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The secondary tumour is composed of the same cell types as the primary tumour. The ability to produce a heterogeneous cell population is linked to cells isolated from a tumour Figure 1B. To show this feature the experimental model should be used. The most appropriate model is transplantation into an immunosuppressed organism whose immune system does not reject grafted cells. The ability to generate a heterogeneous secondary tumour cell population, which is identical to the primary tumour, denotes that there were CSCs amongst transplanted cells.
The term "tumour-initiating cell" or "tumorigenic cell" are often used to emphasize this feature and thus can be treated as the synonyms for CSC.
However, these terms can lead to a confusion with the first cell that was initiated and gave rise to cancer in the patient [13,19]. For that reason some authors avoid using these phrases and propose the term "tumour-propagating cells" TPCs . Morphological diversity of cells, as seen under a microscope, is much more pronounced in the tumour compared to normal tissue. It is one of the features of atypia, the term used to define malignancy in histopathology.
There are also differences amongst tumour cells in a phenotype for instance: expression of surface antigens and cytoplasmic proteins, activity of biochemical processes and functionality for instance: proliferation rate, invasion, metastases forming, activation of neoangiogenesis, resistance to systemic therapy [3,20]. The key factors responsible for tumour heterogeneity are genomic heterogeneity, hierarchical organization of tumour tissue, environmental influences and random processes [21,22]. Genomic heterogeneity results from genomic instability and increased proliferation rate [20,21].
Mutated cells undergo natural selection in the Darwinian evolution mechanisms Figure 2A which favour better adjusted cells. These cells live longer and give rise to descendant cells. The clones are generated as tumour grows. Thus tumour mass is heterogeneous as it consists of clonal variants[21,22]. Figure 2 Basic tumour heterogeneity models. A - Clonal evolution model. High proliferation and genomic instability result in a large number of cells differing in genotype and thus phenotype.
The best fitted cells are selected by Darwinian processes to generate clonal variants of the tumour. B - Cancer stem cell model.
Cancer stem cell - Wikipedia
CSC population is capable of unlimited number of divisions. Tumour heterogeneity results from existence of phenotypically diverse populations of different stages of cell maturation. The cancer stem cell model assumes that tumour tissue is hierarchically organized.
CSCs population is responsible for tumour growth and progression Figure 2B. In this respect heterogeneity means presence of cells at different stages of maturation . Clonal evolution and CSC models describe the basic mechanisms leading to tumour heterogeneity . Genomic heterogeneity has been proved by genomic research results . The question that remains is whether most of tumour cells or only CSCs undergo clonal evolution. It is possible that only a minority of tumours are hierarchically organized and clonal evolution of CSCs occurs only in these cases  Figure 3.
Figure 3 Clonal evolution and CSCs model are not exclusive.
The population of CSCs may undergo clonal evolution. Tumour heterogeneity results from existence of both clonal variants and different stages of cell maturation. Like normal tissue, tumour cells are prone to influences from the microenvironment stromal cells, extracellular matrix. The difference is that tumour tissue is characterized by a profound disarrangement of microenvironment. A wide variety of microenvironmental influences contributes to tumour cell heterogeneity .
The random stochastic processes result from random biochemical reactions. There is also another phenomenon referred to as transcriptional noise. It works by difference in the time of transcription between cells . The concept of CSCs has been discussed in the scientific literature since the 19 th century.
In Durante hypothesised that tumours derive from a rare cell population of stem cell characteristics . Simultaneously, Conheim Virchow's student speculated that these cells may be embryonal cells, which remain in the adult organism, retaining their pluripotency Figure 4A. This concept was called the "embryonal rest theory" [2,7]. In the late 19 th century this hypothesis was gradually replaced by dedifferentiation theory of carcinogenesis Figure 4B. It assumed that adult differentiated cells are the source of cancer stem cells after process of dedifferentiation, i.
In the mid th century, when stem cells were gaining more attention, the concept binding together tumours and stem cells became attractive again. Figure 4 The historical concepts of CSCs origin.
Breast cancer brain metastases: biology and new clinical perspectives
A - Embryonal rest theory. The pluripotent embryonal cells remain in the adult organism in the form of "embryonal rest". They are the origin of CSCs. B - Dedifferentiation theory. Somatic stem cells of adult tissue gain pluripotency through dedifferentiation. It is a common mistake to treat a CSC as a synonym of a normal stem cell which has gone through carcinogenesis to initiate tumour [13,24].
In this regard, some authors prefer using the term "tumour-initiating cells" . To describe the former entity, the term "cancerous stem cell" can be used . There are discrepancies between investigators regarding the source of CSCs. Intuitively, normal stem cells are likely to be the target of oncogenic initiation leading to the formation of CSCs [13,26]. Similarly to normal tissue, CSCs give rise to progenitor cells which are an intensively proliferating cell population.
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Normal progenitors differentiate after a certain numbers of divisions and lose their ability to divide terminal differentiation. However, cancer progenitor cells' ability to proliferate is much higher. Thus, their progeny is much more numerous and accumulates, which leads to an increase in tumour mass . CSCs may also derive from normal progenitor cells which acquired self-renewal ability in the course of accumulating mutations during carcinogenesis [13,25]. Some experiments seem to confirm this hypothesis. In one of them, acute myeloid leukaemia was generated after transplantation of hematopoietic progenitor cells with transduced MLL oncogene [18,27].
The results of the last research revealed unexpectedly that CSCs may derive from differentiated epithelial cells in the process of epithelial-mesenchymal transition EMT [28,29].
Epithelial-mesenchymal transition and metastases. Epithelial-mesenchymal transition is a process occuring during development of multicellular organisms. The epithelial cells acquire mesenchymal properties by loss of cell-cell junctions and polarity . Owing to migratory and invasive capabilities, mesenchymal cells are concordant with cancer phenotype.
Thus it has been proposed that EMT contribute to cancer development.