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 adi...
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| Format: | Article |
| Language: | English |
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BMC
2020-08-01
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| Series: | BMC Pharmacology and Toxicology |
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| Online Access: | http://link.springer.com/article/10.1186/s40360-020-00436-z |
| _version_ | 1818878843224588288 |
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| author | A. Geneste M. N. Duong L. Molina L. Conilh S. Beaumel A. Cleret K. Chettab M. Lachat L. P. Jordheim E. L. Matera C. Dumontet |
| author_facet | A. Geneste M. N. Duong L. Molina L. Conilh S. Beaumel A. Cleret K. Chettab M. Lachat L. P. Jordheim E. L. Matera C. Dumontet |
| author_sort | A. Geneste |
| collection | DOAJ |
| description | 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 adipocyte-conditioned 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. |
| first_indexed | 2024-12-19T14:20:37Z |
| format | Article |
| id | doaj.art-36d983a613c74225b7050053e0d40daf |
| institution | Directory Open Access Journal |
| issn | 2050-6511 |
| language | English |
| last_indexed | 2024-12-19T14:20:37Z |
| publishDate | 2020-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Pharmacology and Toxicology |
| spelling | doaj.art-36d983a613c74225b7050053e0d40daf2022-12-21T20:17:47ZengBMCBMC Pharmacology and Toxicology2050-65112020-08-0121111210.1186/s40360-020-00436-zAdipocyte-conditioned medium induces resistance of breast cancer cells to lapatinibA. Geneste0M. N. Duong1L. Molina2L. Conilh3S. Beaumel4A. Cleret5K. Chettab6M. Lachat7L. P. Jordheim8E. L. Matera9C. Dumontet10Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286Department of Oncology, Lausanne University Hospital Center (CHUV) and University of LausanneCentre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286Hospices Civils de Lyon, Banque de tissus et cellulesCentre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286Abstract 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 adipocyte-conditioned 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.http://link.springer.com/article/10.1186/s40360-020-00436-zHER2Breast cancerResistanceAdipocytesLapatinib |
| spellingShingle | A. Geneste M. N. Duong L. Molina L. Conilh S. Beaumel A. Cleret K. Chettab M. Lachat L. P. Jordheim E. L. Matera C. Dumontet Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib BMC Pharmacology and Toxicology HER2 Breast cancer Resistance Adipocytes Lapatinib |
| title | Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib |
| title_full | Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib |
| title_fullStr | Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib |
| title_full_unstemmed | Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib |
| title_short | Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib |
| title_sort | adipocyte conditioned medium induces resistance of breast cancer cells to lapatinib |
| topic | HER2 Breast cancer Resistance Adipocytes Lapatinib |
| url | http://link.springer.com/article/10.1186/s40360-020-00436-z |
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