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Abstract

Abstract

Recently, a speculative model is proposed that tumor tissue is continuously regenerated by a small population of self-renewing cancer stem cells responsible for initiation, growth and propagation of tumor. Tumor cells reside in a “niche” and have constant interaction with the niche components including tumor vasculature, bone marrow mesenchymal stem cells (BM-MSCs) and the components of the extracellular matrix. It is believed that the growth advantage acquired by tumor cells as well as the ability of cancer stem cells (CSCs) to maintain tumor propagation is partly the outcome of this interaction.

Our study intends to better characterize this crosstalk by looking into the possibility of BM-MSC/endothelial cell-mediated activation of Notch pathway in breast cancer cells through production of certain cytokines aiming at proposing novel therapeutic approaches for targeting this disease.

The CSCs were enriched by culturing breast cancer cells (BCC) in 3D media to obtain multicellular spheres for further analysis. BM-MSC and Akt-activated endothelial cells were co-cultured with BCC and spheres to assess their capability in promoting cancer cell growth. RNA interference approach was applied to Notch3 to determine its role in BCC survival by the niche players. A human cytokine array was used to identify the cytokines that showed different expression patterns in the BCC co-cultures with the niche residents.

BM-MSC or Akt-activated Endothelium was able to increase BCC growth up to 4- and 5-fold, respectively, in contact and under serum-free condition. Blocking Notch3 in BCC or spheres by siRNA or inhibition of notch pathway by GSI reduced the proliferation rate of both entities to 2.5-fold, which might underline the role of notch in the interaction between tumor cells and the niche components. Also, several cytokines were identified that were differentially regulated in co-cultures system among which IL6, IL8, and GROa showed significant up-regulation.

Our preliminary data suggest the role of BM-MSC and endothelial cells in breast cancer growth and survival. Our results propose the idea of notch involvement in this interaction through stimulation by certain cytokines. Further investigation is required to elucidate the exact mechanism that is triggered by these cytokines in tumor propagation and maintenance.

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/content/papers/10.5339/qfarf.2011.BMP22
2011-11-20
2019-12-16
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