Dietary fats suppress the peritoneal seeding of colorectal cancer cells through the TLR4/Cxcl10 axis in adipose tissue macrophages

Signal Transduct Target Ther. 2020 Oct 15;5(1):239. doi: 10.1038/s41392-020-00327-z.

Abstract

Peritoneal carcinomatosis (PC) of colorectal cancer (CRC) is a terminal phase of malignancy with no effective strategies for the prevention of this condition. Here we established PC models in mice by intraperitoneal engraftment of CRC cells and revealed an unexpected role for a high-fat diet (HFD) in preventing metastatic seeding in the visceral fat. Mechanistically, the HFD stimulated the activation of adipose tissue macrophages (ATMs) toward an M1-like phenotype and enhanced ATM tumor phagocytosis in a TLR4-dependent manner. Furthermore, the TLR4-Cxcl10 axis in ATMs promoted T cell recruitment, and M1-like macrophages stimulated T cell activation in tumor-seeded fats. The inhibitory effect of the HFD on tumor seeding was abolished with the ablation of macrophages, inactivation of T cells, or blockade of the TLR4-Cxcl10 axis in macrophages. Finally, we showed that a HFD and conventional chemotherapeutic agents (oxaliplatin or 5-fluorouracil) synergistically improved the survival of tumor-seeded mice. Collectively, our findings demonstrate that peritoneal seeding of CRC can be suppressed by short-term treatment with a HFD in the early phase, providing a novel concept for the management of these patients in the clinic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / immunology*
  • Animals
  • Cell Line, Tumor
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / immunology*
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology*
  • Dietary Fats / pharmacology*
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Nude
  • Neoplasm Metastasis
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / immunology*
  • Peritoneal Neoplasms / prevention & control
  • Peritoneal Neoplasms / secondary
  • Phagocytosis
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology*

Substances

  • Chemokine CXCL10
  • Cxcl10 protein, mouse
  • Dietary Fats
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4