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The Past, Present, & Future For Stem Cells In Glioblastoma Multiforme (GBM)

Varsha Dwarampudi - Rising Junior at Monmouth County Academy of Allied Health & Science - Morganville NJ


Gifted Gabber Research Student

 

ABSTRACT:


Over the past decades, discoveries about stem cell biology have provided new potential approaches to cure cancer patients. Cancer is a disease that degrades human quality of life. Among the many types of cancers, lies the worst brain tumor of them all - the glioblastoma multiforme (GBM). The GBM is caused by uncontrolled cell growth in the body and most advanced treatments essentially rely on the use of cytotoxic drugs which kill cancerous cells. Although cell killing will relieve the immediate symptoms, it cannot cure lethal cancer because it destroys indiscriminately all rapidly dividing cells, which include healthy ones. Therefore, there is a considerable need for effective and non-toxic therapies which can selectively target cancerous cells. Stem cells hold great promise for cancer therapy, because they possess an inherent capacity for self-renewal, multilineage differentiation and modulatory effects on endogenous surrounding cells. This review highlights the mechanisms underlying the use of stem cells in GBM treatment. In addition, there is a summary of recent progress in clinical applications of stem cells as well as common risks involved with this therapy.


Research Paper:


Introduction


Cancer is the most dangerous disease, causing millions of deaths worldwide (Chu 2018). Despite rapid advancements in research of diagnostics and therapeutics, the death rate by cancer only declined ~1.5% annually in the period of 2006–2015 in the United States (Chu 2018). The death rate by cancer has been on a continuous decline since 1990 (Chu 2018). However, even with these improvements, cancer still remains an incredibly deadly disease (Chu 2018). Although there are already prominent treatment options such as surgery, radiotherapy, chemotherapy, and immunotherapy—which are all unspecific target therapies—they’re insufficient for improving outcomes for patients diagnosed with cancer because tumors can recur after treatment stops due to their high mutation rate (Chu 2018). Meanwhile, stem cell therapy—the use of stem cells to treat disease—has provided hope for patients diagnosed with cancer due to its enhanced therapeutic efficacy against tumors through its targeted approach (i.e., it can target only tumor sites without affecting other parts of the body) (Chu 2018). Numerous stem cell-based strategies have now been in preclinical trials and show great promise; they could help improve outcomes for patients diagnosed with cancer (Chu 2018).

Moreover, there is already huge support from millions of awaiting patients who are being given hope through advancements in treatment methods, thanks to the uncovering of many unknowns in cancer biology. In nearly every new treatment method, these advances are the result of breakthroughs in the game of cloning - scientifically known as stem cell therapy. It is surprising that the public knows so little about such a catastrophic development that has the power to determine the fate of so many lives. In hopes of reaching out to the public, this article will provide an in-depth analysis of the origin, current presence, and future of stem cells in glioblastoma multiforme - the most aggressive form of brain tumor.


Brain Cancer


Overview of Brain Cancer


When physicians tell their patients that it’s all in their head, they’re not lying. If you have a broken bone, you can treat it. If you have a failing organ, you can replace it. However, if you have a cancerous brain, the chances of recovery are near to slim - at least that used to be the case. The latest cutting edge technology has enabled researchers to develop a highly effective treatment method that uses functional cells to combat cancerous cells. Most excitingly, this new treatment is being used to treat patients with glioblastoma multiforme, a type of brain cancer that has a 5-year survival rate of only 5% if treated properly (cancerresearchuk 2019). To understand the significance of this advancement in cancer treatment, it’s paramount to have some background knowledge. From a foundational standpoint, what even is brain cancer, let alone glioblastoma multiforme?

Brain cancer is when an abnormal amount of cancerous cells grow and sit as an intrusion in the brain (cancercenter 2022). In fact, due to the brain's association with the body's physical and mental functions, the cancerous mass damages both the body's regulation and control systems (cancercenter 2022). It can essentially override the muscular, gastrointestinal, sensory, and cognitive abilities of the average human body (cancercenter 2022). With these drastic effects, brain cancer has the potential to become a hindrance to the patients' quality of life (cancercenter 2022). Moreover, there is no definitive cause of primary or secondary brain cancer, making prevention difficult beyond maintaining a healthy lifestyle (cancercenter 2022). Several factors contribute to the prevalence of brain cancer (cancercenter 2022). These include family history, infection exposure, radiation exposure, and race or ethnicity (cancercenter 2022). In the already prevalent brain cancer, there are over 120 different types of tumors that can form (cancercenter 2022). Among these, it is known that glioblastoma multiforme is one of the worst types of brain tumor because there is currently no cure that successfully eliminates all the cancerous cells (cancercenter 2022).




