Introduction
The concept of cancer stem cells (CSCs) is not an entirely recent development. In fact, over the last two decades, advancements in understanding normal stem cell biology, coupled with the recent application of these principles to experimentally delineate CSCs, have led to the identification of such cells in various human malignancies. Normal adult stem cells act as internal repair systems of the body. The replenishment and formation of new cells continuously occur as long as an organism is alive. Researchers identified many different types of stem cells and classified them into several main categories including embryonic and non-embryonic, also known as adult, stem cells. Scientific knowledge about cancer formation and progression led to the identification of rare subsets of cancer cells with stem-like characteristics, designated as CSCs, which were later described as the causative agents for cancer initiation, progression, and dissemination to distant organs. Following the discovery of different CSCs, numerous researchers believe that targeting and eliminating these cells specifically could result in the complete eradication of entire tumors. This belief is based solely on the concept that the exclusive origin of tumor self-renewal lies in the CSC. All in all, stem cells have great potential to become one of the most important aspects of medicine. Ultimately, focusing research efforts on the CSCs may drive crucial advances in our understanding of cancer biology and developing potential cures for this devastating disease. This article aims to give a more comprehensive look at the CSC hypothesis, focusing on its history, background, and the clinical relevance of these cells.
Normal human stem cells
Classification of different stem cells
Stem cells are the body’s master cells. They can differentiate into specialized cell types with specific functions, such as blood cells, brain cells, heart muscle cells, or bone cells, depending on their environment and the signals they receive. No other cell in the body has the natural ability to generate new cell types. Stem cells can differentiate into various cell types based on their role and potential.
- Totipotent stem cells possess the highest differentiation potential and can divide and differentiate into cells of the whole organism.
- Pluripotent stem cells (PSCs), such as embryonic stem cells (ESCs) derived from embryos at an early stage of life, can form cells of all germ layers and become any type of cell in the body except extraembryonic tissues such as the placenta.
- Multipotent stem cells, or more commonly known as adult stem cells, have a more limited range of differentiation compared to ESCs. These cells are found in small numbers in most adult tissues, such as bone marrow or fat, and can specialize exclusively in cells of the same lineage only.
- Unipotent stem cells are distinguished by their narrowest differentiation capabilities and a distinctive property of iterative divisions. These cells are only capable of generating one specific cell type.
Stem cells in clinical practice
The significance of stem cells in contemporary medicine is of utmost importance, encompassing their extensive utility in fundamental research and the possibilities they offer for devising novel therapeutic approaches in clinical applications. In addition, stem cells may be able to replace damaged tissue or even regenerate organs. Promising results from preclinical studies and clinical trials have already been described in several degenerative disorders including diabetes mellitus, chronic myeloid leukemia, cirrhosis, pulmonary fibrosis, Crohn’s disease, heart failure, and disorders of the nervous system.
Not until recently, it has been shown that it is possible to reprogram adult stem cells back to their pluripotent stage through genetic reprogramming techniques to an “ESC-like state”. These cells called induced pluripotent stem cells (iPSCs), were reported for the first time by Takahashi and Yamanaka in 2006 in mice. A year later, Yamanaka and colleagues demonstrated the generation of human iPSCs from adult human dermal fibroblasts. These cells exhibit resemblances to human ESCs in terms of morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity, and they are capable of differentiating into cell types of the 3 germs layers in vitro5. Currently, iPSCs serve as valuable instruments in drug development, disease modeling, and the field of regenerative medicine.
Ultimately, it is crucial to note that an uncontrolled proliferation of stem cells could eventually lead to stem cell hyperplasia and/or carcinogenesis, while a reduction in stem cell division would impair organ repair thus, balance in stem cell homeostasis is very important.
Cancer stem cell hypothesis
History and origin
Like normal adult stem cells, CSCs have the capability to self-renew and undergo an unlimited number of cell divisions, and with each division, they produce at least one daughter cell that maintains this indefinite capacity for cell division. However, what distinguishes cancerous tissue from normal tissue is the loss of homeostatic mechanisms that maintain normal cell numbers, and much of this regulation normally occurs at the stem cell level. CSCs thus, give rise to tumors that phenotypically resemble their origin, either by morphology or by expression of tissue-specific genes.
The CSCs population, with an embryonic character, was first noticed by Julius Cohnheim in 1877 when he formulated the theory of the embryonic origin of cancer. His theory states that the origin of tumor development must be attributed to the existence of “embryonic rests” in the body that remain unused during their development. Since then, many milestones have been achieved, and extensive research has been conducted, leading to the current CSC theory postulating that tumor growth is supported by a small fraction of the tumoral cells that have stem-like properties. It was the work of John E. Dick and colleagues in the early 1990s on mice with acute myeloid leukemia that suggested that the presence of undifferentiated cells acts as drivers of tumor establishment and growth, and is often correlated to aggressive, heterogenous, and therapy-resistant tumors. Moreover, John Dick and his co-workers determined that even a small subset of these rare cells with specific surface markers can reinitiate leukemia when transplanted in immunodeficient mice. Approximately, most of the cell surface markers identified on CSCs appear to be present or are derived from known normal embryonic or adult stem cells such as CD44, CD24, CD1333. This suggests that CSCs predominantly originate from normal stem cells via the accumulation of epigenetic and genetic mutations.
