Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib

Abstract

Background: 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. Methods: To 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 adipocyteconditioned medium. Results: Conditioned 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. Conclusions: Overall, 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.

The paracrine effects of adipocytes on lipid metabolism in doxorubicin-treated triple negative breast cancer cells

“…Similar to the findings reported by others [ 66 , 79 ], we did not observe any differences in the proliferation signalling pathways (i.e. PI3K, Akt, ERK1/2 and its phosphorylation, and NFĸB-p65) between the Dox and Dox+CM-treated MDA-MB-231 cells.…”

“…Leptin derived from obese adipocytes attenuated Tamoxifen’s® treatment efficacy [ 68 ], whereas MCP-1 protected breast cancer cells from 5-Fluorouracil [ 69 ]. Trastuzumab® antibody-mediated dependent cellular cytotoxicity was inhibited by adipocyte-derived factors in breast cancer cells [ 70 ], which was corroborated by 66 , for Lapatinib (tyrosine kinase inhibitor). Therefore, we propose that the treatment resistance observed in the Dox+CM group (increased cell-viability) may in part be as a result of secretory factors in the adipocyte-conditioned media stimulating the utilization/internalization of leptin and MCP-1 proteins by doxorubicin-treated MDA-MB-231 TNBC cells.…”

“…Other cancer drug resistance mechanisms linked to adipocyte and/or adipocyte-derived factors include, but are not limited to, alterations in drug uptake (decreased), efflux (increased) and alterations in drug transporter proteins [ 29 , 63 ], increased drug sequestering [ 65 ], alterations in DNA repair mechanisms/signalling/cell cycle pathways [ 66 ], as well as metabolic lipid reprogramming [ 10 , 25 , 36 ], highlighting the complexity of drug resistance.…”

Bone Marrow Adipocytes: A Link between Obesity and Bone Cancer

“…In primary breast cancer, adipocytes and adipocyte-derived factors have been linked to drug resistance and malignancy. In vitro, experiments with HER2+ BT474 and SKBR3 breast cancer cells cultured in the presence or absence of conditioned media from mature adipocytes demonstrated that in basal conditions, tyrosine kinase inhibitors (TKI) (often used to treat HER2+ breast cancer) induced p27 leading to apoptosis, which did not occur in the presence of adipocyte conditioned medium [40]. Contact of breast cancer cells with adipose tissue in vivo also led to reduced sensitivity to TKI [40].…”

“…In vitro, experiments with HER2+ BT474 and SKBR3 breast cancer cells cultured in the presence or absence of conditioned media from mature adipocytes demonstrated that in basal conditions, tyrosine kinase inhibitors (TKI) (often used to treat HER2+ breast cancer) induced p27 leading to apoptosis, which did not occur in the presence of adipocyte conditioned medium [40]. Contact of breast cancer cells with adipose tissue in vivo also led to reduced sensitivity to TKI [40]. In acute lymphoblastic leukemia (ALL), ALL cells migrate toward mature adipocytes in vitro, as well as subcutaneous and visceral adipose explants, which provide protection from daunorubicin and vincristine [41].…”