Figure 1. The brain divided into 5 lobes and labeled with corresponding functions


Overview of Glioblastoma


The figure above identifies the many functions that specific parts of the brain corresponds to. This places into perspective how even a tumor the size of gumball can easily ruin the body’s control systems and affect a person’s life. Here’s an overview on the different parts of the brain and its functions. The brain is broken up into 4 lobes and 3 parts that also hold significance. The 4 lobes include the frontal lobe, the parietal lobe, the occipital lobe, and the temporal lobe. The three parts are the pituitary gland, the brain stem and the cerebellum. The frontal lobe involves movement, reasoning, behavior, memory, decision making, personality, planning, judgment, initiative, and inhibition mood. The parietal lobe involves telling right from left, calculations, sensations, reading, and writing. The occipital lobe involves vision. The temporal lobe involves language comprehension, behavior, memory, hearing, and emotions. The pituitary gland involves hormones, growth, and fertility. The brain stem involves breathing, blood pressure, heartbeat, and swallowing. Lastly, the cerebellum involves balance, coordination, and fine muscle control. It’s integral for anyone to firstly understand the significance of the brain to understand the damage caused by cancers such as glioblastoma multiforme.

Although we know so much about the brain, glioblastoma multiforme - a brain cancer - persistently remains a huge mystery to professionals in all medical fields (pennmedicine 2018). Its origin (how it even comes about) is what puzzles medical experts on a daily basis (pennmedicine 2018). The limited knowledge researchers have acquired has led them to believe there is some initial molecular event that triggers everything (pennmedicine 2018). This initiation appears to lead to other mutations that accumulate and become malignant, growing uncontrollably, invading healthy tissue, and becoming cancerous (pennmedicine 2018). In addition to the misty origin of this tumor, there is no clear indication of its treatment (pennmedicine 2018).

In spite of the ease of surgically removing a tumor, there is much more beneath the surface of the primary mass (pennmedicine 2018). Under the visible tumor portion, tumor cells grow and migrate in an unknown, invasive manner (pennmedicine 2018). Due to the fact that these tumor cells migrate through neural pathways throughout the brain, when the surgery is performed to one main mass, those cancer cells will have already left the area of the primary mass (pennmedicine 2018). Typically, when cancer spreads through the brain, it’s named diffuse disease, surgery cannot be used as a treatment, as it would be impossible to stop the proliferation of cancer cells in the brain (pennmedicine 2018).

Besides surgery, there are a few other treatments that shrink the tumor cells (pennmedicine 2018). These treatments, however, only work on cells which are constantly multiplying, dividing, and growing (pennmedicine 2018). Chemotherapy and radiation are most effective against these types of cells (pennmedicine 2018). In contrast, glioblastoma is a special case, since it contains dormant and non-dividing cancerous cells (pennmedicine 2018). These are known as cancer stem cells, which due to their dormant characteristic, don't die when exposed to treatments such as chemotherapy and radiation (pennmedicine 2018). Eliminating most treatment options, glioblastoma multiforme remains a mystery and challenge for many researchers. Among all this ambiguity, there seems to be some light on this situation. Recently, researchers have been thinking of using stem cells as a new treatment method for cancer - the idea has been floating around many minds.


Stem Cells


History of Stem Cells


In the early 1960s, Ernest McCulloch and James Till discovered stem cells at the University of Toronto (Dr Andreas 2022). McCulloch was a cellular biologist, while Till was a biophysicist (Dr Andreas 2022). They discovered stem cells that develop into all types of blood cells, specifically those involved in hematopoiesis, or the production and regeneration of blood (Dr Andreas 2022). They are particularly useful because they are capable of producing different types of white blood cells, as well as red blood cells (Dr Andreas 2022). These cells—found in the peripheral blood and the bone marrow—are simply known as blood stem cells and remain the driving factor behind some of the most successful cancer treatments today (Dr Andreas 2022).

How did McCulloch and Till come to this discovery? To test their theories, Till and McCulloch injected bone marrow cells into mice and saw that colonies of cells formed in the spleens (Dr Andreas 2022). They named them "spleen colonies” (Dr Andreas 2022). Further experiments showed that these colonies were clones derived from single cells; these became known as stem cells (Dr Andreas 2022). The discovery of stem cells set the stage for a new field of research and development in the area of medicine (Dr Andreas 2022). Professors, scientists, and researchers used their creative abilities to innovate new approaches by mashing up treatment methods with the new breakthrough - stem cells (Dr Andreas 2022).

In the 1990s, scientists discovered that stem cells in bone marrow could be used to cure leukemia and multiple myeloma, two forms of cancer (Dr Andreas 2022). In recent years, researchers have been using stem cells to treat autoimmune diseases such as multiple sclerosis. However, the big question remains—how does this treatment work (Dr Andreas 2022)?


