Sunday, April 17, 2016

Cancer Stem Cells

I have been spending some time on examining the issue of the cancer stem cell concept again. The literature is expanding yet there seems to be no convergence or consensus. This brief set of quotes is from more than a dozen major sources and at best one may become further confused. Just thought this would be an interesting exercise.  

1   The Challenge 

 Definitions are important. In mathematics and law, the definition will determine the outcome. In engineering we define certain parameters and we design accordingly. If there is a concern, we spend a great deal of time on the definition. In cancer studies the term "cancer stem cell" has been introduced.

Definitions should be clear and they should be actionable. Namely the definition should present a way to ascertain through objective measures readily understood by someone trained in the science or art to determine if what is presented satisfies the definition. Namely we should with a good definition know if what we have is a cancer stem cell.

The results below are a sample of what seems to be definitions from the literature. Reading these one can readily see what the complexity is in understanding this topic.The descriptions are each from the source noted. 

2    Definitions 

Ailles, and Weissman: Cancer stem cells (CSCs) are cells that drive tumorigenesis, as well as giving rise to a large population of differentiated progeny that make up the bulk of the tumor, but that lack tumorigenic potential. CSCs have been identified in a variety of human tumors, as assayed by their ability to initiate tumor growth in immuno-compromised mice… In addition, specific signaling pathways play a functional role in CSC self-renewal and/or differentiation, and early studies indicate that CSCs are associated with a micro environmental niche… several important biological properties of CSCs: first, what is the cell of origin for a given tumor? Second, what are the signaling pathways that drive self-renewal and/or differentiation of CSCs? Third, are there molecules uniquely expressed on CSCs, regardless of whether they are functional, that will allow targeted therapies to be developed? Fourth, what are the mechanisms by which CSCs escape conventional therapies and can we defeat these mechanisms?

Burgess: Should stem mitotic activity become unregulated or uncontrolled, a tumorigenic and perhaps malignant phenotype may result hence the term cancer stem cell…tumor initiating sells that have malignant properties have been referred to as CSCs…

Dalerba et al: Stem cells are defined by three main properties:

1. differentiation—the ability to give rise to a heterogeneous progeny of cells, which progressively diversify and specialize according to a hierarchical process, constantly replenishing the tissue of short-lived, mature elements;

2. self-renewal—the ability to form new stem cells with identical, intact potential for proliferation, expansion, and differentiation, thus maintaining the stem cell pool;

3. homeostatic control—the ability to modulate and balance differentiation and self-renewal according to environmental stimuli and genetic constraints   

Like their normal tissue counterparts, tumors are composed of heterogeneous populations of cells that differ in their apparent state of differentiation. Indeed, the differentiation features of a tumor, morphological and architectural, are the key parameter used in routine clinical practice by surgical pathologists to define a tumor’s primary anatomical origin.

This simple observation suggests that tumors are not mere monoclonal expansions of cells but might actually be akin to “abnormal organs,” sustained by a diseased “cancer stem cell” (CSC) population, which is endowed with the ability to self-renew and undergo aberrant differentiation. This hypothesis is further reinforced by the fact that cancer is known to result from the accumulation of multiple genetic mutations in a single target cell, sometimes over a period of many years (3). Because stem cells are the only long-lived cells in many tissues, they are the natural candidates in which early transforming mutations may accumulate.

Dubrovska, A., et al: One possible explanation for the initial positive response to therapy followed by androgen-refractory disease is that although current therapies eliminate the bulk of the tumor, they fail to eliminate cancer stem cells (CSCs) or tumor-initiating cells (TICs). In fact, it has been argued that many cancers are maintained in a hierarchical organization of rare CSCs, rapidly dividing cells, and differentiated tumor cells; the CSCs are not only a renewable source of tumor cells but are also a source of tumor resistance leading to tumor recurrence, metastasis, and tumor progression. Support for this hypothesis came with the identification of TICs in leukemia in 1994 and, subsequently, in a variety of cancers, including solid tumors. In addition, cancer cell lines have been shown to harbor cancer stem-like cells and are a promising model for CSC research because these progenitors can be readily expanded under anchorage independent (sphere formation) serum-free conditions

Fang et al: Recent studies suggest that cancer can arise from a cancer stem cell (CSC), a tumor-initiating cell that has properties similar to those of stem cells. CSCs have been identified in several malignancies, including those of blood, brain, and breast.

Hurt et al: The cancer stem cell hypothesis suggests the existence of a small subpopulation of cells within the tumour that give rise to differentiated tumour cells. It is thought that the cancer stem cells survive conventional treatment to later re-emerge more resistant to therapy. To date, putative cancer stem cells have been identified in blood, brain, breast, lung, skin, pancreas, colon, and prostate….

