Cancer Stem Cells in a Nutshell

Cancer stem cells are the small number of cells within a tumor that drive the tumor’s growth. These cells generally make up just 1% to 3% of all cells in a tumor

What are adult stem cells?

Every organ and tissue in the body contains a small number of what scientists call adult stem cells or progenitor cells. These cells have three characteristics in common: 1). Adult stem cells can renew themselves through cell division for long periods of time. 2). Adult stem cells retain the ability to give rise to several (but not all) types of cells in the body. 3). Different types of adult stem cells give rise to different specialized cells. Pancreatic stem cells, for example, are the ancestors of insulin-producing islet cells in the pancreas. Hematopoietic stem cells develop into all the different types of cells in the human blood and immune systems.

Cancer stem cells are a type of adult or progenitor cell found in most types of cancer. These cells generally represent just 1% to 3% of all cells in a tumor, but they are the only cells with the ability to regenerate malignant cells and fuel the growth of the cancer.

Is this the same as embryonic stem cells?

Embryonic stem cells are primitive cells that form inside an early embryo. These cells also can be generated in a laboratory dish during a process called in-vitro fertilization. Four to five days after a human egg is fertilized by sperm, the dividing mass of cells is called a blastocyst. Scientists can remove the inner cell mass from the blastocyst and grow stem cells in a culture dish in the laboratory. Under the right conditions, these stem cells will retain the ability to divide and make copies of themselves indefinitely.

However, unlike adult stem cells, embryonic stem cells have the ability to give rise to any of the more than 200 different types of cells in the human body.

Why is research on cancer stem cells important?

Cancer research focuses on stem cells present in malignant tumors. More Researchers are starting to  believe like we do at the ACR Institute that most current cancer treatments  fail because they don’t address cancer stem cells (CSCs). One hundreds years ago, a scientist called Paget already developed a carcinogenesis theory that he called the “seed and soil” theory of cancer. In this light, we can see CSCs as the seeds or the roots of a plant. If we remove only the leaves but not the root, the plant or weed will grow back. The same is true for cancer: if you do not address the cancer stem cells, the cancer is likely to return. Today, conventional research is now a little more focused on killing these roots, the csc with drugs. But again and again, we at the ARC don’t believe in violence, in this case, biological violence. We prefer to address the CSC intelligently by modulating the signaling networks so that these malignancy-promoting progenitor cells are either cleared by the immune system and other biological mechanisms or converted back to the living terrain into healthy stem cells.

Recent reports show cancer deaths are decreasing, so aren’t we doing a good job already of killing cancer?

In some cancer types, we are doing a decent job, but only in terms of the five years remission. There are few follow-up studies on definite cancer cures. Many of these five years survivors get new cancers from the conventional treatments or their old ones get reactivated. But because these are diagnosed after the five years mark, they are counted as new cancers. Hence, the statistics on cancer success is not consistent with the facts.

It’s also true that many cancers when caught early can be successfully treated and achieve the five years remission. But dismal failure is for advanced cancers that have started to spread. These have low five years survival rates, especially cancers like pancreatic and lung cancers. Most of these cancers, such as breast, stomach, head and neck cancers etc, will also be often resistant to current allopathic cancer therapies. In addition, current chemotherapies and radiotherapies cause severe side effects because they target rapidly dividing cells that including digestive and immune cells. They are also carcinogenic, so they can cause new cancers.  Treatments that target only cancer stem cells and the immune system would be safer, more efficient and less costly.

In what tumor types have cancer stem cells been identified?

Cancer stem cells were first identified in leukemia, breast cancer as well as in brain, colon, multiple myeloma, head and neck, pancreas and central nervous system tumors. When studies, scientists are finding out that more and more cancers depend on CSCs to thrive and metastasize.

How are cancer stem cells identified?

Researchers take samples of tumors removed from patients during surgery, always with the patient’s informed consent. The cells within the tumor are then sorted based on their expression of certain cell markers on their surface. Sorted cells can be injected into mice, which are then watched for new tumor growth. When only specific sorted cells form new tumors, researchers then test those cells for properties of stem cells.

