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Did you know that some animals, like salamanders and axolotls, can regenerate their limbs? They have this spectacular ability due to a small and rare subset of primitive cells called stem cells. These cells have the ability to differentiate into many different types of specialized cells from brain cells to heart cells following a trigger and the appropriate signals. In addition to their superior regenerative capacity, stem cells can also self-renew readily to maintain their pools.
Just like salamanders, we also possess stem cells; however, our stem cells lose their regenerative capacity significantly as we transition from an embryo to a fetus to a child and to an adult. Embryonic stem (totipotent) cells have the ability to divide into virtually any cell type in the body including the placenta. However, as the fetus develops, these cells lose this capacity and become more and more restricted in the cell types they can differentiate into. Adult stem cells are present in all postnatal humans and are also a primitive, undifferentiated cell population, similar to embryonic stem cells, that repairs and maintains various tissues such as our liver, muscles, and blood cells. However, adult stem cells are tissue-specific and can only differentiate into a small number of specialized cells from their tissue-of-origin, so a liver-specific stem cell would only be able to produce mature liver cells.
Recent research has identified a small subpopulation of cancer stem-like cells (CSCs) in many different types of cancers, including sarcomas. These CSCs have many properties in common with adult stem cells, as implied by the name, such as the ability to self-renew and differentiate into various mature (or tumorigenic) cell types. Transplanting CSCs from a human tumor into a mouse or animal model can trigger the development of the donor tumor in the animal model as well. From a cancer treatment development perspective, this incredible tumor-regenerating capacity of CSCs is quite remarkable as it can potentially be used as a source to study treatment/drug resistance and metastasis.
As a matter of fact, the identification of CSCs and their characteristics provides support for the “Stem cell theory of cancer”. This theory proposes that a very small subset of cells from all tumor cells act as stem cells by replenishing their own pools through self-renewal and maintaining cancer through differentiation. Therefore, according to this theory, CSCs are the major cancer-driving culprit that needs to be eliminated completely from one’s body. On the other hand, the non-stem cancerous cells still cause damage and are harmful, but alone they do not have the capacity to maintain or restart cancer. With that being said, it is important to note that there are other challenging theories that suggest that even the non-stem-cell-like cancer cells have the ability to convert to CSCs. Nonetheless, treatments or therapies targeting and “un-stemming” CSCs can be an interesting and valuable new approach for cancer treatments.
Yoon et al. (2021) explored just this approach in relation to sarcomas and sarcoma CSCs which share many properties with mesenchymal stem cells. Previously, embryonic and adult stem cell research has allowed us to identify various proteins and pathways that are critical for maintaining “stemness”, including a protein called Nanog. Nanog plays a critical role in maintaining embryonic stem cells and pluripotency using a positive feedback mechanism, where it upregulates its own expression as well as many other “stemness” proteins. In fact, Nanog expression has been implicated in promoting CSC properties and oncogenesis in numerous human cancer types.
Given that, Yoon et al. (2021) explored whether sarcoma cells grown as spheroids (3D cell cultures which enrich for CSCs) had increased Nanog expression in comparison to monolayer cultures (do not enrich for CSCs). Indeed, they found that spheroids had increased Nanog expression compared to monolayer cultures. Additionally, in a separate experiment, they overexpressed Nanog protein and observed an increase in spheroid formation as well as an increase in the number of CSCs identified by a marker surface protein called CD133+. To further confirm their findings, researchers found that upon inhibiting Nanog expression, a decrease in spheroid formation and CD133+ CSCs was observed. Overall, these findings suggest that sarcoma CSCs upregulate Nanog expression and it is required for spheroid formation.
Following that, Yoon et al. (2021) sought to study if Nanog inhibition could reverse cancer treatment resistance. First, they confirmed that CSCs do indeed contribute to chemotherapy and radiation resistance in the in vitro sarcoma cell cultures (spheroid vs monolayer growth) as well as in vivo sarcoma xenograft assays in mice. They then inhibited Nanog expression in both the in vitro and in vivo models and observed that this alone was able to reduce tumor growth and reverse some of the resistance that developed following either chemotherapy or radiation alone. Additionally, this Nanog inhibition also significantly reduced the number of CD133+ CSCs in sarcoma xenografts in comparison to either chemotherapy or radiation alone. In summary, these results highlight the key role of Nanog in sarcoma CSC maintenance as well as the promising potential of therapies that target Nanog and could reverse CSC development, resistance to current first-line cancer treatments, and even reverse tumor progression.
Overall, these results are quite promising and provide support for a brand new avenue of cancer treatments. However, this research area is still in preliminary steps and several other milestones need to be reached before we could see this as a common cancer therapy option.
Edited by Sushma Teegala
Yoon, C., Lu, J., Yi, B. C., Chang, K. K., Simon, M. C., Ryeom, S., & Yoon, S. S. (2021). PI3K/Akt pathway and NANOG maintain cancer stem cells in sarcomas. Oncogenesis, 10(1). https://europepmc.org/article/pmc/pmc7815726
Header image: Nissim Benvenisty
Benvenisty, N. (2011). Category:human embryonic stem cells. Wikimedia Commons. Retrieved February 9, 2022, from https://commons.wikimedia.org/wiki/Category:Human_embryonic_stem_cells