Adipose stem cell crosstalk with chemo-residual breast cancer cells: implications for tumor recurrence

Breast Cancer Res Treat. 2019 Apr;174(2):413-422. doi: 10.1007/s10549-018-05103-w. Epub 2018 Dec 29.

Abstract

Purpose: Most triple-negative breast cancer (TNBC) patients exhibit an incomplete response to neoadjuvant chemotherapy, resulting in chemo-residual tumor cells that drive tumor recurrence and patient mortality. Accordingly, strategies for eliminating chemo-residual tumor cells are urgently needed. Although stromal cells contribute to tumor cell invasion, to date, their ability to influence chemo-residual tumor cell behavior has not been examined. Our study is the first to investigate cross-talk between adipose-derived stem cells (ASCs) and chemo-residual TNBC cells. We examine if ASCs promote chemo-residual tumor cell proliferation, having implications for tumor recurrence.

Methods: ASC migration toward chemo-residual TNBC cells was tested in a transwell migration assay. Importance of the SDF-1α/CXCR4 axis was determined using neutralizing antibodies and a small molecule inhibitor. The ability of ASCs to drive tumor cell proliferation was analyzed by culturing tumor cells ± ASC conditioned media (CM) and determining cell counts. Downstream signaling pathways activated in chemo-residual tumor cells following their exposure to ASC CM were studied by immunoblotting. Importance of FGF2 in promoting proliferation was assessed using an FGF2-neutralizing antibody.

Results: ASCs migrated toward chemo-residual TNBC cells in a CXCR4/SDF-1α-dependent manner. Moreover, ASC CM increased chemo-residual tumor cell proliferation and activity of extracellular signal-regulated kinase (ERK). An FGF2-neutralizing antibody inhibited ASC-induced chemo-residual tumor cell proliferation.

Conclusions: ASCs migrate toward chemo-residual TNBC cells via SDF-1α/CXCR4 signaling, and drive chemo-residual tumor cell proliferation in a paracrine manner by secreting FGF2 and activating ERK. This paracrine signaling can potentially be targeted to prevent tumor recurrence.

Keywords: Adipose-derived stem cells (ASCs); Fibroblast growth factor 2 (FGF2); Migration; Proliferation; Recurrence; Triple-negative breast cancer (TNBC).

MeSH terms

  • Adipose Tissue / cytology*
  • Adipose Tissue / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Chemokine CXCL12 / metabolism*
  • Culture Media, Conditioned / chemistry
  • Drug Resistance, Neoplasm*
  • Female
  • Fibroblast Growth Factor 2 / metabolism*
  • Humans
  • MAP Kinase Signaling System
  • Neoplasm Recurrence, Local / metabolism
  • Paracrine Communication
  • Receptors, CXCR4 / metabolism*
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology*
  • Tumor Microenvironment

Substances

  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Culture Media, Conditioned
  • Receptors, CXCR4
  • Fibroblast Growth Factor 2