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

• Published in: Cell death & disease 2019-07, Vol.10 (8), p.562-13, Article 562
• Main Authors: Ieranò, Caterina, D’Alterio, Crescenzo, Giarra, Simona, Napolitano, Maria, Rea, Giuseppina, Portella, Luigi, Santagata, Assunta, Trotta, Anna Maria, Barbieri, Antonio, Campani, Virginia, Luciano, Antonio, Arra, Claudio, Anniciello, Anna Maria, Botti, Gerardo, Mayol, Laura, De Rosa, Giuseppe, Pacelli, Roberto, Scala, Stefania
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/51; 14/63; 38/77; 42/109; 631/67/1813/1634; 631/67/322; 64/60; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Bone marrow; c-Kit protein; Cancer; CD11b antigen; CD45 antigen; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Movement - genetics; Cell Survival - genetics; Chemokine CXCL12 - administration & dosage; Chemokine CXCL12 - metabolism; Chemokines; CXCL12 protein; CXCR4 protein; Dermal fillers; Dermal Fillers - administration & dosage; Dermal Fillers - metabolism; Female; Gels; Heterografts; Hyaluronic acid; Immunology; Injections, Subcutaneous; Leukocyte migration; Leukocytes (neutrophilic); Life Sciences; Lung Neoplasms - secondary; Lungs; Lymph nodes; Macrophages; Melanin; Melanoma; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Metastases; Metastasis; 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; Skin; Stromal cells; Transfection; Tumor cells; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1796-6

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.