Cancer stem cells are capable of initiating and sustaining a tumor. Current cancer therapies may fail, leaving patients prone to recurrence because the cancer stem cells have not been eradicated. This problem has been likened to "pulling out a weed while leaving the roots."
Cancer stem cells were first conclusively identified in association with hematological malignancies and our understanding of them continues to be derived largely from findings related to leukemic stem cells. In addition to their role in leukemias, cancer stem cells are being increasingly identified in solid tumors. Recent findings continue to underscore the importance of understanding the unique features of these cells in order to target them therapeutically.
Stem cell quiescence is one feature of stem cells involving unique, and thus potentially targetable, factors. Quiescence, the slow cell cycling of a stem cells, makes cancer stem cells unresponsive to many chemotherapeutics that typically target rapidly proliferating cells. Understanding the factors involved in stem cell quiescence is critical since their mutation or deletion causes the cells to begin cycling more rapidly. This can result in tumor growth and metastasis but also render the cells more sensitive to chemotherapeutics and increase the likelihood of their progression to terminal differentiation and therefore departure from the stem cell pool.
Recent papers exploring the potential of quiescence factors as therapeutic targets have yielded promising results. In a recent paper by Ito et al. (Ito et al., 2008), the researchers explore the role of PML as a hematopoietic stem cell (HSC) quiescence factor. PML is a protein that encodes a protein localizing to PML nuclear bodies in the cell and acts as a tumor suppressor, affecting a number of cellular processes including apoptosis, cellular proliferation, and senescence. The Pml gene is involved in the chromosomal translocation implicated in acute promyelocytic leukemia (APL). The researchers investigated the association between PML levels in Leukemia-initiating cells (LIC) and clinical outcome in patients with chronic myeloid leukemia (CML) and found that positive clinical outcomes were associated with low PML levels. This result prompted them to investigate the stem cell pool in mice lacking PML and they found, by examining marker expression, that there were fewer quiescent stem cells and more differentiating cells. This suggests that the PML mutant mice are defective in stem cell maintenance, which in turn suggests that PML acts to maintain HSCs in normal mice. Ito et al further found that PML is needed for LIC maintenance as well. In order to test whether down-regulation of PML in LICs facilitates their eradication by increasing their cell cycling and making them increasingly sensitive to chemotherapy, they treated the cells with arsenic trioxide. Arsenic trioxide is known to target PML and is a historic treatment for APL. Treatment with arsenic trioxide, which increases the rate of cell cycle entry by eliminating PML, significantly decreased the number of LICs in response to chemotherapy. These results highlight the role of PML in LIC quiescence and demonstrate the usefulness of compounds such as arsenic trioxide in promoting the eradication of LICs. PML's utility could be further expanded if its usefulness in cancer stem cells in solid tumors could be demonstrated.
PML is not the only potential therapeutic target identified in leukemia stem cells (LSCs). Recent work by Guo et al. (Guo et al., 2008) has made significant progress toward defining the molecular mechanisms that PTEN uses to maintain quiescence in LSCs. PTEN, like PML, is a tumor suppressor protein. It is a phosphatase which functions in the PI(3)K-AKT pathway and previously found to be involved in development of human leukemia. The group showed that loss of PTEN in mice leads to defects in adult HSC self-renewal and eventually T-lymphoblastic leukemia (T-ALL). Further, they identify the players involved in LSC formation. They measure the levels of beta-catenin, a key component of the Wnt pathway, and examine the effects of its partial depletion, finding that lower beta catenin levels incompletely inhibits the PTEN caused T-ALL development and suggests that beta catenin may contribute to LSC formation and expansion. Additionally, the researchers find a chromosomal translocation overly represented in leukemia blast cells that causes overexpression of c-myc. These results suggest a multi-hit model of leukemia development, with PTEN activation as the first step activating the PI(3)K-AKT pathway, promoting proliferation and setting the stage for genomic instability caused by beta-catenin activation and c-myc overexpression. These factors may lead to LSC self renewal and T-ALL development in a Pten mutant background. The scenario elaborated in this work informs a number of potential therapeutic options whose goal would be to promote LSC cell cycling, thereby make them more susceptible the cytotoxic effects of chemotherapy.
Therapeutic targeting of cancer stem cell quiescence factors, such as PML and PTEN, represent a means by which we may be able to get a specific handle on cancer stem cells. This has been an elusive goal because many of the standard chemotherapeutic approaches target rapidly proliferating cells. As we continue to identify factors involved in quiescence, and the pathways in which they act, additional targets will reveal themselves. Additionally, the solid footing gained in our understanding of leukemic stem cells will inform studies on cancer stem cells in solid tumors.
- Guo, W., Lasky, J.L., Chang, C.J., Mosessian, S., Lewis, X., Xiao, Y., Yeh, J.E., Chen, J.Y., Iruela-Arispe, M.L., Varella-Garcia, M., Wu, H. (2008) Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature 453, 529-33.
- Ito, K., Bernardi, R., Morotti, A., Matsuoka, S., Saglio, G., Ikeda, Y., Rosenblatt, J., Avigan, D.E., Teruya-Feldstein, J., Pandolfi, P.P. (2008). PML targeting eradicates quiescent leukaemia-initiating cells. Nature May 11. [Epub ahead of print]