Because the esophageal epithelium lacks a defined stem cell niche, it is unclear whether all basal epithelial cells in the adult esophagus are functionally equivalent. In this study, we showed that basal cells in the mouse esophagus contained a heterogeneous population of epithelial cells, similar to other rapidly cycling tissues such as the intestine or skin. Using a combination of cell-surface markers, we separated primary esophageal tissue into distinct cell populations that harbored differences in stem cell potential. We also used an in vitro 3D organoid assay to demonstrate that Sox2, Wnt, and bone morphogenetic protein signaling regulate esophageal self-renewal. Finally, we labeled proliferating basal epithelial cells in vivo to show differing cell-cycle profiles and proliferation kinetics. Based on our results, we propose that a nonquiescent stem cell population resides in the basal epithelium of the mouse esophagus.

The mammalian target of rapamycin (mTOR) has emerged as a potential target for drug development, particularly due to the fact that it plays such a crucial role in cancer biology. In addition, next-generation mTOR inhibitors have become available, marking an exciting new phase in mTOR-based therapy. However, the verdict on their therapeutic effectiveness remains unclear. Here we review phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling as one of the primary mechanisms for sustaining tumor outgrowth and metastasis, recent advances in the development of mTOR inhibitors, and current studies addressing mTOR activation/inhibition in colorectal cancer (CRC). We will also discuss our recent comparative study of different mTOR inhibitors in a population of colon cancer stem cells (CSCs), and current major challenges for achieving individualized drug therapy using kinase inhibitors.

Human cancers have been found to include transformed stem cells that may drive cancer progression to metastasis. Here, we report that metastatic colon cancer contains clonally derived tumor cells with all of the critical properties expected of stem cells, including self-renewal and the ability to differentiate into mature colon cells. Additionally, when injected into mice, these cells initiated tumors that closely resemble human cancer. Karyotype analyses of parental and clonally derived tumor cells expressed many consistent (clonal) along with unique chromosomal aberrations, suggesting the presence of chromosomal instability in the cancer stem cells. Thus, this new model for cancer origin and metastatic progression includes features of both the hierarchical model for cancerous stem cells and the stochastic model, driven by the observation of chromosomal instability. [Cancer Res 2008;68(17):6932–41]

Komori et al. show that hepatocytes, pancreatic islets and thymocytes flourish in the mouse lymph node, suggesting that lymph nodes could serve as a transplantation site for cell therapies. Cell-based therapy has been viewed as a promising alternative to organ transplantation, but cell transplantation aimed at organ repair is not always possible. Here we show that the mouse lymph node can support the engraftment and growth of healthy cells from multiple tissues. Direct injection of hepatocytes into a single mouse lymph node generated enough ectopic liver mass to rescue the survival of mice with lethal metabolic disease. Furthermore, thymuses transplanted into single lymph nodes of athymic nude mice generated functional immune systems that were capable of rejecting allogeneic and xenogeneic grafts. Additionally, pancreatic islets injected into the lymph nodes of diabetic mice restored normal glucose control. Collectively, these results suggest the practical approach of targeting lymph nodes to restore, maintain or improve tissue and organ functions.

Metastatic colorectal cancer (CRC) is incurable for most patients. Since mammalian target of rapamycin (mTOR) has been suggested as a crucial modulator of tumor biology, we aimed at evaluating the effectiveness of mTOR targeting for CRC therapy. To this purpose, we analyzed mTOR expression and the effect of mTOR inhibition in cancer stem-like cells isolated from three human metastatic CRCs (CoCSCs).

Biologic scaffolds composed of extracellular matrix (ECM) have been used to facilitate repair or remodeling of numerous tissues, including the esophagus. The theoretical ideal scaffold for tissue repair is the ECM derived from the particular tissue to be treated; i.e., site-specific or homologous ECM. The preference or potential advantage for the use of site-specific ECM remains unknown in the esophageal location. The objective of the present study was to characterize the in-vitro cellular response and in-vivo host response to a homologous esophageal mucosal ECM (eECM) vs. non-homologous ECMs derived from small intestinal submucosa and urinary bladder. The in-vitro response of esophageal stem cells was characterized by migration, proliferation, and three dimensional (3D) organoid formation assays. The in-vivo remodeling response was evaluated in a rat model of esophageal mucosal resection. Results of the study showed that eECM retains favorable tissue-specific characteristics that enhance the migration of esophageal stem cells and supports the formation of 3D organoids to a greater extent than heterologous ECMs. Implantation of eECM facilitates the remodeling of esophageal mucosa following mucosal resection but no distinct advantage vs. heterologous ECM could be identified.