PROSPECTIVE IDENTIFICATION AND CHARACTERIZATION OF BREAST CANCER STEM CELLS

摘要

Human breast tumors contain heterogeneous cancer cells. Using an animal xenograft model in which human breast cancer cells were grown in immunocompromised mice, we found that only a small minority of breast cancer cells had the capacity to form new tumors. The ability to form new tumors was not a stochastic property, rather certain populations of cancer cells were depleted for the ability to form new tumors, while other populations were enriched for the ability to form new tumors. Tumorigenic cells could be distinguished from non-tumorigenic cancer cells based on surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD44<+>CD24<-/lo>LINEAGE<->. As few as 100 cells from this population were able to form tumors the animal xenograft model, while tens of thousands of cells from non-tumorigenic populations failed to form tumors. The tumorigenic cells could be serially passaged, each time generating new tumors containing an expanded numbers of CD44<+>CD24<-/low>Lineage<- >tumorigenic cells as well as phenotypically mixed populations of non-tumorigenic cancer cells. This is reminiscentof the ability of normal stem cells to self-renew and differentiate. The expression of potential therapeutic targets also differed between the tumorigenic and non-tumorigenic populations. Notch activation promoted the survival of the tumorigenic cells, and a blocking antibody against Notch4 induced tumorigenic breast cancer cells to undergo apoptosis.