What is the Origin of CSCs & Research Update

Cancer stem cells (CSCs) have the ability to self-renew and are present in most tissues including, but not limited to breast, brain, lung, head and neck, prostates, testis, ovary, esophagus, colon and liver. To address CSCs holistically, without significant collateral damage, it is first necessary to understand CSCs behavior and origin. (*) In this Article, I will review what the research has found in this regard.

History & Context

Cancer stem cells (CSCs) were first identified by John Dick in acute myeloid leukemia in the late 1990s. As a stem cell biologist, John Dick showed that CSCs are key players in malignancy. For close to twenty years, there’s been a relatively strong focus on CSCs cancer research. (**)

CSCs are cancer cells that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. CSCs are therefore tumorigenic (tumor-forming). CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells appear to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors.[1,2]

“Cancer stem cells are rare immortal cells within a tumour that can both self-renew by dividing and give rise to many cell types that constitute the tumour, and can therefore form tumours”. (Nature, April 2019)

Origins of CSCs

The premise underlying the CSC hypothesis is that not all tumor cells in a cancer are equal.[3] The CSC hypothesis is fundamentally based on the application of stem cell concepts derived from embryogenesis.Which makes Beard’s carcinogenesis contribution (more than 100 years ago) all the more interesting (See Beard File)

The following are up-to-now key features of the CSC Pathway

(1) Only a small fraction of the cancer cells within a tumor have tumorigenic potential when transplanted into immunodeficient mice; (2) the CSC subpopulation can be separated from the other cancer cells by distinctive surface markers; (3) tumors resulting from the CSCs contain the mixed tumorigenic and nontumorigenic cells of the original tumor and (4) the CSC subpopulation can be serially transplanted through multiple generations, indicating that it is a self-renewing population” Therefore, CSCs are capable of self-renewal and differentiating into other distinctive cells that make up the tumor mass.[3]

Various types of stem cells give rise to progenitor cell which have the ability to further divide into specialized or differentiated cells that carry out the specific functions of the body. (Proginotor cells come from stem cells).

It is still controversial as to whether CSCs arise from stem cells, progenitor cells or differentiated cells present in adult tissue. The issue is currently under debate.[3]. Today, however, much of the cancer stem cell biology research is focused on thetumor microenvironment.

“Cancer stem cells (CSCs) comprise the subpopulation of tumor bulk and acquire resistant to conventional therapies and are considered as the primary tumor initiator cells. Nowadays,the tumor heterogeneity originated from CSCs, and its progenitors are accepted as a mortifying drawback in front of the cancer therapies. However, escalating knowledge gained from studies investigating the biology of CSCs will open up new frames for targeted therapies and decrease the chance of recurrence of the disease. In this review, the general understanding of CSCs and current studies were discussed briefly. Considering the latest data collected from studies of CSCs, defining the tumor heterogeneity and tumor microenvironment comprehensively will be very important to step up the cancer research. (Gene.2019 Jan 10;681:80-85. doi: 10.1016/j.gene.2018.09.052. Epub 2018 Sep 27).

Below, a summary of the most credible hypotheses.

CSCs arise from Stem Cells

In this hypothesis, cancer cells could utilize the existing stem cell regulatory pathways to promote their self-renewal. The ability to self-renew gives stem cells long lifespan relative to those of mature, differentiated cells. It has therefore been hypothesized that the limited lifespan of a mature cell makes it less likely to live long enough to undergo the multiple mutations necessary for tumor formation and metastasis.[4,5]

CSC come from Progenitor cells

The number of progenitor cells is more abundant in adult tissue than the stem cells and they have partial capacity for self-renewal. Their abundance relative to stem cells in adult tissue forms the basis of hypothesis suggesting progenitor cells as a source of CSC.[4,6]

CSCs arrise from Differentiated Cells

Another school of researchers have suggested that cancer cells could arise from mature, differentiated cells that somehow dedifferentiate to become more stem cell like. In this scenario, the requisite oncogenic (cancer-causing) genetic mutations would need to drive the dedifferentiation process as well as the subsequent self-renewal of the proliferating cells.