Jordan et al: Stem cells have three distinctive properties: self renewal (i.e., at cell division, one or both daughter cells retain the same biologic properties as the parent cell), the capability to develop into multiple lineages, and the potential to proliferate extensively. The combination of these three properties makes stem cells unique. The attribute of self-renewal is especially notable, because its subversion is highly relevant to oncogenesis and malignancy. Aberrantly increased self-renewal, in combination with the intrinsic growth potential of stem cells, may account for much of what is considered a malignant phenotype.   Biologically distinct and relatively rare populations of “tumor-initiating” cells have been identified in cancers of the hematopoietic system, brain, and breast. Cells of this type have the capacity for self-renewal, the potential to develop into any cell in the overall tumor population, and the proliferative ability to drive continued expansion of the population of malignant cells. Accordingly, the properties of tumor-initiating cells closely parallel the three features that define normal stem cells. Malignant cells with these functional properties have been termed “cancer stem cells”

Lawson and Witte: Two theories were proposed to explain this paradox. The stochastic theory suggested that all cancer cells are equally malignant but only clones that randomly possess favorable biological properties will grow upon transplantation. An alternative theory predicted that tumors are hierarchical like normal tissues and only the rare subpopulation of cells at the pinnacle of that hierarchy have the unique biological properties necessary for tumor initiation. Studies by John Dick and colleagues provided evidence for the hierarchy model. This group demonstrated that only the small subpopulation (0.1%–1.0%) of Lin–CD34+CD38– cells within human acute myelogenous leukemia samples were capable of initiating disease when transplanted into immune-deficient mice (10). These cells possessed the same antigenic profile as normal human HSCs, which are at the pinnacle of the normal hematopoietic hierarchy. This population also had the unique capacity to selfrenew to propagate the disease as well as differentiate to produce the many leukemic cell types represented in the original leukemia. Since these cancer cells possess properties unique to normal tissue stem cells, they have been termed “cancer stem cells” (CSCs).

Lobo et al: Stem cell: a primitive cell defined by its capacity to self-renew and differentiate into at least one mature cell type Cancer stem cell: a self-renewing cell within a tumor that has the capacity to regenerate the phenotypic diversity of the original tumor

NCI: The theory of the cancer stem cell (CSC) has generated as much excitement and optimism as perhaps any area of cancer research over the last decade. Biologically, the theory goes, these cells are distinct from the other cells that form the bulk of a tumor in that they can self-perpetuate and produce progenitor cells, the way that traditional stem cells do. The progenitors’ job is then to repopulate tumor cells eradicated by treatments such as chemotherapy or radiation.  But for all the attention and fanfare CSC research has received, the findings reported to date are far from clear-cut, investigators acknowledge. For example, most of the studies that have identified human CSCs have used mouse xenograft assays and cells from only a small number of human tumor samples, making it difficult to draw firm conclusions. In addition, other researchers haven’t always been able to replicate initially reported findings. And while these tumor-initiating cells, as they are also called, have been described as being a rare class, several studies have found that the number of cells that can form tumors in these mouse experiments is actually quite large, suggesting that perhaps CSCs aren’t such a privileged breed.

Pavlovic and Balint: As the stem cells that created the tumor to begin with are so few in number, scans following treatment usually fail to identify populations of CSCs in this limited population….[1]

Perego et al: Although there is no definitive consensus on the phenotype and frequency of CSCs in the majority of human tumors, much experimental evidence supports the contentions that many tumors of both epithelial and nonepithelial origin have operationally defined CSCs (cells able to propagate tumors in immunodeficient mice) and that the presence of these CSCs affects tumor biology. 

Rajasekhar: The "cancer stem cell model" CSC …envisions tumors as "pathological organs" sustained in their aberrant growth by a mutated population of stem cells, in which normal homeostatic controls on tissue expansion have been lost.

Roesch et al: The CSC concept postulates a unidirectional hierarchy of tumor cells…According to the traditional CSC concept, tumor initiation is regarded as an exclusive characteristic of CSCs

Rosen and Jordan: Thus, the CSC paradigm refers to the ability of a subpopulation of cancer cells to initiate tumorigenesis by undergoing self-renewal and -differentiation, like normal stem cells, whereas the remaining majority of the cells are more “differentiated” and lack these properties.

