Self-Renewal Inhibition in Breast Cancer Stem Cells: Moonlight Role of PEDF in Breast Cancer

SIMPLE SUMMARY: While more efficient cancer treatments have led to a better quality of life and to five-year survival rates of over 85% for localized tumors, these rates remain below 30% for metastatic tumors. Maintenance of these tumors is due to a population of resistant “cancer stem cells” characterized by their self-renewal. More specifically, the original malignant cell divides into a series of identical stem cells (with low division rate and high resistance to treatment) and other tumor cells that respond to treatment; in this way, when the original tumor disappears, the first cells form a new more resistant tumor and lead to metastasis. In an effort to force the tumor cells to divide into cells that are responsive to chemotherapy, leaving no “cancer stem cells” left to metastasize, we have studied the combination of the Carboxy-PEDF fragment with standard treatments. As our experiments show, this combination could be used to lower chemotherapy doses as well as reduce the likelihood of relapse and metastasis. ABSTRACT: Breast cancer is the leading cause of death among females in developed countries. Although the implementation of screening tests and the development of new therapies have increased the probability of remission, relapse rates remain high. Numerous studies have indicated the connection between cancer-initiating cells and slow cellular cycle cells, identified by their capacity to retain long labeling (LT+). In this study, we perform new assays showing how stem cell self-renewal modulating proteins, such as PEDF, can modify the properties, percentage of biomarker-expressing cells, and carcinogenicity of cancer stem cells. The PEDF signaling pathway could be a useful tool for controlling cancer stem cells’ self-renewal and therefore control patient relapse, as PEDF enhances resistance in breast cancer patient cells’ in vitro culture. We have designed a peptide consisting of the C-terminal part of this protein, which acts by blocking endogenous PEDF in cell culture assays. We demonstrate that it is possible to interfere with the self-renewal capacity of cancer stem cells, induce anoikis in vivo, and reduce resistance against docetaxel treatment in cancer patient cells in in vitro culture. We have also demonstrated that this modified PEDF protein produces a significant decrease in the percentage of expressed cancer stem cell markers.