This model leaves open the possibility that a relatively large population of cells in the tissue could have tumorigenic potential; a small subset of these would actually initiate the tumor. Specific mechanisms to select which cells would dedifferentiate have not been proposed. However, if a tissue contains a sufficient population of differentiated cells, the laws of probability indicate that a small portion of them could, in principle, undergo the sequence of events necessary for de-differentiation. Induction of Epithelial–Mesenchymal Transition (EMT) in differentiated human epithelial cells leads to the acquisition stem cell-like phenotype and formation of CSCs. The role of EMT in carcinomas including HNSCCs has now been well established. [4,7)

There are currently two accepted models for cancer development as follows:[8] The stochastic model suggests that every cancer cell is able to initiate new tumor growth equally. The alternate hypothesis is that every tumor contains a rare population of cells termed CSCs or cancer-initiating cells.

Stem Cell Niche

Physiological stem cells and CSCs depend on their immediate microenvironment or niche for their survival and function (Borovski et al., 2011). The cellular and noncellular components of the niche provide signals that regulate proliferative and self-renewal signals, thereby helping CSCs to maintain their undifferentiated state (Kuhn and Tuan, 2010).

Nonepithelial stromal cells, inflammatory cells and the vasculature have been proposed as key components of the niche that support and sustain CSCs (Fuchs et al., 2004).

This raised the hypothesis that one could suppress the survival of CSCs by disrupting the interactions with their supportive niche. Indeed, it has been recently suggested that the hematopoietic stem cell niche is a potential therapeutic target for metastatic bone tumors (Shiozawa et al., 2011). In HNSCCs, the majorities of the stem cells are localized close to blood vessels and depend on interactions with components of the niche for their survival (Krishnamurthy et al., 2010). In addition to providing nutrients and oxygen to cells, endothelial cells secrete factors that promote the self-renewal and survival of head and neck CSCs.

How to Identify CSCS ?

CSC expresses specific markers that vary considerably depending on tumor type or tissue of origin. As of today, there appears to be no universal marker for CSCs.The most commonly applied methods for the identification of CSCs are as follows.[8] Xenotransplantation assays, the gold-standard for identification of CSCs, are used to assess the tumorigenicity and self-renewing potential of the putative CSC population CD44, the most well-recognized CSC marker, is a large cell surface glycoprotein that isinvolved in cell adhesion and migration ALDH (an intracellular enzyme normally present in the liver) activity is known to enrich hematopoetic stem cells and recently has been revealed to enrich cells with increased stem-like properties in solid malignancies. More research is still needed to better identify these cells.

Signaling Pathways of CSCs

Wnt/β–Catenin

An important pathway involved in maintaining the stem cell niche and tumorigenesis is Wnt/β-catenin signaling, normally involved in regulating pluripotency in embryonic and somatic stem cells and intimately involved in tissue homeostasis. There are three different pathways involved in Wnt signaling: the canonical Wnt/β-catenin cascade, the noncanonical planar cell polarity pathway and the Wnt/Ca2+ pathway. The canonical pathway is the one implicated in tumorigenesis. Wnt receptor complexes are bound by Wnt ligand, leading to intrinsic kinase activity of the APC complex to inhibit β-catenin. Specifically, Wnt stabilizes β-catenin and enhances ABCB1/MDR-1 transcription, which is multidrug resistance genes expressed in stem cells. Furthermore, β-catenin accumulates and translocates to the nucleus to bind the N terminus of LEF/TCF transcription factors. Binding subsequently causes activation of Myc, AXIN2and CYCLIND1genes. Wnt, through the activation of β-catenin, also plays a role in metastasis and EMT. When this pathway becomes dysregulated, neoplastic proliferation occurs. Inhibiting these pathways is another potential target of therapeutic agents.[10]

Epithelial–mesenchymal transition

EMT plays a significant role in normal development and wound healing by inducing cellular changes leading to breakdown of cell-to-cell interactions. Breaking cell communications is a critical step in transforming adherent, stationary epithelial cells into migratory cells. Based on its role in normal tissues, researchers have studied and proven how EMT transforms an epithelial cell into a cancer cell capable of migration, leading to increased metastasis and progression of solid tumors.

