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The tumor suppressor Semaphorin 3B triggers a pro-metastatic program mediated by IL-8 and the tumor microenvironment

ABSTRACT: Semaphorins are a large family of evolutionary conserved morphogenetic signals originally identified as repelling cues in axonal guidance. Intriguingly, Semaphorins have recently been implicated to play a role in cancer progression. In particular, Semaphorin 3B (SEMA3B) is considered a putative tumor suppressor, and yet we found that it is expressed at high levels in many invasive and metastatic human cancers. By investigating experimental tumor models, we confirmed that SEMA3B expression inhibited tumor growth, whereas metastatic dissemination was surprisingly increased. Interestingly, we found that SEMA3B induced the production of Interleukin-8 (IL-8) by tumor cells, by activating p38-MAPK pathway, in a Neuropilin-1 dependent manner. Further, by silencing the expression of endogenous SEMA3B in tumor cells, IL-8 transcription was impaired. The release of IL-8, in turn, induced tumor-associated macrophage recruitment and metastatic dissemination to the lung that could be rescued by using neutralizing antibodies against IL-8. In conclusion, we report here that SEMA3B plays unexpected functions in cancer progression, as it fosters a pro-metastatic environment, through elevated IL-8 secretion and recruitment of macrophages, coupled to suppression of tumor growth. By performing micro-array analysis of gene expression on mRNA derived from MDA-MB-435 cells transduced with SEMA3B or control Empty Vector (EV), we found that one of the most regulated genes was Interleukin-8 (IL-8) (p< 0.001). Interestingly, IL-8 is known to be a chemo-attractant for leucocytes, endothelial and smooth muscle cells, further implicated in human cancer biology. We thus confirmed micro-array data by real-time quantitative PCR in tumor cell lines transduced with SEMA3B: i.e. A549 lung carcinoma, HeLa cervical carcinoma, HT29 colon carcinoma, and GTL16 gastric carcinoma. In addition, western blotting revealed that IL-8 secretion was strongly induced upon SEMA3B expression. Moreover, IL-8 protein levels were specifically up-regulated by treatment with doxycycline in A549 carcinoma cells expressing SEMA3B under control of a drug-inducible promoter. Keywords: Cell type comparison

ORGANISM(S): Homo sapiens

PROVIDER: GSE10431 | GEO | 2008/04/10

SECONDARY ACCESSION(S): PRJNA108089

REPOSITORIES: GEO

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Project description:Tumor cell-monocyte interactions play crucial roles in shaping up the pro-tumorigenic phenotype and functional output of tumor-associated macrophages. Within the tumor microenvironment, such heterotypic cell–cell interactions are known to occur via secretory proteins. Secretory proteins establish a diabolic liaison between tumor cells and monocytes, leading to their recruitment, subsequent polarization and consequent tumor progression. We co-cultured model lung adenocarcinoma cell line A549 with model monocytes, THP-1 to delineate the interactions between them. The levels of prototypical pro-inflammatory cytokines like TNF-?, IL-6 and anti-inflammatory cytokines like IL-10 were measured by ELISA. Migration, invasion and attachment independence of lung cancer cells was assessed by wound healing, transwell invasion and colony formation assays respectively. The status of EMT was evaluated by immunofluorescence. Identification of secretory proteins differentially expressed in monocultures and co-culture was carried out using SILAC LC–MS/MS. Various insilico tools like Cytoscape, Reacfoam, CHAT and Kaplan–Meier plotter were utilized for association studies, pathway analysis, functional classification, cancer hallmark relevance and predicting the prognostic potential of the candidate secretory proteins respectively. Co-culture of A549 and THP-1 cells in 1:10 ratio showed early release of prototypical pro-inflammatory cytokines TNF-? and IL-6, however anti-inflammatory cytokine, IL-10 was observed to be released at the highest time point. The conditioned medium obtained from this co-culture ratio promoted the migration, invasion and colony formation as well as the EMT of A549 cells. Co-culturing of A549 with THP-1 cells modulated the secretion of proteins involved in cell proliferation, migration, invasion, EMT, inflammation, angiogenesis and inhibition of apoptosis. Among these proteins Versican, Tetranectin, IGFBP2, TUBB4B, C2 and IFI30 were found to correlate with the inflammatory and pro-metastatic milieu observed in our experimental setup. Furthermore, dysregulated expression of these proteins was found to be associated with poor prognosis and negative disease outcomes in lung adenocarcinoma compared to other cancer types. Pharmacological interventions targeting these proteins may serve as useful therapeutic approaches in lung adenocarcinoma. In this study, we have demonstrated that the lung cancer cell-monocyte cross-talk modulates the secretion of IFI30, RNH1, CLEC3B, VCAN, IGFBP2, C2 and TUBB4B favoring tumor growth and metastasis.

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The tumor suppressor Semaphorin 3B triggers a pro-metastatic program mediated by IL-8 and the tumor microenvironment

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