P5-06-08: Mesenchymal Stem Cells and Carcinoma-Associated Fibroblasts Sensitize Breast Cancer Cells in 3D Cultures to Kinase Inhibitors.

Abstract

Background: Bone-derived mesenchymal stem cells (MSCs) are attracted to cancer lesions and may differentiate to CAFs. By interacting with cancer cells, MSCs and CAFs may promote cancer progression and modulate drug sensitivity. Material and Methods: To analyze ability of MSCs and CAFs 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) as used in cancer therapy. Results: While MSCs and CAFs did not affect the response of either breast cancer cell line to 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 PKCalpha (protein kinase Calpha) and prevented RAF265-induced conversion of LC3B, a marker of autophagy. To mimic the changes in ERK1/2 phosphorylation and PKCalpha expression in response to the stromal cells, we treated cells with MEK1 inhibitor U0126 or PKCalpha inhibitor Gö6976, respectively. U0126, but not Gö6976, was as effective as hMSCs in sensitizing MDA-MB-231 cells to RAF265. Discussion: Our data suggest 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. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-06-08.

3D hydrogel mimics of the tumor microenvironment: the interplay among hyaluronic acid, stem cells and cancer cells

“…15,40 The presence of MSCs in the TME also increases the sensitivity of CCs to anti-cancer drugs. 41 The MSC : CC ratio is also critical for any outcome, including changes in CC invasiveness and tumor progression. 18,26 To mimic the complexity of the TME, we encapsulated MSCs in the shell of the construct, which was designed to be in direct contact with the core (representing the cancer site) containing the encapsulated CCs.…”

Mesenchymal Stem Cells Relevance in Multicellular Bioengineered 3D In Vitro Tumor Models

“…In a different approach, Dittmer also evaluated if the presence of MSCs in MCF‐7 and MDA‐MB‐231 spheroids affected their susceptibility to 4 tyrosine kinase inhibitors. The interesting results that were obtained indicate that in both spheroids (MCF‐7:MSCs and MDA‐MB‐231:MSCs), the effect of the administered therapeutic anti‐cancer drugs was augmented, pinpointing the decreased resistance to alterations in ERK1/2 phosphorylation and PKCα …”

“…Regarding the available studies, in most circumstances MSCs exert a positive influence in cancer progression, either by increasing malignant cells proliferation, migration, invasion, drug resistance, and/or cancer stem cell proliferation. Alternatively, only few studies report MSCs as having negative effects in cancer cells . The report by Dittmer and co‐workers, demonstrated that BM‐MSCs can invade MCF‐7 and MDA‐MB‐231 breast cancer 3D aggregates, originating a disorganized structures by disrupting cell–cell adhesion, mainly through E‐cadherin cleavage and nuclear translocation, without however increasing EMT and ERK1/2 activity.…”

Acquired Radioresistance in Cancer Associated Fibroblasts is Concomitant with Enhanced Antioxidant Potential and DNA Repair Capacity

“…Particularly, CAFs play critical roles in resistance to targeted therapeutics such as tamoxifen and Gefitinib (15,16). Beyond their contribution to chemo-, endocrine-, and targeted therapy-resistance, CAFs have been implicated in treatment failure and associated poor clinical outcomes following radiotherapy.…”