Brabletz et al. hypothesized that there were two types of CSCs: stationary CSCs (sCSCs) and migrating CSCs (mCSCs). sCSCs are embedded in the epithelia and are nonmobile, while mCSCs mediate tumor cell metastasis. They proposed that mCSCs were derived from sCSCs who underwent EMT. In other words, EMT was an essential component involved in promoting metastasis from the CSCs protected within the niche. In EMT, E-cadherin and β-catenin are downregulated while vimentin, fibronectin and N-cadherin are upregulated. Mani et al. demonstrated this upregulation in mammary epithelial and breast cancer cells.[10]

Hypoxia-inducible factors

Hypoxic stress is one important factor in the niche. Numerous studies have demonstrated that tumor hypoxia is an independent factor leading to increased metastatic potential, malignancy and resistance to treatment. Hypoxia is thought to contribute to the malignant transformationof cells by increasing expression of drug-resistant genes, facilitating tumor invasion and metastasis, reducing expression of DNA repair genes and decreasing genomic stability. It was also shown that tumor hypoxia may regulate cell differentiation, supporting the theory that it may facilitate the maintenance of CSCs. The primary mediator of hypoxia-induced cell signaling is hypoxia-inducible factor-1 (HIF-1), which is often correlated with tumor development and decreased patient survival. HIF proteins play a critical role in angiogenesis, facilitating the growth of vasculature within tumors.[10]

In this perspective, it was shown that CSCs are metabolically flexible. There are complex interactions within the microenvironment and cellular communications in the CSC niche to interfere with CSC growth and metastasis and all the more so that it relies on oxidative phosphorylation.

“As metabolic plasticity is a hallmark of cancer cell adaptation, the intricacies of CSC metabolism and their phenotypic behavior are critical areas of research. Unlike normal stem cells, which rely heavily on oxidative phosphorylation (OXPHOS) as their primary source of energy, or cancer cells, which are primarily glycolytic, CSCs demonstrate a unique metabolic flexibility.CSCs can switch between OXPHOS and glycolysis in the presence of oxygen to maintain homeostasis and, thereby, promote tumor growth”(Source).

More research is still nonetheless needed to better identify these cells.

Discussion

Metastasis is a complex, multistep process that involves a specific sequence of events; namely, cancer cells must escape from the original tumor, migrate through the blood or lymph to a new site, adhere to the new site, move from the circulation into the local tissue, form micrometastases, develop a blood supply and grow to form macroscopic and clinically relevant metastases. It has been suggested that a small, and most likely specialized, subset of cancer cells drives the spread of disease to distant organs. Some researchers have proposed that these unique cells may be CSCs.[4]

In this context, it was demonstrated a few years ago that cells in individual tumors can interconvert into different cell types including reverting into cancer stem cells in order to maintain equilibria in terms of the proportion of cells existing in different states within the cancer and further it’s ultimate mission of subduing the host via metastatic cascades that will overwhelming the patient. What researchers then found is that cancer cells live less in  a hierarchical society in which all cells are derived from cancer stem cells than in a  a decentralized society of different cell types that can sense when one type of cell has been depleted and generate new cells of the relevant type to take their place.

The group that found this inter-convertibility included scientists at the Massachusetts of Institute of TechnologyBroad Institute,Tufts University, andHarvardMedical School. Details are published in Cellin a paper titled “Stochastic State Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells.”

“Cancer cells within individual tumors often exist in distinct phenotypic states that differ in functional attributes. While cancer cell populations typically display distinctive equilibria in the proportion of cells in various states, the mechanisms by which this occurs are poorly understood. Here, we study the dynamics of phenotypic proportions in human breast cancer cell lines.We show that subpopulations of cells purified for a given phenotypic state return towards equilibrium proportions over time. These observations can be explained by a Markov model in which cells transition stochastically between states. A prediction of this model is that, given certain conditions, any subpopulation of cells will return to equilibrium phenotypic proportions over time. A second prediction is that breast cancer stem-like cells arise de novo from non-stem-like cells. These findings contribute to our understanding of cancer heterogeneity and reveal how stochasticity in single-cell behaviors promotes phenotypic equilibrium in populations of cancer cells.”

