Mesenchymal stem cells and carcinoma-associated fibroblasts sensitize breast cancer cells in 3D cultures to kinase inhibitors

A Dittmer, A Fuchs, I Oerlecke, B Leyh, S Kaiser, John Martens, J Lutzkendorf, L (Lutz) Muller, J Dittmer

Research output: Contribution to journalArticleAcademicpeer-review

28 Citations (Scopus)


Stromal cells, such as mesenchymal stem cells (MSCs) and carcinoma-associated fibroblasts (CAFs), play a role in cancer progression. To analyze their ability to modulate drug response, we generated spheroids of MCF-7 or MDA-MB-231 breast cancer cells in the absence or presence of human (h)MSCs or hCAFs and tested the susceptibility of the breast cancer cells to three different kinase inhibitors (TKI258, RAD001 and RAF265) used in cancer therapy. While stromal cells did not affect the response of either breast cancer cell line to the PDGFR/FGFR/VEGFR inhibitor TKI258, they sensitized breast cancer cells to the mTOR inhibitor RAD001. In MCF-7 cells, this was accompanied by increased apoptosis. hMSCs and to a lesser extent hCAFs also enhanced the cytotoxic effect of RAF inhibitor RAF265 on MDA-MB-231 cells. Searching for the mechanism that underlies the effect of stromal cells on RAF265 response we found that stromal cells inhibited RAF265-induced increase in ERK1/2 phosphorylation, supported RAF265-dependent downregulation of PKC alpha (protein kinase C alpha) and prevented RAF265-induced conversion of LC3B, a marker of autophagy. To mimic the changes in ERK1/2 phosphorylation and PKC alpha expression in response to the stromal cells, we treated cells with MEK1 inhibitor U0126 or PKC alpha PKC alpha inhibitor Go6976, respectively. U0126, but not Go6976, was as effective as hMSCs in sensitizing MDA-MB-231 cells to RAF265. This suggests that hMSCs and hCAFs increased the cytotoxic effect of RAF265 on MDA-MB-231 cells by downregulating ERK1/2 phosphorylation. In summary, this study shows that hMSCs are able to render breast cancer cells more susceptible to kinase inhibitors and that, to the most part, hCAFs to which hMSCs can differentiate are able to mimic the drug-sensitizing effects of hMSCs.
Original languageUndefined/Unknown
Pages (from-to)689-696
Number of pages8
JournalInternational Journal of Oncology
Issue number3
Publication statusPublished - 2011

Cite this