Biology of Stem Cells


Stem cells are undifferentiated cells (cells that haven't yet specialized) that can divide and turn into other types of cells, making them useful for treating a variety of conditions (mayoclinic 2022). This means that they have the potential to fix damaged or diseased tissues or even entire organs (mayoclinic 2022). They don't get old or die like normal cells, which means they could keep growing and dividing in your body for years (mayoclinic 2022). There are different types of stem cells (mayoclinic 2022). These include pluripotent stem cells, multipotent stem cells, and unipotent stem cells (mayoclinic 2022). The process starts by extracting adult stem cells from the patient's bone marrow or blood and then injecting them into the patient's bloodstream or directly into the site of injury or disease (mayoclinic 2022). Stem cells undergo a complex process to be harvested and have the potential to save lives (mayoclinic 2022).



Figure 2. A blood stem cell undergoing several steps to become a red blood cell, platelet, or white blood cell


An example of how normal cells are broken down into specialized cells can be seen in the figure below. The stem cells provide the foundation for the development of other cells with specific functions (mayoclinic 2022). It is under laboratory conditions that stem cells divide into more cells called daughter cells (mayoclinic 2022). As a result of differentiation, these daughter cells develop into blood cells, brain cells, heart muscle cells, or bone cells with specific functions (mayoclinic 2022). In the body, stem cells are the only cells capable of generating new types of cells (mayoclinic 2022).

Stem cells have many different sources some of which include embryonic stem cells, adult stem cells, and perinatal stem cells (mayoclinic 2022). A set of stem cells that develops from an embryo between the ages of 3 and 5 days is called embryonic stem cells (mayoclinic 2022). As pluripotent stem cells, these cells are capable of dividing into many kinds of cells and becoming any type of cell in the body (mayoclinic 2022). In the case of diseased tissues or organs, embryonic stem cells can provide regeneration or repair (mayoclinic 2022). As opposed to embryonic stem cells, adult stem cells have a more limited ability to initiate various body processes (mayoclinic 2022). The bone marrow or fat of adults contain a small number of these cells (mayoclinic 2022). The last type of stem cells to be discovered have been perinatal stem cells found in both amniotic fluid and umbilical cord blood (mayoclinic 2022). In the uterus, a fetus is enclosed in a sac of fluid called amniotic fluid (mayoclinic 2022). Amniocentesis, the procedure in which pregnant women are sampled for blood or tissue testing or treatment, has identified stem cells in amniotic fluid (mayoclinic 2022). Although researchers are looking for more feasible ways to harvest stem cells, the public has their own opinion on the ethics of the process being used to attain them. This ethical controversy has been spotlighted mainly towards the embryonic stem cells (mayoclinic 2022).

Early-stage embryos are developed through the fertilization of eggs and sperm at a fertility clinic, resulting in the formation of embryonic stem cells (mayoclinic 2022). The ethical implications of embryonic stem cell research have been raised due to the fact that these cells are derived from human embryos (mayoclinic 2022). Those who remain skeptical should be aware that embryonic stem cells from vitro fertilized embryos can only be used once the embryo is no longer needed. It is important to note that embryonic stem cell research “uses eggs that were fertilized in vitro but never implanted in women's uteruses” (mayoclinic 2022). This is a huge controversy that has been on the high for years as researchers are avidly looking for other more successful methods to retrieve the stem cells (mayoclinic 2022). Like all discoveries in medicine, there is the good side and the not so good side; however at the end of the day, all treatments are working towards the same means - finding a cure for a specific disease (mayoclinic 2022). Lately, these advances have been made with one key partner - medicine and technology (mayoclinic 2022). So, how did researchers combine stem cells and technology to bring cancer patients the successful treatment they trust today?


Stem Cell Therapy


Stem Cell Therapy Technology


Regenerative medicine is a new field of research that might provide ways to heal damaged tissue or organs (mayoclinic 2022). Potential treatments include injecting stem cells into an injured or diseased organ or tissue, replacing or repairing damaged tissue with healthy cell transplants from the patient or others, or even genetically modifying an individual's own body cells so they will act as disease fighters (mayoclinic 2022). These stem cells are manipulated to specialize into specific types of cells, such as heart muscle cells, blood cells or nerve cells (mayoclinic 2022). The specialized cells can then be implanted into a person. For example, scientists can use stem cells to regenerate new heart muscle in patients who have suffered a heart attack due to damaged muscle (mayoclinic 2022). This example only provides the most basic explanation for how this technology works, the figure below illustrates the process when doctors use fat stem cells for treatment, which is one method where technology is combined into the vast stem cell sciences field.