If this model is correct, it would eventually condemn conventional oncology’s race to find the blockbuster CSCs kill drug,  because removing cancer stem cells will just prompt other cell types in the tumor to convert into stem cells to balanced their milieu and further their mission. (Source) https://www.ncbi.nlm.nih.gov/pubmed/21854987

In Conventional Cancer Care

Conventional therapies become less effective when tumors progress from an organ-confined disease into locally invasive and metastatic cancers. This is due togenetic abnormalities causing overexpression of oncogenic signaling pathways as well as downregulation of tumor suppressor gene products such as p53, PTEN or Rb in cancer cells.

Conventional chemotherapeutic drugs are successful in debulking the tumor. However, slow-growing CSCs evade conventional therapies, and with the passage of time,these cells are activated and regenerate tumors locally or at distant sites. Furthermore, CSCs’ quiescent state makes them resistant to standard chemotherapy. Chemotherapeutic agents normally act on rapidly dividing cells that are actively synthesizing DNA. In comparison to other cells within the tumor, because CSCs are not rapidly synthesizing DNA, they are relatively protected from the toxicity of chemotherapy, leading to resistance.

This fact explains the relatively high recurrence rates in patients with  cancer. In contrast, targeting the CSCs either directly or viatheir niche could lead to a more definitive response, since the CSCs are the putative drivers of recurrence and metastatic spread.  Based on the identification of the above cell surface and functional markers, conventional researchers started developing targeted therapies to attack these cells normally resistant to conventional therapy.[10]

However, because of the inter-convertibility mechanism and CSCs plasticity, a drug kill approach may not work, and none up to now has been shown to definitively work. To better this approach, an emerging concept is the combined use of conventional chemotherapy and CSC targeted therapy. [3]

So far, the Conventional CSCs approach goes like this: (a) Conventional chemotherapy targets primarily the highly proliferative cells that constitute the bulk of the tumor. With suitable microenvironments, the cancer stem cells proliferate and the tumor recurs. (b) Direct cancer stem cell targeting or (c) indirect cancer stem cell targeting via disruption of their perivascular niche can potentially eliminate cancer stem cells. Ablation of the stem cells may inhibit the regeneration of the tumor and ultimately result in tumor regression.

In Holistic Cancer Care

The ACR Institute’s approach is more gentle, metabolic and holistic than conventional  cancer care in that we first attempt to encourage the cancer stem cells toredifferentiateback into what they were, either a stem cell, a progenitor cell or just another somatic differentiated cell.

To redifferentiate CSCs, it’s necessary to address both the tumor microenvironment and cells metabolism, if only because CSCs are driven by mitochondria.(Source) Cells get energy through mitochondria, which depends on oxygen, and through sugar, or glucose. Cancer stem cells pull energy both ways. In the dormant state, it uses glucose; in the proliferative state it depends on oxygen.Lipids, pyruvateandproteinis also relevant for CSCs functioning.

The immune system is also regulated by metabolism, hence, the ACR institute’s approach in combining cancer stem-cell therapy with immunotherapies,inter alia, but holistically based immunotherapies because conventional immunutherapies have shown to be successful in only a small percentage of patients. For the majority of conventional immunotherapy patients, there is either-and a strong immune reaction against innocent tissues, or the immune system only works temporarily in that the cancer comes back, just like with chemotherapy (Source).

Hence, the ACR Institute prefers a more holistic approach, including the immune system, the microbiota and among others, the cancer stem cells and detoxification pathways. (Yes, among other toxicities, arseniccan induce the emergence of CSCs).

