CXCL12 loaded-dermal filler captures CXCR4 expressing melanoma circulating tumor cells

Cell Death Dis. 2019 Jul 22;10(8):562. doi: 10.1038/s41419-019-1796-6.

Abstract

Development of distant metastasis relies on interactions between cancer and stromal cells. CXCL12, also known as stromal-derived factor 1α (SDF-1α), is a major chemokine constitutively secreted in bone marrow, lymph nodes, liver and lung, playing a critical role in the migration and seeding of neoplastic cells. CXCL12 activates the CXCR4 receptor that is overexpressed in several human cancer cells. Recent evidence reveals that tumors induce pre-metastatic niches in target organ producing tumor-derived factors. Pre-metastatic niches represent a tumor growth-favoring microenvironment in absence of cancer cells. A commercially available dermal filler, hyaluronic acid (HA) -based gel, loaded with CXCL12 (CLG) reproduced a "fake" pre-metastatic niche. In vitro, B16-hCXCR4-GFP, human cxcr4 expressing murine melanoma cells efficiently migrated toward CLG. In vivo, CLGs and empty gels (EGs) were subcutaneously injected into C57BL/6 mice and 5 days later B16-hCXCR4-GFP cells were intravenously inoculated. CLGs were able to recruit a significantly higher number of B16-hCXCR4-GFP cells as compared to EGs, with reduced lung metastasis in mice carrying CLG. CLG were infiltrated by higher number of CD45-positive leukocytes, mainly neutrophils CD11b+Ly6G+ cells, myeloid CD11b+Ly6G- and macrophages F4/80. CLG recovered cells recapitulated the features of B16-hCXCR4-GFP (epithelial, melanin rich, MELAN A/ S100/ c-Kit/CXCR4 pos; α-SMA neg). Thus a HA-based dermal filler loaded with CXCL12 can attract and trap CXCR4+tumor cells. The CLG trapped cells can be recovered and biologically characterized. As a corollary, a reduction in CXCR4 dependent lung metastasis was detected.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Survival / genetics
  • Chemokine CXCL12 / administration & dosage
  • Chemokine CXCL12 / metabolism*
  • Dermal Fillers / administration & dosage
  • Dermal Fillers / metabolism*
  • Female
  • Heterografts
  • Injections, Subcutaneous
  • Lung Neoplasms / secondary
  • Melanoma, Experimental / metabolism*
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / genetics
  • Neoplastic Cells, Circulating / metabolism*
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism*
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / metabolism
  • Signal Transduction / genetics
  • Transfection

Substances

  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Dermal Fillers
  • Receptors, CXCR4
  • Recombinant Proteins