ABSTRACT
The immunosuppressive tumor microenvironment is a hallmark of cancer. Myeloid-derived suppressor cells (MDSCs) are CD11b+ Gr-1+ tumor-infiltrating immature myeloid cells that strongly mediate tumor immunosuppression. The CD11b+ Gr-1+ cells are a heterogeneous cell population, and the impacts of each subpopulation on tumor progression are not yet completely understood. In the present study, we identified a novel subpopulation of CD11b+ Gr-1+ cells from murine lung carcinoma tumors according to their strongly adherent abilities. Although strong adherent activity is a unique property of macrophages, their marker expression patterns are similar to those of MDSCs; thus, we named this novel subpopulation MDSC-like adherent cells (MLACs). Unlike known MDSCs, MLACs lack the ability to suppress cytotoxic T lymphocytes and differentiate into tumor-associated macrophages (TAMs), but could still directly facilitate tumor growth and angiogenesis through secreting CCL2, CXCL1/2/5, PAI-1, MMPs, and VEGFA. Furthermore, MLACs recruited MDSCs via the secretion of CCL2/5 and CXCL1/2/5, thereby enhancing the immunosuppressive tumor microenvironment and promoting TAMs-mediated tumor progression. Our findings suggest that MLACs may function as an initiator of the immunosuppressive tumor microenvironment and highlight a new therapeutic target to prevent the onset or delay malignant progression.
ABSTRACT
Cell-penetrating peptides (CPPs), also referred to as protein transduction domains (PTDs), can mediate the cellular uptake of a wide range of macromolecules including peptides, proteins, oligonucleotides, and nanoparticles, and thus have received considerable attention as a promising method for drug delivery in vivo. Here, we report that CPP/PTDs facilitate the extravasation of fused proteins by binding to neuropilin-1 (NRP1), a vascular endothelial growth factor (VEGF) co-receptor expressed on the surface of endothelial and some tumor cells. In this study, we examined the capacity of the amphipathic and cationic CPP/PTDs, PTD-3 and TAT-PTD, respectively, to bind cells in vitro and accumulate in xenograft tumors in vivo. Notably, these functions were significantly suppressed by pre-treatment with NRP1-neutralizing Ab. Furthermore, co-injection of iRGD, a cyclic peptide known to increase NRP1-dependent vascular permeability, significantly reduced CPP/PTD tumor delivery. This data demonstrates a mechanism by which NRP1 promotes the extravasation of CPP/PTDs that may open new avenues for the development of more efficient CPP/PTD delivery systems.
Subject(s)
Cell-Penetrating Peptides/administration & dosage , Neoplasms/metabolism , Neuropilin-1/metabolism , Animals , Cell Line , Cell Line, Tumor , Cell-Penetrating Peptides/chemistry , Drug Delivery Systems , Gene Products, tat/administration & dosage , Gene Products, tat/chemistry , Humans , Male , Mice, Inbred BALB C , Oligopeptides/administration & dosage , Protein Structure, Tertiary , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/chemistryABSTRACT
We have developed Fe-In-Sn-O fine particle or powder catalysts for synthesizing carbon nanocoils by catalytic thermal chemical vapor deposition. The coprecipitation technique was used to produce the powder catalysts. By optimizing the composition ratios of Fe, In (between 10 and 33% of Fe), and Sn (less than 3.3% of Fe), carbon nanocoils could be grown in high yield. From the study of optimizing the compositions of In and Sn and the study of crystal structures of the catalysts using X-ray diffraction measurements, it was also found that Sn in the catalysts was required to grow carbon nanocoils and that In plays roles in increasing the yield of carbon nanocoils and controlling the coil diameters. This study will lead to the mass production of carbon nanocoils and therefore widen their applications.
