Abstract
BackgroundThe existence of a cross-talk between peritumoral adipocytes and cancer cells has been increasingly investigated. Several studies have shown that these adipocytes protect tumor cells from the effect of anticancer agents.MethodsTo investigate a potential protective effect of adipocyte-conditioned medium on HER2 positive breast cancer cells exposed to tyrosine kinase inhibitors (TKI) such as lapatinib, we analyzed the sensitivity of HER2 positive breast cancer models in vitro and in vivo on SCID mice in the presence or absence of adipocytes or adipocyte-conditioned medium.ResultsConditioned medium from differentiated adipocytes reduced the in vitro sensitivity of the HER2+ cell lines BT474 and SKBR3 to TKI. Particularly, conditioned medium abrogated P27 induction in tumor cells by lapatinib but this was observed only when conditioned medium was present during exposure to lapatinib. In addition, resistance was induced with adipocytes derived from murine NIH3T3 or human hMAD cells but not with fibroblasts or preadipocytes. In vivo studies demonstrated that the contact of the tumors with adipose tissue reduced sensitivity to lapatinib. Soluble factors involved in this resistance were found to be thermolabile. Pharmacological modulation of lipolysis in adipocytes during preparation of conditioned media showed that various lipolysis inhibitors abolished the protective effect of conditioned media on tumor cells, suggesting a role for adipocyte lipolysis in the induction of resistance of tumor cells to TKI.ConclusionsOverall, our results suggest that contact of tumor cells with proximal adipose tissue induces resistance to anti HER2 small molecule inhibitors through the production of soluble thermolabile factors, and that this effect can be abrogated using lipolysis inhibitors.
Highlights
The existence of a cross-talk between peritumoral adipocytes and cancer cells has been increasingly investigated
In order to investigate whether the protective effect of adipocyte-secreted factors is dependent on human epidermal growth factor receptor 2 (HER2) expression, we explored the lapatinib-induced cytotoxic effect on different breast cancer cell lines in the presence or absence of adipocyte-conditioned medium
Adipocyte-conditioned medium reduces lapatinibinduced cell cycle blockade in tumor cells To assess lapatinib-induced cell cycle blockade, we stained the SKBR3 cells with propidium iodide and performed flow cytometry analyses of cells cultured in control medium or in #3T3-CM in the presence or absence of lapatinib
Summary
The existence of a cross-talk between peritumoral adipocytes and cancer cells has been increasingly investigated. Several studies have shown that these adipocytes protect tumor cells from the effect of anticancer agents. Geneste et al BMC Pharmacology and Toxicology (2020) 21:61 another HER receptor through heterodimerization Targeted therapies such as monoclonal antibodies or tyrosine kinase inhibitors (TKI) have provided a significant improvement in patient outcome by targeting HER2 or its dimerization partners. Several in vitro studies have demonstrated a decrease of efficacy of targeted therapies on breast tumor cells when cells are cultured in the presence of adipocytes or adipocyte-conditioned medium (CM) [16,17,18,19]. Our team showed that adipocyte-secreted factors decreased the efficacy of trastuzumab on BT-474 and SKBR-3 breast cancer cell lines [16]. More recently we have shown that MVP could be involved in adipocyte-induced resistance of breast cancer cells to doxorubicin [23]
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