Roles of cancer stem cell
CSCs are highly tumorigenic. They depend on specific reprogrammed pathways to sustain their stem-like characteristics and contribute to the advancement of tumors by fueling the fundamental processes involved in tumor development. One of the most important functional aspects of CSCs is that they tend to regulate self-survival and differentiation by promoting the bypass of protective mechanisms in cells, which leads to uncontrolled proliferation and avoidance of apoptosis. This rare subset of cells can also induce angiogenesis and lymphangiogenesis by secreting elevated levels of vascular endothelial growth factors, critical for tumor growth, invasion and metastasis. Moreover, CSCs promote the progression of cancer by escaping the immune system response, dysregulating the cellular metabolism, and inducing genomic instability, which will relocate the cancer to new organs. In addition to being the key drivers in metastatic dissemination, CSCs are responsible for the recurrence of the tumor after a period of apparent remission.
Understanding the properties and functions of CSCs is critical in developing more effective cancer therapies. Targeting these cells specifically may be key to eradicating the cells responsible for initiating tumors and driving their growth, potentially leading to better treatment outcomes. For instance, three studies on brain, intestinal, and skin tumors used in vitro cell line tracing techniques to demonstrate the existence of CSC concluded that it is necessary to target and eliminate CSC to deracinate cancer. The resistance to treatment of this small subpopulation of stem cells may be attributed to numerous factors including the tumor microenvironment, which is generally rich in a diversity of proteins important in activating pathways that impact the survival of CSCs. For instance, interesting studies involving breast cancer microenvironment showed that elevated levels of the cytokine Oncostatin M are associated with aggressive metastatic disease and chemotherapy resistance. What is more appealing is that chemotherapy induced further Oncostatin M secretion, which ultimately aggravates the characteristics and treatment resistance of CSCs.
Clinical relevance
The understanding of the CSC model may not only offer a novel pathophysiological framework for elucidating the resistance of tumors to treatment but also holds the potential to enhance clinicians’ capabilities in a more effective diagnosis, prognosis, and treatment of cancer. Current treatment to destroy cancer cells, succeeds mainly in killing only nonstem cancer cells, which may explain the phenomenon of successful therapeutic tumor shrinkage without a corresponding improvement in patient survival. For that reason, this occurrence indicates an urgent need to modify treatment approaches so that tumor shrinkage is not itself the determinant of therapeutic success. Therefore, multiple novel strategies have been conceived with the specific aim of destroying CSCs and their niche. Some of the most important and successful attempts include immunotherapy that involves antibodies targeting CSCs specific surface markers used as a combination with chemotherapy, radiotherapy, and surgery. Moreover, many studies have focused on dysregulating signaling pathways in CSCs as a new target for cancer therapy. This line of treatment proves to be successful because, like normal stem cells, CSCs, up or down, regulate the same signaling cascades that are essential for self-renewal, proliferation, and differentiation10. Another novel therapeutic strategy may involve targeting the tumor microenvironment which will act on the self-regulating process, vasculature, and essential features like oxygen level and acidity needed by CSCs. However, this plan of treatment is not specific enough and might affect also normal stem cells. Furthermore, the induction of apoptosis in CSCs holds great promise for eradicating cancer. The resistance of cancer-initiating cells mainly is conferred to their ability to impair apoptotic mechanisms through various strategies. Therefore, many compounds have been or are being developed to target intrinsic and extrinsic apoptotic pathways inciting self-death of the CSCs. At the moment, some of the above-mentioned strategies are successfully used in clinics, primarily in combination with traditional therapies, and others are still under evaluation. Nonetheless, all these alternative therapies are very promising, so future works should focus on increasing the specificity and efficiency in targeting CSCs, avoiding harm and toxicity of normal tissue stem cells.
Conclusion
Despite the longstanding presence of the CSCs model for over 50 years, recent advancements in modern stem cell biology techniques have accelerated progress in the field over the past several years. Our discussion has underscored the pivotal role of CSCs in driving tumorigenesis, tumor heterogeneity, and resistance to therapy. By possessing self-renewal and differentiation capabilities akin to normal stem cells, CSCs contribute to tumor initiation, progression, and metastasis. Furthermore, their dysregulated signaling pathways and interactions within the tumor microenvironment reinforce their prominence as key players in cancer biology. Importantly, we have emphasized the clinical relevance of CSCs, recognizing their potential as therapeutic targets and prognostic indicators. Insights gleaned from ongoing research on CSCs hold promise for the development of innovative treatment modalities aimed at eradicating cancer at its roots. Moreover, the identification and characterization of CSCs offer valuable opportunities for refining diagnostic techniques and tailoring treatment strategies to individual patients.
As we continue to unravel the complexities of CSCs, it is evident that their elucidation represents a cornerstone in the pursuit of more effective cancer therapies and improved patient outcomes. Through interdisciplinary collaboration and relentless scientific inquiry, we endeavor to translate our understanding of cancer stem cells into tangible advancements in the fight against cancer.
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