Contribution of CXCL12 secretion to invasion of breast cancer cells

Breast Cancer Res. 2012 Feb 7;14(1):R23. doi: 10.1186/bcr3108.

Abstract

Introduction: Neu (HER2/ErbB2) is overexpressed in 25% to 30% of human breast cancer, correlating with a poor prognosis. Researchers in previous studies who used the mouse mammary tumor virus Neu-transgenic mouse model (MMTV-Neu) demonstrated that the Neu-YB line had increased production of CXCL12 and increased metastasis, whereas the Neu-YD line had decreased metastasis. In this study, we examined the role of increased production of CXCL12 in tumor cell invasion and malignancy.

Methods: We studied invasion in the tumor microenvironment using multiphoton intravital imaging, in vivo invasion and intravasation assays. CXCL12 signaling was altered by using the CXCR4 inhibitor AMD3100 or by increasing CXCL12 expression. The role of macrophage signaling in vivo was determined using a colony-stimulating factor 1 receptor (CSF-1R) blocking antibody.

Results: The Neu-YD strain was reduced in invasion, intravasation and metastasis compared to the Neu-YB and Neu deletion mutant (activated receptor) strains. Remarkably, in the Neu-YB strain, in vivo invasion to epidermal growth factor was dependent on both CXCL12-CXCR4 and CSF1-CSF-1R signaling. Neu-YB tumors had increased macrophage and microvessel density. Overexpression of CXCL12 in rat mammary adenocarcinoma cells increased in vivo invasion as well as microvessel and macrophage density.

Conclusions: Expression of CXCL12 by tumor cells results in increased macrophage and microvessel density and in vivo invasiveness.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / blood supply
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / secondary*
  • Animals
  • Cell Movement
  • Chemokine CXCL12 / metabolism*
  • Chemokine CXCL12 / physiology
  • Female
  • Humans
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Macrophage Activation
  • Macrophages / metabolism
  • Macrophages / physiology
  • Mammary Neoplasms, Experimental / blood supply
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology*
  • Mice
  • Microscopy, Video
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Neoplastic Cells, Circulating / pathology
  • Paracrine Communication
  • Rats
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Receptors, CXCR4 / metabolism
  • Signal Transduction
  • Tumor Burden
  • Tumor Cells, Cultured
  • Tumor Microenvironment

Substances

  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Receptors, CXCR4
  • Erbb2 protein, mouse
  • Receptor, ErbB-2