What happens after stem cells are identified?

The next step in conventional oncology is to understand how cancer stem cells work and identify drugs that will kill the stem cells without harming normal cells. In Holistic Oncology, we work differently.

What research is the ACR Institute doing in cancer stem cells?

The work on cancer stem cells is still in early stages, primarily taking place in the clinical setting, on the terrain and we are working on financing a clinical trials on the HIP protocol. Initial case study results are positive, but trials in a larger number of patients is necessary if the goal is to convince oncologists to go holistic.

 Scientific Debate on CSCs

The existence of CSCs is under debate, because different studies found no cells with their specific characteristics Cancer cells must be capable of continuous proliferation and self-renewal to retain the many mutations required for carcinogenesis and to sustain the growth of a tumor, since differentiated cells (constrained by the Hayflick Limitcannot divide indefinitely.

For conventional oncology, if most tumor cells are endowed with stem cell properties, targeting tumor size directly is a valid strategy. If CSCs are a small minority, targeting them may be more effective. Another debate is over the origin of CSCs – whether from disregulation of normal stem cells or from a more specialized population that acquired the ability to self-renew (which is related to the issue of stem cell plasticity). Confounding this debate is the discovery that many cancer cells demonstrate a Phenotypic plasticity under therapeutic challenge, altering their transcriptomes to a more stem-like state to escape destruction.

The Preponderance of the Evidence

The first conclusive evidence for CSCs came in 1997. Bonnet and Dick isolated a subpopulation of leukemia cells that expressed surface marker CD34, but not CD38.

Further evidence comes from histology. Many tumors are heterogeneous and contain multiple cell types native to the host organ. Tumour heterogeneity is commonly retained by tumor metastases. This suggests that the cell that produced them had the capacity to generate multiple cell types, a classical hallmark of stem cells.

Professor Wicha believes that all tumors are driven by cancer stem cells. CSCs reported in more and more cancer tumors. (Source)


The “mutation in stem cell niche populations during development” hypothesis claims that these developing stem populations are mutated and then reproduce so that the mutation is shared by many descendants. These daughter cells are much closer to becoming tumors and their numbers increase the chance of a cancerous mutation.(Source)

Another theory associates adult stem cells (ASC) with tumor formation. This is most often associated with tissues with a high rate of cell turnover (such as the skin or gut). In these tissues, ASCs are candidates because of their frequent cell divisions (compared to most ASCs) in conjunction with the long lifespan of ASCs. This combination creates the ideal set of circumstances for mutations to accumulate: mutation accumulation is the primary factor that drives cancer initiation. Evidence shows that the association represents an actual phenomenon, although specific cancers have been linked to a specific cause. (Source)

De-differentiation of mutated cells may create stem cell-like characteristics, suggesting that any cell might become a cancer stem cell. In other words, a fully differentiated cell undergoes mutations or extracellular signals that drive it back to a stem-like state. This concept has been demonstrated most recently in Prostate cancer models, whereby cells undergoing androgen deprivation therapy appear to transiently alter their transcriptome to that of a neural crest stem-like cell, with the invasive and multipotent properties of this class of stem-like cells. (Source)

The concept of tumor hierarchy claims that a tumor is a heterogeneous population of mutant cells, all of which share some mutations, but vary in specific phenotype. A tumor hosts several types of stem cells, one optimal to the specific environment and other less successful lines. These secondary lines may be more successful in other environments, allowing the tumor to adapt, including adaptation to therapeutic intervention. If correct, this concept impacts cancer stem cell-specific treatment regimes.[45]Such a hierarchy would complicate attempts to pinpoint the origin. (Source)

Immunity may be a Key Mechanism

The CSCs model suggests that immunological properties may be important for understanding tumorigenesis and heterogeneity.  CSCs can be rare in some tumors, (Source) but some researchers found that a large proportion of tumor cells can initiate tumors if transplanted into severely immuno-compromised mice, and thus questioned the relevance of rare CSCs. (Source)

However, both stem cells and CSCs possess unique immunological properties which render them highly resistant towards immunosurveillance. Thus, only CSCs may be able to seed tumors in patients with functional immunosurveillance, and immune privilege may be a key criterion for CSCs. (Source)

Furthermore, the model suggests that CSCs may initially be dependent on stem cell niches, and CSCs may  function as a reservoir in which mutations can accumulate over decades unrestricted by the immune system.

