CXCR4+ circulating tumor cells (CTCs) accumulate in subcutaneous, immune suppressive, CXCL12-loaded-hydrogel

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Circulating tumor cells (CTCs) sensing the chemokine CXCL12 and invading hyaluronic acid hydrogel (CXCL12 loaded hydrogel, CLG) might display metastatic attitude. CLG recovered-human lung (H460, A549), and ovarian cancer cells (IGROV-1) overexpressed the CXCL12 receptor, CXCR4, developed larger spheres and activate transcriptional programs of invasion and stemness. Interestingly, CLG-U87 glioblastoma cells highly expressed EpCAM and significantly upregulated the very specific NGFR, NTS, AQP1 and CMKLR1 genes, associated with cell proliferation, migration/invasion and metastasis. In a syngeneic model, subcutaneous CLG significantly attracted GFP-Lewis lung carcinoma (LLC) cells impairing lung colonization within four hours from cell injection and up to twenty-one days. In lung, M1 macrophages rapidly increased post cancer cells injection while M2 prevailed after 10 days (T10). Neutrophils (Ly6G high and Ly6G low ) infiltrated the lungs after ten days from cells injection with late expansion of immature Ly6G low . According to lung niche, Empty gel (EG) and CLG were early infiltrated by macrophages and later by neutrophils. CLG generated an immunosuppressive environment defined by M1/M2/Ly6G low able to capture and divert metastatic CTCs from the lung colonization.

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