Stem Cells & The Heart of Cancer

Stem Cells & The Heart of Cancer

The quest for the cure for cancer is like that of a hero on his journey to vanquish an age-old curse plaguing his beloved land, as the knight in shining armour rides into battle to finally bring peace one and for all. However, while he may be cutting down his foes left and right, what happens if he discovers that the true enemy he is fighting is not unlike himself?

The discovery of stem cells and their unique characteristics of self-renewal and the ability to become any and every human cell depending on their potency, has been revolutionary, initiating the foray into the field of regenerative medicine. In the context of cancer treatment, generating brand new functional cells, tissues, and organs in the laboratory can replace those damaged by radiation, chemotherapy, or trauma from surgery. It could also theoretically regenerate the damaged tissue or organs in the body itself, allowing cancer survivors a new lease on life. Until that is a reality, stem cells have also been serving another purpose in research: providing insight about the very heart of cancer.

Most people may understand cancer as cells gone rogue as a result of genetic mutations, causing it to divide uncontrollably and create tumours, draining the body of much-needed nutrients and oxygen. If left unchecked, the cells become cancerous as it invades and spreads to other tissue. This line of thinking has been useful in investigating cancer development, as scientists develop drugs and treatment that take advantage of their proliferation rate, damage their genetic code beyond repair, or activate their kill switch. However, such treatment only resolves the proliferating cells and fails to strike the true root of the cancer, leading to recurrence. Additionally, genetic mutations alone fail to explain the persistence of cancer cells since mutations and random – the right combination of mutations for the resistance to anti-proliferation signals, limitless replication, tissue invasion and the like, are rare and hard to come by. What, then, can explain the initiation and development of cancer tissues, and what do stem cells have to do with it?

Cancer, Initiated

            The stem cell theory of cancer is nothing new and has been posited by scientists since the 1800s, who thought that tumours arose from left over embryonic stem cells after development and would become cancerous once activated. Alternatively, since stem cells live longer than normal somatic cells, some scientists thought that these stem cells had a higher chance of accumulating genetic mutations, causing the cell to lose control of its ability to self-renew and proliferate, and become cancerous. However, after 200 years’ worth of understanding and characterising tumours and cancers, our understanding of the stem cell theory has changed as well.

First, it is important to note that tumours are comprised of a mix of cells with various characteristics. Among these subpopulations, there are a handful of self-sustaining cells with special abilities that others do not, namely the ability to renew and proliferate themselves, and the potential to differentiate and generate a hierarchy of the various cell types in a single tumour. Additionally, when these cells are transplanted into an immunodeficient mouse, not only can they generate tumours, they recreate the original parent tumour, with the same mixture of cells. With these superpowers of self-renewal and differentiation in a hierarchical structure unique to stem cells, these cells have been dubbed cancer stem cells (CSCs). The stem cell theory of cancer has gained traction, as more evidence unveils subpopulations of self-renewing cancer cells in hematopoietic cancers, solid tumours like brain, breast, colon, and ovarian cancer.

Metastasis, the ability of cancer to migrate and initiate in a secondary location, can also be explained using CSCs, as cancer cells could undergo a process known as epithelial-mesenchymal transition (EMT). During EMT, a cancer cell could switch between two cell fates from one to the other: an epithelial cell that is static and associates itself to the basal surface of a tumour could become a mesenchymal cell that can migrate and circulate, and then revert to an epithelial cell again, allowing the cancer cell to take root in a new location. In a study done on breast epithelial cells undergoing EMT, they acquired CSC characteristics, such as an increase expression of CSCs biomarkers, stem cell properties, drug resistance, and even the ability to initiate tumours.

With the ability to self-renew and propagate themselves, initiate tumour formation, generate diverse tumour cells, acquire drug resistance, and change its cell type to migrate and metastasise, it is no wonder that cancer is able to persist even after treatment, equipped and ready to strike again and again. 

CSCs, The Evil Twin?

Evidently, stem cells and CSCs share several similarities, to the point that it is tempting to say that CSCs do arise directly from stem cells. They two cells make use of the same developmental pathways for self-renewal and differentiation, such as Wnt, Notch, Shh, and BMP, and the molecular signals involved, such as Sox2, Oct4, Nanog, and Notch-1 are even used as identification biomarkers to locate and characterise CSCs. The parallels in between the two are also uncanny, especially since the process of dedifferentiation and transdifferentiation (in the case of cells switching fates during EMT) were elucidated from the study of reprogramming somatic cells back to stem cells. However, just because there is “stem cell” in its title, it is a grievous mistake to assume that they are one and the same.