Clinically overt tumors may grow if: A) CSCs lose their dependence on niche factors (less differentiated tumors), B) immunogenic normal tumor cells evolve means to escape immunosurveillance or C) the immune system may lose its tumorsuppressive capacity, e.g. due to ageing. (Source)


Metastasis is the major cause of tumor lethality. However, not every tumor cell can metastasize. This potential depends on factors that determine growth, angiogenesis, invasion and other basic processes. In epithelial tumors, the epithelial-mesenchymal transition (EMT) is considered to be a crucial event. EMT and the reverse transition from mesenchymal to an epithelial phenotype (MET) are involved in embryonic development, which involves disruption of epithelial cell homeostasis and the acquisition of a migratory mesenchymal phenotype. EMT appears to be controlled by canonical pathways such as WNT and transforming growth factor β. (Source)

EMT’s important feature is the loss of membrane E-cadherin in adherens junctions, where β-catenin may play a significant role. Translocation of β-catenin from adherens junctions to the nucleus may lead to a loss of E-cadherin and subsequently to EMT. Nuclear β-catenin apparently can directly, transcriptionally activate EMT-associated target genes, such as the E-cadherin gene repressor SLUG (also known as SNAI2). Mechanical properties of the tumor microenvironment, such as hypoxia, can contribute to CSC survival and metastatic potential through stabilization of hypoxia inducible factors through interactions with ROS (reactive oxygen species). (Source)

Tumor cells undergoing an EMT may be precursors for metastatic cancer cells, or even metastatic CSCs. In the invasive edge of pancreatic carcinoma, a subset of CD133+CXCR4+ (receptor for CXCL12 chemokine also known as a SDF1 ligand) cells was defined. These cells exhibited significantly stronger migratory activity than their counterpart CD133+CXCR4 cells, but both showed similar tumor development capacity. Moreover, inhibition of the CXCR4 receptor reduced metastatic potential without altering tumorigenic capacity..(Source)

Chemo-Resistance Explained

CSCs have implications for cancer therapy, including for disease identification, selective drug targets, prevention of metastasis and intervention strategies. Somatic stem cells are naturally resistant to chemotherapeutic agents. They produce various pumps (such as MDR that pump out drugs and DNA repair proteins. They have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells). CSCs that develop from normal stem cells may also produce these proteins, which could increase their resistance towards chemotherapy. The surviving CSCs then repopulate the tumor, causing a relapse. (Source)

Selectively targeting CSCs may allow treatment of aggressive, non-resectable tumors, as well as prevent metastasis and relapse. The hypothesis suggests that upon CSC elimination, cancer could regress due to differentiation and/or cell death. The fraction of tumor cells that are CSCs and therefore need to be eliminated is unclear. Studies looked for specific markers and for proteomic and genomic tumor signatures that distinguish CSCs from others.


In 2009, scientists identified the compound salinomycin, which selectively reduces the proportion of breast CSCs in mice by more than 100-fold relative to Paclitaxel, a commonly used chemotherapeutic agent. (Source) Some types of cancer cells can survive treatment with salinomycin through autophagy  whereby cells use acidic organelles such as lysosomes to degrade and recycle certain types of proteins. The use of autophagy inhibitors can kill cancer stem cells that survive by autophagy.(Source)

A 2018 study identified inhibitors of the ALDH1A family of enzymes and showed that they could selectively deplete putative cancer stem cells in several ovarian cancer cell lines. (Source)

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