Endogenous stem cells are important in the normal physiology of tissues that undergo constant regeneration, such as hematopoietic cells or those lining the gastrointestinal tract. The enhanced proliferative capacity of stem cells is necessary for the regeneration and healing of damaged tissue, but can also lead to cancer. The carcinogenic potential of stem cells is a significant limitation for their potential use in treating disease. Understanding the mechanisms and signaling pathways that allow stem cells to serve in a controlled regenerative capacity is necessary before their safe therapeutic potential can be realized.
The PTEN protein is a key regulator of cell proliferation, differentiation and motility that is frequently mutated in cancer. PTEN exerts its influence on cellular functions by suppressing the PI3-kinase (PI3K) and AKT pathways. In normal cells, PTEN balances PI3-kinase and AKT activities that otherwise would contribute to the genesis of malignant cancer cells.
Here the planarian is used as a model organism for studying PTEN in stem cells for tissue regeneration. Planarians contain large numbers of adult stem cells (neoblasts) that constantly renew and differentiate into all known planarian cell types.
In the planarian, Schmidtea mediterranea, the authors identify two orthologues to the human PTEN gene, which they name Smed-PTEN-1 and Smed-PTEN-2. They find the genes expressed in many cell types, including the planarian stem cells. Reduced expression of Smed-PTEN-1 and Smed-PTEN-2 encoded proteins using RNAi resulted in abnormal growths, dramatic anatomical changes and the eventual demise of the organism. As in mammals, administration of the drug rapamycin to RNAi-treated worms prevents all of these abnormalities and the death of the animal.
Implications and future directions
An important finding here is the extent of evolutionary conservation of the PTEN pathway that allows researchers to use planaria as a model organism for stem cell biology. This work demonstrates the fundamental importance of PTEN in cellular proliferation and differentiation processes. Work on the PTEN pathway in this system will advance our understanding of the mechanisms regulating proliferation, migration and motility that are likely operating in the emergence of human cancers. It also expands opportunities to understand the relationship between pathways that similarly regulate cancer growth and stem cell potential.