ).…”

“…Referring to potential mechanisms that contribute to CRLM, Li et al ( 39 ) found that mice with hepatic steatosis have a marked predisposition to liver metastasis, which is unusual in non-steatotic mice. The mechanism is that lipolytic products are transferred to cancer cells via fatty acid transporter protein 1, and promote cancer cells growth by mitochondrial oxidation ( 39 ). 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 ).…”

PCBP1 regulates the transcription and alternative splicing of metastasis‑related genes and pathways in hepatocellular carcinoma

“…Previous studies have shown that glucose metabolism, particularly glycolysis, is of great significance in tumour development and metastasis 20 – 22 . Abnormal lipid metabolism is associated with the growth and metastatic cascade of HCC and other tumours 23 , 24 .…”