Mesenchymal stem cells confer chemoresistance in breast cancer via a CD9 dependent mechanism

// Mujib Ullah 1 , Asma Akbar 2 , Nathan Norton Ng 1 , Waldo Concepcion 1 and Avnesh S. Thakor 1 1 Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, Department of Radiology, Palo Alto, CA 94304, USA 2 Mid-Florida Research and Education Center, Department of Pathology, University of Florida, Apopka, FL 32703, USA Correspondence to: Mujib Ullah, email: ullah@stanford.edu Keywords: MSCs; CD9; chemoresistance; cytokine; xenograft tumors Received: March 28, 2019 Accepted: May 05, 2019 Published: May 28, 2019 ABSTRACT The development of chemotherapy drug resistance remains a significant barrier for effective therapy in several cancers including breast cancer. Bone marrow-derived mesenchymal stem cells (BMMSCs) have previously been shown to influence tumor progression and the development of chemoresistance. In the present study, we showed that when GFP labelled BMMSCs and RFP labelled HCC1806 cells are injected together in vivo , they create tumors which contain a new hybrid cell that has characteristics of both BMMSCs and HCC1806 cells. By labelling these cells prior to their injection, we were then able to isolate new hybrid cell from harvested tumors using FACS (DP-HCC1806:BMMSCs). Interestingly, when DP-HCC1806:BMMSCs were then injected into the mammary fat pad of NOD/SCID mice, they produced xenograft tumors which were smaller in size, and exhibited resistance to chemotherapy drugs (i.e. doxorubicin and 5-fluorouracil), when compared tumors from HCC1806 cells alone. This chemoresistance was shown to associated with an increased expression of tetraspanins (CD9, CD81) and drug resistance proteins (BCRP, MDR1). Subsequent siRNA-mediated knockdown of BMMSC-CD9 in DP-HCC1806:BMMSCs resulted in an attenuation of doxorubicin and 5-fluorouracil chemoresistance associated with decreased BCRP and serum cytokine expression (CCL5, CCR5, CXCR12). Our findings suggest that within the tumor microenvironment, CD9 is responsible for the crosstalk between BMMSCs and HCC1806 breast cancer cells (via CCL5, CCR5, and CXCR12) which contributes to chemoresistance. Hence, BMMSC-CD9 may serve as an important therapeutic target for the treatment of breast cancer.