C3a-C3aR signaling promotes breast cancer lung metastasis via modulating carcinoma associated fibroblasts

J Exp Clin Cancer Res. 2020 Jan 13;39(1):11. doi: 10.1186/s13046-019-1515-2.

Abstract

Background: Mounting evidence suggests that complement components promote tumor progression via modulating immune suppression, angiogenesis, or tumor cell proliferation. However, the role of C3a-C3aR signaling in regulating lung metastasis of breast cancer remains unknown.

Methods: We performed various ex-vivo and in-vivo assays. Genetic and pharmacological C3aR blockade models were applied to investigate the role of C3a-C3aR in metastasis of breast cancer.

Results: C3a-C3aR signaling in CAFs facilitates the metastasis of breast cancer. Mechanically, C3a-C3aR signaling augments pro-metastatic cytokine secretion and extracellular matrix components expression of CAFs via the activation of PI3K-AKT signaling. Genetic or pharmacological blockade of C3aR signaling effectively inhibited lung metastasis of breast cancer in mouse models.

Conclusions: C3a-C3aR signaling in CAFs facilitates the metastasis of breast cancer. Targeting C3aR signaling is a potential anti-metastasis strategy for breast cancer therapy.

Keywords: Breast cancer; C3a; C3a receptor; Cancer-associated fibroblast; Complement; Metastasis.

MeSH terms

  • Animals
  • Arginine / administration & dosage
  • Arginine / analogs & derivatives
  • Arginine / pharmacology
  • Benzhydryl Compounds / administration & dosage
  • Benzhydryl Compounds / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cancer-Associated Fibroblasts / drug effects
  • Cancer-Associated Fibroblasts / metabolism*
  • Cell Line, Tumor
  • Complement C3 / genetics
  • Complement C3 / metabolism*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / secondary*
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Complement / genetics
  • Receptors, Complement / metabolism*
  • Signal Transduction

Substances

  • Benzhydryl Compounds
  • C3 protein, human
  • Complement C3
  • Cytokines
  • Extracellular Matrix Proteins
  • Receptors, Complement
  • SB 290157
  • complement C3a receptor
  • Arginine
  • Proto-Oncogene Proteins c-akt