The evidence that cancer stem cells can be redifferentiated has existed for close to ten years. In one more recent study, this finding has been corroborated with genistein. “These results indicate that GEN was able to induce the differentiation of breast cancer stem/progenitor cells through interaction with ER+ cancer cells by a paracrine mechanism”. Source.

But there is little investment in this realm, most likely because the Cancer Industry prefers to reap huge profits from more complicated approaches. Professor Weissman as well as many other cancer experts have confirmed Cancer Industry’s way of suppressing holistic or innovative cancer care. First they buy the promising cancer care industry. Then they shut it down. Other suppression approaches exist (See File).

Conclusion

Cancer is like a game of whack-a-mole. Strike it down in one place and it pops back up in another.  Researchers have found that cancer stem cells exist in more than one state and are very plastic, meaning they can change form, sliding back and forth between a dormant state and a rapidly growing state.This plasticity is responsible for cancer’s two key characteristics: multiplying and spreading.

Today, the cancer stem cells are considered to have a strong role in cancer growth, metastasis, invasion and recurrence of all cancer. Cancer stem cells are typically characterized by continuous proliferation and self-renewal as well as by differentiation potential, while stem cells are considered to differentiate into tissue- specific phenotype of mature cells under the influence of micro-environment. Cancer stem cells should be traced to the stem cells under the influence of a micro-environment, which induces malignant tumors. From a close examination of the evidence,  the micro-environment appears to be the decisive ‘cancerous niche’. (J Stem Cells Regen Med. 2014; 10(1): 2–7). In particular, the conversion of iPSCs to CSCs appears to follow a metabolically impaired and inflammatory tumor microenvironment.

Currently, there is no single biomarker to define the CSC population accurately. Eventually, it will be necessary to identify a set of markers  to more narrowly define this population, in this way we can better monitor progress. (See testing category)

Meanwhile, the conventional cancer industry and research is continuing to focus on CSCs biology in order to bring CSCs therapy to the clinic, in particular by finding targeted drugs that can eradicate cancer stem cells.

As mentioned however, the ACR Institute questions this approach ascancer cells, in particular CSCs have already shown how they can bypass single drug agents. Furthermore, it is likely that when CSCs are killed, that thecancer microenvironment and cancer cells will find other ways to re-create CSCs and the like, including ways that will be evolutionarily more robust.This is why we prefer the holistic route, focusing on developing strong healthy stem cells within a context of immunity excellence.  (11)

Pr Joubert (ACR Institute)

To Read the ACR Institute’s proposals for CSC Holistic Therapy, consider scheduling a coaching Session

References

(*)  This piece describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process—each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research.

(**). The idea that the remnants of our embryonic past could lead to our demise through cancer is actually a longstanding hypothesis, tracing back to 1829. Throughout the mid-19th century, theories and observations accumulated that tumors were linked to embryonal tissue growth, culminating in a comprehensive “embryonal rest” theory put forward by Julius Cohnheim in 1875. The theory stated that tumors may arise from embryonic cells left over from development, and that lie dormant until activated to become cancerous. Today’s theories about the involvement of stem cells in cancer are really an update of the embryonal rest theory, only now we know more precisely which types of cells are involved. This advance in knowledge, more than 150 years after the theory was first proposed, came about because we now know how to identify stem cells within tumors by the protein markers on their surface.

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(11). Stem cells are key to our normal development and health from conception through adulthood. Embryonic stem cells produce the progenitors and patterns that determine how our organs, muscles, sinews, and skeletons are formed and how they are arranged in the body. After their work is done, they leave behind a guardian population of stem cells that repair each tissue as the need arises. When the stem cell divides into two, it creates one progenitor and renews itself. The progenitor continues its path of differentiation into mature, specialized cells, while the new stem cell waits for the next round when it is called upon to replenish tissue. Stem cells survive much longer than ordinary cells, increasing the chance that they might accumulate genetic mutations however. It might take only a few mutations for one cell to lose control over its self-renewal and growth and become the source of cancer. But with holistic living, tumor suppressor genes are activated while oncogenes are down regulated as the immune cells continue to protect us from bacteria, virus and malignant cells.

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