The FBW7-MCL-1 axis is key in M1 and M2 macrophage-related colon cancer cell progression: validating the immunotherapeutic value of targeting PI3Kγ

Exp Mol Med. 2020 May;52(5):815-831. doi: 10.1038/s12276-020-0436-7. Epub 2020 May 22.

Abstract

Colorectal cancer is a devastating disease with a low 5-year survival rate. Recently, many researchers have studied the mechanisms of tumor progression related to the tumor microenvironment. Here, we addressed the prognostic value of tumor-associated macrophages (TAMs) using a total of 232 CRC patient tissue samples and investigated the mechanisms underlying TAM-related colon cancer progression with respect to PI3Kγ regulation using in vitro, in vivo, and ex vivo approaches. Patients with M2/M1 < 3 had significantly improved progression-free survival and overall survival compared with patients with M2/M1 > 3. M1 and M2 macrophages elicited opposite effects on colon cancer progression via the FBW7-MCL-1 axis. Blocking macrophage PI3Kγ had cytotoxic effects on colon cancer cells and inhibited epithelial-mesenchymal transition features by regulating the FBW7-MCL-1 axis. The results of this study suggest that macrophage PI3Kγ may be a promising target for immunotherapy in colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers
  • Cell Line, Tumor
  • Cell Movement
  • Cell Plasticity / genetics
  • Cell Plasticity / immunology*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Class Ib Phosphatidylinositol 3-Kinase / metabolism
  • Colonic Neoplasms / etiology
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / therapy
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics
  • Epithelial-Mesenchymal Transition / immunology
  • F-Box-WD Repeat-Containing Protein 7 / metabolism*
  • Female
  • Humans
  • Macrophage Activation / genetics
  • Macrophage Activation / immunology*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Phenotype
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Prognosis
  • Tumor-Associated Macrophages / drug effects
  • Tumor-Associated Macrophages / immunology
  • Tumor-Associated Macrophages / metabolism
  • Tumor-Associated Macrophages / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Phosphoinositide-3 Kinase Inhibitors
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human