Cancer-Promoting and Initiating Stem Cells Can Be Derived from Ectopic Locations in Breast Cancer
SH Barsky, Y Xiao, Y Ye, K Yearsley. The Ohio State University College of Medicine, Columbus, OH
Background: Although human breast cancer is all too common, circumstantial evidence exists to suggest that cancer transformation is a rare event. Even in the setting of inherited breast cancer, eg. BRCA1 when all the cells of the breast contain the inherited BRCA1 mutations, transformation on a cellular level is still rare. This suggests that only certain cells are capable of cancer initiation and promotion. Cancer-promoting and cancer-initiating stem cells, while mainly residing in the organ of cancer origin, can also be derived from ectopic locations. In a previous study of human transplant recipients who had received sex-mismatched bone marrow and other organ transplants for various diseases and later developed secondary solid cancers including breast cancer, cancer-promoting stem cells of donor origin giving rise to lymphocytes, fibroblasts, myofibroblasts, tissue macrophages and endothelial cells and rarely, cancer-initiating stem cells were observed within the secondary solid cancer.
Design: Carrying forward these observational human studies to testing these hypotheses experimentally in mouse models, we conducted bone marrow transplantations in transgenic mice genetically engineered to develop breast cancer. Being able to mark the donor bone marrow enzymatically, we were able to study the breast cancers that developed in the mammary gland for the presence of stem cells of donor origin. Using either the bitransgenic MMTV-pymT/ROSA26 or the MMTV-erbb2/neu/ROSA26 models as donors and either sublethally irradiated wild type or single unmarked transgenics as recipients, we investigated the donor v recipient origin of the cancer cells and the cells of the tumor microenvironment.
Results: With either bitransgenic model as donor, we were able to demonstrate that the breast cancers that emerged contained significant percentages of tissue macrophages, lymphocytes, fibroblasts, myofibroblasts and endothelial cells, which represented the progeny of cancer-promoting stem cells of donor origin. These cells were present at very early stages of tumor progression. Rare cancer-initiating stem cells of donor origin were also observed.
Conclusions: These ectopically-derived cells of bone marrow origin present within the tumoral microenvironment may affect breast cancer progression differently from those of endogenous orign and may further contribute to the heterogeneity of the tumor microenvironment. The rare cancer-initiating stem cells of donor origin are additional proof that stem cells can initiate breast cancer.
Tuesday, March 10, 2009 8:00 AM
Platform Session: Section G 1, Tuesday Morning