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Endocytic and signalling function of stabilin-1 in tumor associated macrophages

ABSTRACT: Stabilin-1 is a scavenger/sorting receptor expressed by sinusoidal endothelial cells, alternatively-activated and tumor-associated macrophages (TAM) in several types of human cancer and mouse tumor models. We have found abundant expression of stabilin-1 on TAM in mouse model of mammary adenocarcinoma (TS/A) We performed microarrays with TAM isolated from wild type (wt) and stabilin-1 knock out (ko) mice in order to examine if stabilin-1 affects gene expression in TAM using mouse model of TS/A mammary adenocarcinoma

ORGANISM(S): Mus musculus

PROVIDER: GSE55595 | GEO | 2014/10/30

SECONDARY ACCESSION(S): PRJNA240198

REPOSITORIES: GEO

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Project description:Tumor-associated macrophages (TAMs) represent alternatively activated (M2) macrophages that support tumor growth. Previously, we have described a special LYVE-1(+) M2 TAM subset in vitro and in vivo; gene profiling of this TAM subset identified MS4A8A as a novel TAM molecule expressed in vivo by TAM in mammary carcinoma and malignant melanoma. In vitro, Ms4a8a mRNA and MS4A8A protein expression was strongly induced in bone marrow-derived macrophages (BMDMs) by combining M2 mediators (IL-4, glucocorticoids) and tumor-conditioned media (TCM). Admixture of MS4A8A(+) TCM/IL-4/GC-treated BMDM significantly enhanced the tumor growth rate of subcutaneously transplanted TS/A mammary carcinomas. Upon forced overexpression of MS4A8A, Raw 264.7 macrophage-like cells displayed a special gene signature. Admixture of these MS4A8A(+) Raw 264.7 cells also significantly enhanced the tumor growth rate of subcutaneously transplanted mammary carcinomas. To identify the signaling pathways involved in synergistic induction of MS4A8A, the major signaling cascades with known functions in TAM were analyzed. Although inhibitors of NF-M-NM-:B activation and of the MAPK JNK and ERK did not show relevant effects, the p38M-NM-1/M-NM-2 MAPK inhibitor SB203580 strongly and highly significantly (p > 0.001) inhibited MS4A8A expression on mRNA and protein level. In addition, MS4A8A expression was restricted in M2 BMDM from mice with defective GC receptor (GR) dimerization indicating that classical GR gene regulation is mandatory for MS4A8A induction. In conclusion, expression of MS4A8A within the complex signal integration during macrophage immune responses may act to fine tune gene regulation. Furthermore, MS4A8A(+) TAM may serve as a novel cellular target for selective cancer therapy. A recombinant Ms4a8a cDNA was amplified by PCR (primer: Ms4a8a-SpeI-fw 5M-bM-^@M-^YATCGAATTCACTAGTAGCAAAGAGTTGGGAACCGGAGCAAGA3M-bM-^@M-^Y and Ms4a8a-NotI-rv: 5M-bM-^@M-^YATATGCGGCCGCTAGAGCATCTTTAT3M-bM-^@M-^Y) from Ms4a8a cDNA RZPDp981B0530D (IMAGE ID 905005), purified on agarose gel and subcloned after digestion with SpeI and NotI restriction enzymes into the expression vector pEF6/V5-His Topo (Invitrogen) according to standard molecular biology protocols. After confirming sequence identity, we transfected RAW264.7 cells with Ms4a8a vector DNA using Lipofectamine 2000 (Invitrogen) transfection reagent. Transfectants were selected by resistance to blasticidin (Invitrogen). Raw264.7Ms4a8a clone K8 with recombinant Ms4a4a expression were propagated. As a negative control, a vector-transfected RAW264.7mock (clone K3) was selected under parallel culture conditions.

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Endocytic and signalling function of stabilin-1 in tumor associated macrophages

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