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ANXA10 induction by interaction with tumor-associated macrophages promotes the growth of esophageal squamous cell carcinoma

ABSTRACT: Tumor-associated macrophages (TAMs) have important roles in the progression, angiogenesis and motility of various cancers. To study the effects of TAMs on the tumor microenvironment of ESCCs, we constructed an in vitro system for the differentiation of peripheral blood monocyte (PBMo)-derived macrophages into TAM-like PBMo-derived macrophages. We established a co-culture assay using a human ESCC cell line and TAM-like PBMo-derived macrophages and we performed a cDNA microarray analysis between monocultured and co-cultured ESCC cell lines. Our qRT-PCR confirmed that in the co-cultured ESCC cell lines, CYP1A1, DHRS3, ANXA10, KLK6 and CYP1B1 mRNA were highly up-regulated; AMTN and IGFL1 mRNA were down-regulated. We observed that a high ANXA10 expression was closely associated with the depth of invasion and high numbers of infiltrating CD68+ and CD204+ TAMs. ESCC patients with high ANXA10 expression were significantly correlated with poor disease-free survival (p = 0.0216). ANXA10 knockdown using siRNA significantly suppressed the cell growth of TE-8 and TE-9 ESCC cells by inhibiting Akt and Erk1/2 signaling pathways. We confirmed that ANXA10 overexpression induced the cell growth of TE-15 ESCC cells by activating Akt and Erk1/2 phosphorylation. These results suggest that ANXA10 induced by TAMs in the tumor microenvironment is associated with aberrant growth and a poor prognosis in human ESCC tissues.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118642 | GEO | 2018/08/17

REPOSITORIES: GEO

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Project description:Tumor-associated macrophages (TAMs), often adopting an immunosuppressive M2-like phenotype, correlate with unfavorable cancer outcomes. Our investigation unveiled elevated expression of the butyrophilin (BTN)2A1 in M2-like TAMs across diverse cancer types. We developed anti-BTN2A1 monoclonal antibodies (mAb) and notably, one clone demonstrated a robust inhibitory effect on M2-like macrophage differentiation, inducing a shift towards an M1-like phenotype both in vitro and ex vivo in TAMs from patients with cancer. Macrophages treated with this anti-BTN2A1 mAb exhibited enhanced support for T-cell proliferation and IFNγ secretion. Indeed, M1-like and M2-like macrophage differentiation involves complex signaling pathways leading to specific gene expression profiles. Typically, stimuli from the TME induce pathways including JAK/STATs, MAPK, PI3K/AKT, NOTCH and NF-κB influencing TAMs polarization. We investigated the signaling pathways activated in monocytes and M-CSF-induced M2-like macrophages upon BTN2A1 engagement using anti-BTN2A mAb5. After 30 min of treatment, we observed phosphorylation of MAPKs (i.e. ERK1/2, P38 and JNK) in CD14+ monocytes and in M2-like macrophages, unlike isotype control-treated cells. In contrast, the PI3K/AKT, JAK/STAT, and NF-kB pathways were not consistently activated after 30 min of anti-BTN2A mAb5 treatment. Since BTN2A1 lacks intrinsic kinase activity, we explored whether BTN2A1 could form complexes with molecular partners in M2-like macrophages that provide kinase activity. We prepared lysates from M2-like macrophages treated with mAb5 or with its isotype control for 30 min and performed immunoprecipitation (IP) using another anti-BTN2A mAb followed by western blotting with anti-phosphoTyrosine (pTyr). A 70 kDa was co-immunoprecipitated with BTN2A1 and revealed by the anti-pTyr in lysates from anti-BTN2A mAb5-treated M2-like macrophages. To identify which Tyrosine kinase is enriched in anti-BTN2A mAb5-treated M2-like macrophages, we performed LC-MS/MS on anti-pTyr immunoprecipitates from treated cells. Several tyrosine kinases, including P38α/δ and JNK, were enriched. Notably, SYK was also identified and matched the 72kDa molecular weight of the pTyr band co-immunoprecipitated with BTN2A1.

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ANXA10 induction by interaction with tumor-associated macrophages promotes the growth of esophageal squamous cell carcinoma

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