Mesenchymal Stem Cell-Induced Doxorubicin Resistance in Triple Negative Breast Cancer

Abstract

Triple negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and a worse clinical outcome compared with other breast cancer subtypes. Doxorubicin is considered to be one of the most effective agents in the treatment of TNBC. Unfortunately, resistance to this agent is common. In some drug-resistant cells, drug efflux is mediated by adenosine triphosphate-dependent membrane transporter termed adenosine triphosphate-binding cassette (ABC) transporter, which can drive the substrates across membranes against concentration gradient. In the tumor microenvironment, upon interaction with mesenchymal stem cells (MSCs), tumor cells exhibit altered biological functions of certain gene clusters, hence increasing stemness of tumor cells, migration ability, angiogenesis, and drug resistance. In our present study, we investigated the mechanism of TNBC drug resistance induced by adipose-derived MSCs. Upon exposure of TNBC to MSC-secreted conditioned medium (CM), noticeable drug resistance against doxorubicin with markedly increased BCRP protein expression was observed. Intracellular doxorubicin accumulation of TNBC was also decreased by MSC-secreted CM. Furthermore, we found that doxorubicin resistance of TNBC was mediated by IL-8 presented in the MSC-secreted CM. These findings may enrich the list of potential targets for overcoming drug resistance induced by MSCs in TNBC patients.

Peri-foci adipose-derived stem cells promote chemoresistance in breast cancer

“…The tumor microenvironment can also stimulate the development of drug resistance by changing the gene transcription within cancer cells to override the cytotoxicity or increase efflux of anticancer drugs [ 53 ]. Numerous in vitro and in vivo studies reported that cytokines are capable of modulating the expression and function of different drug transporters including P-gp, MRPs, and ABCG2 [ 22 , 54 ]. In our previous study [ 22 ], we also found that a cell line established from adipose-derived mesenchymal stem cell (MSC-ad) secretes IL-8 and gives rise to resistance against chemotherapy in breast cancer cells.…”

“…Cells are maintained in 10-cm dishes in Leibovitz’s L-15 medium (Thermo Fisher Scientific, Waltham, MA, USA). All cells were supplemented with 10% fetal bovine serum (FBS; Thermo Fisher Scientific, Waltham, MA, USA), penicillin (100 U/mL) and streptomycin (100 μg/ml) cocktail (Thermo Fisher Scientific, Waltham, MA, USA), and were maintained in a 37 °C incubator without CO 2 supply [ 22 ].…”

Differential properties of human stromal cells from bone marrow, adipose, liver and cardiac tissues

“…In our co-culture, stromal cells from liver and adipose also supported the proliferation of K562 cells. Recent reports have demonstrated that adipose tissue and associated stroma can maintain breast cancer cells and induce pharmacological resistance [34,35]. Additionally, the links between adipose tissue and activation of inflammation and chemokine pathways with regard to oncogenesis is becoming more recognized [36].…”

Bone marrow mesenchymal stem cells promote head and neck cancer progression through Periostin‐mediated phosphoinositide 3‐kinase/Akt/mammalian target of rapamycin

“…A number of studies have shown that BMMSC play important roles in tumor progression and promote invasion and metastasis in various cancers . In the tumor microenvironment, upon interaction with MSC, breast cancer cells showed altered biological functions of certain gene clusters, hence increasing stemness of tumor cells, migration ability, angiogenesis, and drug resistance . Li et al showed that MSC were mainly distributed in the tumor stroma after i.v.…”

“…13,14 In the tumor microenvironment, upon interaction with MSC, breast cancer cells showed altered biological functions of certain gene clusters, hence increasing stemness of tumor cells, migration ability, angiogenesis, and drug resistance. 15 Li et al 16 showed that MSC were mainly distributed in the tumor stroma after i.v. injection and a low frequency MSC were found to be merged into hepatocellular carcinoma tissue.…”