Soltysova, et al: Normal stem cells in the adult organism are responsible for tissue renewal and repair of aged or damaged tissue. A substantial characteristic of stem cells is their ability for self-renewal without loss of proliferation capacity with each cell division. The stem cells are immortal, and rather resistant to action of drugs. They are able to differentiate and form specific types of tissue due to the influence of microenvironmental and some other factors. Stem cells divide asymmetrically producing two daughter cells – one is a new stem cell and the second is progenitor cell, which has the ability for differentiation and proliferation, but not the capability for self-renewal. Cancer stem cells are in many aspects similar to the stem cells. It has been proven that tumor cells are heterogeneous comprising rare tumor initiating cells and abundant non-tumor initiating cells. Tumor initiating cells – cancer stem cells have the ability of self-renewal and proliferation, are resistant to drugs, and express typical markers of stem cells. It is not clear whether cancer stem cells originate from normal stem cells in consequence of genetic and epigenetic changes and/or by redifferentiation from somatic tumor cells to the stem-like cells. Probably both mechanisms are involved in the origin of cancer stem cells. Dysregulation of stem cell self-renewal is a likely requirement for the development of cancer. Isolation and identification of cancer stem cells in human tumors and in tumor cell lines has been successful.

Visvader: It is important to note that the cell of origin, the normal cell that acquires the first cancer-promoting mutation(s), is not necessarily related to the cancer stem cell (CSC), the cellular subset within the tumour that uniquely sustains malignant growth. That is, the cell-of-origin and CSC concepts refer to cancer-initiating cells and cancer-propagating cells, respectively. Although the tumourinitiating cell and the CSC have been used interchangeably, the tumour-initiating cell more aptly denotes the cell of origin. There is considerable evidence that several diverse cancers, both leukaemias and solid tumours, are hierarchically organized and sustained by a subpopulation of self-renewing cells that can generate the full repertoire of tumour cells (both tumorigenic and non-tumorigenic cells). The cell of origin, the nature of the mutations acquired, and/ or the differentiation potential of the cancer cells are likely to determine whether a cancer follows a CSC model. In most instances, the phenotype of the cell of origin may differ substantially from that of the CSC. Normal cellular hierarchy comprising stem cells that progressively generate common and more restricted progenitor cells, yielding all the mature cell types that constitute a particular tissue. Although the cell of origin for a particular tumour could be an early precursor cell such as a common progenitor, the accumulation of further epigenetic mutations by a cell within the aberrant population (in this case expanded) during neoplastic progression may result in the emergence of a CSC. In this model, only the CSCs (and not other tumour cells) are capable of sustaining tumorigenesis. Thus, the cell of origin, in which tumorigenesis is initiated, may be distinct from the CSC, which propagates the tumour. 

3    References

1.     Ailles, L and I. Weissman, Cancer stem cells in solid tumors, Current Opinion in Biotechnology 2007, 18:460–466
2.     Burgess, R., Stem Cells, Wiley (New York) 2016.
3.     Dalerba et al, Cancer Stem Cells: Models and Concepts, Annu. Rev. Med. 2007. 58:267–84
4.     Dubrovska, A et al, The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations, PNAS, Jan 2009 V 106 N 1
5.     Fang et al, A Tumorigenic Subpopulation with Stem Cell Properties in Melanomas, Cancer Res 2005; 65: (20). October 15, 2005
6.     Hurt et al, CD44þCD24prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis, British Journal of Cancer (2008) 98(4), 756 – 765
7.   Jordan et al, Cancer Stem Cells, NEJM, 355;12 September 21, 2006
8.     Lawson, Witte, Stem cells in prostate cancer initiation and progression, The Journal of Clinical Investigation Volume 117 Number 8 August 2007
9.     Lobo et al, The Biology of Cancer Stem Cells, Annu. Rev. Cell Dev. Biol. 2007. 23:675–99
10.  Pavlovic, M., B. Balint, Bioengineering and Cancer Stem Cell Concept, Springer (New York) 2015
11.            Perego et al, Heterogeneous Phenotype of Human Melanoma Cells with In Vitro and In Vivo Features of Tumor-Initiating Cells, Journal of Investigative Dermatology (2010), Volume 130
12.            Rajasekhar, V., Cancer Stem Cells, Wiley (New York) 2014.
13.  Roesch et al, A Temporarily Distinct Subpopulation of Slow-Cycling Melanoma Cells Is Required for Continuous Tumor Growth, Cell 141, 583–594, May 14, 2010
14.  Rosen, J., C. Jordan, The Increasing Complexity of the Cancer Stem Cell Paradigm, Science, 26 JUNE 2009 VOL 324.
15.  Soltysova, A., et al, Cancer stem cells, NEOPLASMA, 52, 6, 2005
16.  Visvader, J., Cells of Origen in Cancer, Nature, V 469 20 Jan 2011.

[1] This book is near incomprehensible in my opinion. It appears impossible to find a definition, only secondary referral characteristics at best!