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TGF-b1 stimulates lymphatic endothelial cells to produce IL-7 and IL-15, which act as chemotactic factors for breast cancer cells with EMT properties

ABSTRACT: The lymphatic system is a major gateway for tumor cell dissemination but the mechanisms of how tumor cells gain access to lymphatic vessels are not completely understood. Breast cancer cells undergoing epithelial-mesenchymal transition (EMT) gain invasive and migratory properties. Overexpression of the cytokine transforming growth factor β1 (TGF-b1), a potent inducer of EMT, is frequently detected in the tumor microenvironment and correlates with invasion and lymph metastasis. Recently, we reported that TGF-b1 stimulated breast cancer cells with EMT properties migrate in a targeted fashion towards the lymphatic system via CCR7/CCL21-mediated chemotaxis, similar to dendritic cells during inflammation. Here, we aimed to identify additional chemotactic factors and receptors that could be involved in this. Through a combination of RNA sequencing analysis, database screening and invasion assays we identified IL-7/IL7R and IL-15/IL15R as pairs of chemokines and chemokine receptors with potential roles in promoting chemotactic migration of breast cancer cells with EMT properties towards the lymphatics. The results warrant studies to further explore their possible roles in lymph metastasis in breast cancer. Moreover, they demonstrate the capacity of TGF-b1 to orchestrate crosstalk between tumor cells and lymphatic endothelial cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE241881 | GEO | 2023/12/13

REPOSITORIES: GEO

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TGF-b1 stimulates lymphatic endothelial cells to produce IL-7 and IL-15, which act as chemotactic factors for breast cancer cells with EMT properties

Project description:TGF-b1 stimulates lymphatic endothelial cells to produce IL-7 and IL-15, which act as chemotactic factors for breast cancer cells with EMT properties

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Expression data from Control and Six1 expressing MCF7 cells

Project description:Inappropriate activation of developmental pathways is a well-recognized tumor-promoting mechanism. Here we show that overexpression of the homeoprotein Six1, normally a developmentally restricted transcriptional regulator, increases Transforming Growth Factor-beta (TGF-beta) signaling in mammary carcinoma cells and induces an epithelial to mesenchymal transition (EMT) that is in part dependent on its ability to increase TGF-beta signaling. TGF-beta signaling and EMT have been implicated in metastatic dissemination of carcinoma. Using spontaneous and experimental metastasis mouse models, we demonstrate that Six1 overexpression promotes breast cancer metastasis. In addition, we show that, like its induction of EMT, Six1-induced experimental metastasis is dependent on its ability to activate TGF-beta signaling. Importantly, in human breast cancers Six1 significantly correlates with nuclear Smad3, and thus increased TGF-beta signaling. Further, breast cancer patients whose tumors overexpress Six1 have a shortened time to relapse and metastasis, and an overall decrease in survival. Finally, we show that the effects of Six1 on tumor progression likely extend beyond breast cancer, since its overexpression correlates with adverse outcomes in numerous other cancers, including brain, cervical, prostate, colon, kidney, and liver, amongst others. Our findings argue that Six1, acting through TGF-beta signaling and EMT, is a powerful and global promoter of cancer metastasis.

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