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Adipose cells promote resistance of breast cancer cells to trastuzumab-mediated antibody-dependent cellular cytotoxicity
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Edité par CCSD ; BioMed Central -
International audience. Introduction: Trastuzumab has been used in the treatment of human epidermal growth factor receptor 2 (HER2)-expressing breast cancer, but its efficacy is limited by de novo or acquired resistance. Although many mechanismshave been proposed to explain resistance to trastuzumab, little is known concerning the role of the tumormicroenvironment. Given the importance of antibody-dependent cellular cytotoxicity (ADCC) in the antitumor effectof trastuzumab and the abundance of adipose tissue in the breast, we investigated the impact of adipocyteson ADCC.Methods: We set up a coculture system to study the effect of adipocytes on ADCC in vitro. The results werevalidated in vivo in a mouse xenograft model.Results: We found that adipocytes, as well as preadipocytes, inhibited trastuzumab-mediated ADCC in HER2-expressing breast cancer cells via the secretion of soluble factors. The inhibition of ADCC was not due to titration ordegradation of the antibody. We found that adipose cells decreased the secretion of interferon-γ by natural killercells, but did not alter natural killer cells’ cytotoxicity. Preincubation of breast cancer cells with the conditionedmedium derived from adipocytes reduced the sensitivity of cancer cells to ADCC. Using a transcriptomic approach,we found that cancer cells undergo major modifications when exposed to adipocyte-conditioned medium.Importantly, breast tumors grafted next to lipomas displayed resistance to trastuzumab in mouse xenograft models.Conclusions: Collectively, our findings underline the importance of adipose tissue in the resistance to trastuzumaband suggest that approaches targeting the adipocyte–cancer cell crosstalk may help sensitize cancer cells totrastuzumab-based therapy.
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