Abstract

The role of mesenchymal stem cells (MSCs) on breast cancer progression, growth and tumorigenesis remains controversial or unknown. In the present study, we investigated the role of MSCs on breast tumor induction and growth in a clinically relevant somatic breast cancer model. We first conducted in vitro studies and found that conditioned media (CM) of RCAS-Neu and RCAS-PyMT breast cancer cell lines and tumor cells themselves dramatically increased the proliferation and motility of MSCs and induced morphological changes of MSCs and differentiation into fibroblast-like cells. In contrast, the CM of MSCs inhibited the proliferation of two breast cancer cell lines by arresting the cell cycle at the G0/G1 phase. In vivo studies revealed that fluorescence dye-labeled MSCs migrated into tumor tissues. Unexpectedly, single or multiple intravenous injections of MSCs did not affect the latency of breast cancer in TVA- transgenic mice induced by intraductal injection of the RCAS vector encoding polyoma middle-T antigen (PyMT) or Neu oncogenes. Moreover, MSCs had no effect on RCAS-Neu tumor growth in a syngeneic ectopic breast cancer model. While our studies consistently demonstrated the ability of breast cancer cells to profoundly induce MSCs migration, differentiation, and proliferation, the anti-proliferative effect of MSCs on breast tumor cells observed in vitro could not be translated into an antitumor activity in vivo, probably reflecting the antagonizing or complex effects of MSCs on tumor environment and tumor cells themselves.

Highlights

  • Mesenchymal stem cells (MSCs) are bone marrow–derived nonhematopoietic precursor cells that contribute to the maintenance and regeneration of connective tissues through engraftment

  • MSCs cultured in the presence of high glucose, bglycerol-phosphate, ascorbic acid, and dexamethasone for three weeks differentiated into osteocytes, as indicated by dark red staining of Alizarin Red (Fig. 1C)

  • The inflammatory milieu produced by healing wounds and tumors play an important role in developing tumor tropism of MSCs

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Summary

Introduction

Mesenchymal stem cells (MSCs) are bone marrow–derived nonhematopoietic precursor cells that contribute to the maintenance and regeneration of connective tissues through engraftment. MSCs can be obtained from bone marrow aspirates, umbilical cord blood, or adipose tissues and expanded in vitro. MSCs are capable of differentiating into bone, cartilage, muscle, fat, and connective tissues throughout the body [1,2]. MSCs delivered intravenously are able to engraft in tumor tissues and differentiate into carcinoma-associated fibroblast cells. Induction of chemotaxis and a pro-inflammatory environment induced by radiation therapy can further promote the engraftment of MSCs into subcutaneous tumors formed after transplantation of cells of the 4T1 breast cancer cell line in Balb/c mice [7]

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