Natural killer cells inhibit breast cancer cell invasion through downregulation of urokinase­type plasminogen activator.

Triple­negative breast cancer (TNBC) is one of the most aggressive types of breast cancer, and there is no effective therapeutic target to date. Natural killer (NK) cells are functionally diverse lymphocytes that recognize and kill cancer cells. Although it is clear that NK cells exert antitumor activity in the tumor microenvironment, their role in the aggressive progression of TNBC has not been elucidated in detail. In the present study, we investigated the effect of NK cells on MDA­MB­231 TNBC cells using an indirect co­culture system. The invasive phenotype of MDA­MB­231 cells was significantly inhibited by co­culture with NK cells. Notably, the expression of urokinase­type plasminogen activator (uPA) was markedly reduced by NK cells. Cytokine array analysis showed that the levels of interleukin (IL)­10, IL­6, IL­8, C­C motif ligand (CCL)5, and CCL2 were increased in conditioned media from the co­cultured cells. Among these cytokines, IL­6 played a crucial role in the NK cell­induced uPA downregulation and inhibition of the invasive phenotype of MDA­MB­231 cells and Hs578T cells. We analyzed the Gene Expression Profiling Interactive Analysis database for correlations between IL­6 and uPA with the overall survival of breast cancer patients. The Kaplan­Meier survival analysis revealed that a low IL­6/uPA ratio was associated with the poor survival of breast cancer patients, suggesting it as an important factor for determining the overall survival of breast cancer patients. Taken together, our findings demonstrate that NK cells in the tumor microenvironment inhibit the invasiveness of TNBC cells through the IL­6­mediated inhibition of uPA.

Correction to: Crosstalk between cancer cells and endothelial cells: implications for tumor progression and intervention.

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Crosstalk between cancer cells and endothelial cells: implications for tumor progression and intervention.

Communication between tumor cells and stromal cells is crucial to tumor development and progression. Fibroblasts and macrophages are the most common stromal cells in the tumor microenvironment. Endothelial cells are another type of stromal cell in the tumor microenvironment required for angiogenesis via interaction with tumor cells. Tumor angiogenesis provides not only oxygen and nutrients for tumor cells but also the necessary anchorage to facilitate tumor metastasis. The present review summarizes studies on the crosstalk between cancer cells and endothelial cells with a focus on implications for tumor progression. The following four categories are discussed in this review: (1) cell-cell communication in tumor microenvironment; (2) induction of metastasis by interaction between cancer cells and endothelial cells; (3) angiogenesis induced by tumor cells; (4) therapeutic strategies targeting adhesion and signaling molecules as well as chemokines. This review provides useful information highlighting the process of cancer aggressiveness affected by the crosstalk between cancer cells and endothelial cells, and suggests therapeutic strategies against tumor progression.