Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity

作者：Louis Vermeulen, Matilde Todaro, F. de Sousa Mello, Martin Ronald Sprick, Kristel Kemper, M. Perez Alea, Dick J. Richel, Giorgio Stassi, Jan Paul Medema · 发表于：Proceedings of the National Academy of Sciences · 年份：2008 · DOI：10.1073/pnas.0805706105 · 被引用次数：727 · 研究领域：Cancer Cells and Metastasis、Cancer Genomics and Diagnostics、Cancer Immunotherapy and Biomarkers

Colon carcinoma is one of the leading causes of death from cancer and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, it was reported that a population of undifferentiated cells from a primary tumor, so-called cancer stem cells (CSC), can reconstitute the original tumor on xenotransplantation. Here, we show that spheroid cultures of these colon CSCs contain expression of CD133, CD166, CD44, CD29, CD24, Lgr5, and nuclear beta-catenin, which have all been suggested to mark the (cancer) stem cell population. More importantly, by using these spheroid cultures or freshly isolated tumor cells from multiple colon carcinomas, we now provide compelling evidence to indicate that the capacity to propagate a tumor with all differentiated progeny resides in a single CSC. Single-cell-cloned CSCs can form an adenocarcinoma on xenotransplantation but do not generate the stroma within these tumors. Moreover, they can self-renew and are capable of multilineage differentiation. Further analysis indicated that the lineage decision is dictated by phosphoinositide 3-kinase (PI3K) signaling in CSCs. These data support the hypothesis that tumor hierarchy can be traced back to a single CSC that contains multilineage differentiation capacity, and provides clues to the regulation of differentiation in colon cancers in vivo.