Epithelial-mesenchymal transition in breast cancer lines is mediated through PDGF-D released by tissue-resident stem cells

Epithelial-mesenchymal transition (EMT) generates tumor cells with stem cell properties. The aim of our study was to investigate the effects of adipose tissue-derived stem cells (ASCs) on EMT of cancer cells and to further investigate the mechanisms involved. We demonstrate that conditioned medium from ASCs induces breast cancer cells (4T1) to express mesenchymal markers such as fibronectin, alpha smooth muscle actin and vimentin. Flow cytometry analyses show that ASC-conditioned medium promotes the expansion of CD44 ^high/CD24^low cancer stem cells. Soft agar assays using T47D, BT474 and MCF-7 breast cancer cells reveals that ASC conditioned medium promotes the anchorage-independent growth of cancer cells. These effects were inhibited by a neutralizing antibody against platelet-derived growth factor-D (PDGF-D). Furthermore, PDGF-D treated breast cancer cells grow faster in a mouse model, and this effect could be neutralized by a PDGF antibody. In conclusion, our data show that tissue-resident stem cells interact with the cancer microenvironment via PDGF-D, induce EMT in the cancer cells in a paracrine fashion, thereby increasing the number of cancer stem cells and increase tumor growth in a PDGF dependent manner. Our findings shed new light on mechanisms where local tissue-resident stem cells are able to promote the growth of breast cancer cells. Possibly this could open up a novel selective therapeutic strategy targeting EMT pathways and the specific communication between tissue-resident normal stem cell and cancer stem cells, assuming that the blockage of PDGF-D pathways is critical for tumor growth but would not affect normal tissue homeostasis.