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.
Highlights
Treatment of early-stage cancer, including surgery, hormone therapy, and chemotherapy, has improved substantially, but preventing metastasis remains a more elusive target
Given steatosis is preventable and we find its eradication eliminates metastatic predisposition, if our observations translate to patients, the implications would be significant
While bioluminescence imaging (BLI) and gross and microscopic examination revealed a paucity of hepatic metastasis in control mice, breast cancer was abundant in the livers of FF mice (Figure 1, A–D)
Summary
Treatment of early-stage cancer, including surgery, hormone therapy, and chemotherapy, has improved substantially, but preventing metastasis remains a more elusive target. The most common malignancy in women, recurs in 1 of 5 patients, despite ideal therapy. Obesity is expected to affect 1 in 2 adults by 2030 [3] and is associated with increased incidence of at least 13 types of cancer [4] and poorer prognosis [5]; yet the mechanisms of these associations remain unresolved. There is, experimental evidence that the products of adipocytes, juxtaposed to the tumor, promote its growth. The means by which obese adipocytes enhance tumor growth is postulated to involve inflammatory factors, fatty acid transfer, and/or direct interaction with the tumor [6]
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