The origin story of cancer stem cells is mysterious and has yet to be revealed, but there are some speculations. One possibility is like the one suggested 200 years ago, that it was a normal stem cell that accumulated just the right mutations to become cancerous. A similar scenario is that a progenitor cell, just a few stages after stem cells, was the one to possess the mutations for cancer and self-renewal instead. Alternatively, a somatic cell had accumulated oncogenic mutations, including a mutation for dedifferentiation to revert to a more proliferative state, resulting in multiple mutated, cancerous cells. To truly get at the heart of the situation, however, it is worth investigating the microenvironment in which they grew up in.

Just like how people are shaped and by the social environment they are exposed to, stem cells are influenced by their microenvironment, also known as a niche, where cell-to-cell interactions and molecular signals from neighbouring tissues direct stem cell development. In general, the niche maintains the pool of stem cells by regulating their proliferation and cell fate, in preparation for the replacement of old or damaged cells as and when is necessary. The niche’s physical size also restricts the number of stem cells that can be present, preventing uncontrolled cell divisions as any stem cell left outside undergoes differentiation, leaving the niche and migrates to their destination.

CSCs develop in a microenvironment similar to healthy stem cells’ by using the same signalling molecules and pathways that sustain self-renewal. However, CSCs can genetically mutate to function independently of their original niche and ignore the signals inhibiting proliferation, resulting in an accumulation of CSCs. They can even reprogram their niche, regulating the composition and function of their niche in their favour. The CSCs and its niche then feed into each other, creating a positive cycle to maintain a conducive environment for the growth and development of tumours.

Stem Cell’s Fate in Cancer’s Story

Even though it is understood that stem cells and CSCs are two separate entities, the use of stem cell therapy and regenerative medicine is a challenge to be overcome, as it potentially could give rise to tumourigenesis or aggravate the existing cancer in cancer patients. For example, a study published in Nature by the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology showed, that when mesenchymal stem cells derived from the bone marrow were mixed with weakly metastatic breast cancer cells, the cancer’s metastatic potential increased when grafted onto an animal model. What they discovered was that the cancer cell promoted the stem cells to secrete factors that enhanced the cancer cell’s ability to mobilise, invade, and metastasise. Despite such a dreary outlook regarding the curative potential of stem cells, such research sheds much needed light and understanding on how stem cells act in the presence of cancer, particularly the role played by the microenvironment created by cancer cells.

Additionally, not all stem cells are created equal, and curing cancer may be a matter of looking in the right place. Pluripotent stem cells, the ones with the capacity to differentiate into any and every cell type in the human body, seem likes the panacea because of its infinite possibilities. However, it is also well-established that when transplanted into immunodeficient mice without directing and guiding its differentiation into a specific cell, it results in a teratoma, a mass of various tissues, from teeth to intestinal lining. Instead, multipotent stem cells, which can differentiate into a handful of tissues, are a safer bet for clinical use.

Alternatively, the effectiveness of stem cells may be an issue of strategy and understanding the enemy. For example, the pluripotent stem cells unique to the patient can be derived from their skin cell, and differentiated in culture to generate the patient’s cancer cells. These cells allow the researcher to test drugs that best eradicate the cancer cells with the patient’s cell signature, informing them of the treatment with the most probable efficacy. The resemblance between stem cells and CSCs may even mean that the root cause of cancer could be generated for drug testing as well, bringing the patient and medical professionals one step closer to eliminating the cancer for good.

Ultimately, stem cell research has given scientists a greater understanding of cancer, and how they are initiated and propagated by cancer stem cells. It had, however, sowed doubts and concerns about the feasibility of using stem cells to treat cancer, especially in terms of tissue and organ regeneration in the body itself. Even so, in the face of the final boss that bears many similarities to the heroic protagonist, the centuries-old story of cancer may come to its end as the up-and-coming, fresh-faced stem cell finally seals the darkness away. While there is plenty of work to be done, the unimaginable conclusion may just be a reality in the near future.

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Written as an assignment for LSM 4227: Stem Cell Biology, where I wrote a popular science article about the relationship between stem cells and cancer stem cells, its role in cancer development, and the potential consequences of such information on cancer treatment.