Figure 3. Process for patients to use own fat stem cells for treatment

Many patients have used their own fat stem cells for treatment. To do this, they must go through four steps: harvesting, separating, activating, and returning. In the harvesting step, a small amount of fat is taken from the waist area. In the separating step, the stem cells are separated from fat cells. The activating step is exactly what it sounds like: it activates the stem cells with laser and platelet-rich plasma (PRP). PRP is a type of blood product that has been shown to help activate and increase the number of stem cells in your body. After activation and return through an IV line, the activated stem cells will be reintroduced back into your body. This stem cell technology is one of many that are being put to the test through clinical trials. However, this one has been used successfully in patients and is available for others to use as a treatment method.


Efficacy Rates


Unfortunately, there is no absolute scientific proof on the effectiveness of stem cell therapy as a treatment option for glioblastoma multiforme. However, by looking at some studies regarding other diseases with similar characteristics to this disease, we may be able to get an idea of whether or not stem cell therapies work for glioblastoma multiforme. The table below provides the efficacy rates for clinical trials that were testing for the effectiveness “of MCS’s on reducing GVHD caused by allogeneic HSC transplantation in cancer patients” (Chu, Dinh-Toi, et al. 2020). Mesenchymal stem cells (MCS) are multipotent stem cells found in bone marrow that play a role in making skeletal tissues, such as cartilage and bone. With age and disease, MSCs predominantly convert into lipid-accumulating fat cells (mayo 2020). Graft-versus-host disease (GVHD) is a disorder that occurs when the donor's immune system attacks host tissue (ncbi n.d.). “Graft” refers to transplanted or donated tissue, while “host” refers to the recipient's body tissue (ncbi n.d.). Lastly, allogeneic hematopoietic transplantation uses hematopoietic progenitor cells collected from an unrelated donor (not from the patient's own bloodline) (uptodate n.d.). Allogeneic hematopoietic transplantation is increasingly used to treat a variety of hematologic neoplasms and nonmalignant marrow disorders (acquired and inherited), including inborn errors of metabolism (uptodate n.d.). The recently published and completed trials are a compilation of 5 trials with mostly success rates that remained on the higher end of the scale which goes to show that more clinical trials should be combining the uses of stem cells as a potential treatment method for glioblastoma multiforme.



Conclusion


A lot of modern medicine is designed to treat symptoms rather than cure them. This can be problematic as, in many cancer patients for example, it's the cause that is really needed to be treated and so if one doesn't do that, then it won't make that drastic of a difference. Thankfully, stem cells are derived directly from the patient and so not only do they come from the source but, in theory at least, they should be charged with the patient's own healing energy. Stem cells are unique in many ways: they can self-renew indefinitely and differentiate into a wide variety of other cells (termed pluripotent). They also have unique migratory properties that allow them to move to sites of injury or infection. Finally, stem cells interact differently with other cells in their local environment.

As a final note, stem cells can regenerate and differentiate into specialized cells like muscle tissue, nerve tissue, and heart tissue. As well as being renewable sources of cells, they can also be harvested from embryonic tissue or other tissues in adults. The future of medicine depends on them. Understanding these properties has allowed scientists to develop new treatments using stem cells to improve the quality of life of cancer sufferers. Since discoveries about stem cells' properties emerged over the last decade, demand for stem cell research has increased dramatically. But demand continues to rise due to advances in technology providing hope for many hopeless cases such as patients with glioblastoma multiforme. The hope is that more studies and research will be done and that stem cells will be used to cure one of the worst types of brain cancer - glioblastoma multiforme.


 

References



Chu, Dinh-Toi, et al. “Recent Progress of Stem Cell Therapy in Cancer Treatment: Molecular Mechanisms and Potential Applications.” Cells, MDPI, 28 Feb. 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140431/.


“Determining Eligibility for Allogeneic Hematopoietic Cell Transplantation.” UpToDate, https://www.uptodate.com/contents/determining-eligibility-for-allogeneic-hematopoietic-cell-transplantation.



“Graft versus Host Disease - Statpearls - NCBI Bookshelf.” Ncbi, https://www.ncbi.nlm.nih.gov/books/NBK538235/.




“Survival.” Survival | Brain and Spinal Cord Tumours | Cancer Research UK, 5 Nov. 2019, https://www.cancerresearchuk.org/about-cancer/brain-tumours/survival.


“Types of Brain Cancer: Common, Rare and More Varieties.” Cancer Treatment Centers of America, 8 June 2022, https://www.cancercenter.com/cancer-types/brain-cancer/types#:~:text=Brain%20tumors%20have%20more%20than,be%20slow%2Dgrowing%20and%20benign.



Research Paper Link:

The Past, Present, & Future For Stem Cells In Glioblastoma Multiforme (GBM)
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