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2011, Volume 27, Number 2, Page(s) 093-097
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DOI: 10.5146/tjpath.2011.01055
Stem Cell - Is There Any Role in Tumorigenic Activity
Sonal SAIGAL, Ankur BHARGAVA
Department of Oral and Maxillofacial Pathology, Government Dental College, RAIPUR, INDIA
Keywords: Stem cell, Carcinogenesis, Squamous cell carcinoma
Abstract
Stem cells are a quintessential key to proper behavior of homeostatic processes. They are often thought of as the solution to a wide range of human conditions, with the ability to rescue malfunctioning or non-functioning organs and tissues. However, there is increasing evidence that stem cells can play a central role in disease. Most recently stem cells have been implicated in cancer after not responding to homeostasic controls such as proliferation and differentiation. Cancer has long been seen as a disease that arises from mutations that impair the capacity of any cell within the organism to respond to the signals that regulate proliferation. Besides their scarcity or abundance, a second important issue with respect to cancer stem cells is their origin. A new defining model for carcinogenesis, the “cancer stem cell hypothesis” was put forward in 2006, according to which cancer is a stem cell disease that places malignant stem cells at the centre of its tumorigenic activity as they have the capacity to undergo self-renewal, and have the potential to differentiate into different types of cells in a specific lineage.
Introduction
Stratified squamous epithelia act as a protective interface between the body and the environment. They have a simple organization: proliferation takes place in the basal layer of cells attached to an underlying basement membrane and cells undergo terminal differentiation as they move towards the tissue surface. The outermost cell layers are shed throughout adult life and are replaced through proliferation of a subpopulation of cells in the basal layer known as stem cells1. In cancers such as squamous cell carcinomas, stem cells may more likely undergo transformation than the proliferating basal layer cells since the latter divide for relatively short periods before terminally differentiating. It is less likely that a large proliferating population could acquire the self renewal potential of stem cells in order to accumulate additional mutations leading to tumorigenesis2. Nowadays, cancer is increasingly being viewed as a stem cell disease, both in its propagation by a minority of cells with stem-cell-like properties and in its possible derivation from normal tissue stem cells but stem cell activity is tightly controlled, raising the question of how normal regulation might be subverted in carcinogenesis3. These Cancer Stem Cells (CSCs) are defined as a small subset of cancer cells that constitute a pool of self-sustaining cells with the exclusive ability to maintain the tumor. Currently, there are two hypothetical explanations for the existence of CSCs that state they may arise from normal stem cells by mutation of genes that render the stem cells cancerous or they may come from differentiated tumor cells that experience further genetic alterations and, therefore, become dedifferentiated and acquire CSC-like features4.

Types and Properties of Stem Cells
Stem cells have been classified based on their developmental potential (Table I)3-7. However the two main categories of stem cells are embryonic and adult stem cells, defined by their source (Table II)6,7. The types of differentiation in stem cells are shown in Table III8.


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Table I: Classification of stem cells based on developmental potential with its properties and examples


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Table II: Types of stem cells with their sources of origin


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Table III: Types of differentiation in stem cells

Other Properties
Self-renewal: They can divide without differentiation and create everlasting supply.

Plasticity: MSCs have plasticity and can undergo differentiation. The trigger for plasticity is stress or tissue injury which upregulates the stem cells and releases chemoattractants and growth factors6,8.

CSCs could support metastasis
The process of metastasis consists of a series of linked, sequential steps that must be completed by tumor cells if a metastasis is to develop. Although some of the steps in this process contain stochastic elements, metastasis as a whole favors the survival and growth of a few subpopulations of tumor cells that pre-exist within the heterogeneous parent neoplasm. Metastases can have a clonal origin, and different metastases can originate from the proliferation of single cells. The outcome of metastasis depends on the interaction of metastatic cells with different organ environments9. There are three main characteristics that define CSCs: differentiation, which provides the ability to give rise to a heterogeneous progeny, self-renewal capability that maintains an intact stem cell pool for expansion, and homeostatic control that ensures an appropriate regulation between differentiation and self renewal according to the environmental stimuli and genetic constraints of each organ tissue, which accounts for the tissue specificity of CSCs10.

Cancer metastasis requires seeding and successful colonization of specialized CSCs at distant organs. The biology of normal stem cells and CSCs share remarkable similarities and may have important implications when applied to the study of cancer metastasis. Furthermore, overlapping sets of molecules and pathways have recently been identified to regulate both stem cell migration and cancer metastasis11.

Insights of the differentiation signals for tumorigenesis
Understanding what controls the maintenance of stem cells and differentiation signals may give insights into the cellular signals involved in cancer, and may ultimately lead to new approaches to differentiation therapy. The signal that controls which daughter cell of an adult stem cell remains a stem cell and which begins the process of determination may be mediated through a number of signaling pathways including the Oct-4, Wnt/-catenin, Notch, Bone Morphogenic Protein (BMP), Janus family kinase, or sonic hedgehog signaling pathways, etc. (Table IV)12-15.


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Table IV: Cellular signals involved in cancer and their associated mechanism

Cancer has long been seen as a disease that arises from mutations that impair the capacity of any cell within the organism to respond to the signals that regulate proliferation. Besides their scarcity or abundance, a second important issue with respect to CSCs is their origin. The cells of most adult organs can be grouped in three classes: stem cells, Transit Amplifying Cells (TACs) and differentiated cells. Stem cells are capable of forming all the cell types that compose the mature organ. They divide throughout the life of the organism to replace dying cells and maintain tissue homeostasis. In many instances, the division of a stem cell gives rise to one new stem cell and one TAC. TACs undergo a limited number of cell divisions before giving rise to the differentiated cells that ensure organ function. One of the main problems in studying the role of stem cells in tumourigenesis has been the lack of stem-cell markers16.

Future perspective
The introduction of the CSC concept has provided exciting insights into the roots of carcinogenesis and sheds light on the future cure of cancer. The impact from current and future studies of CSC will revolutionize clinical practice with regards to both cancer diagnosis and therapy. Two of the implicated changes will be the re-classification of human tumors and development of novel therapeutic strategies targeting CSC17.

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    The discovery of CSCs in some tumor types has ushered in a new era of cancer research. CSC science is an emerging field that will ultimately impact researchers' understanding of cancer processes and may identify new therapeutic strategies. CSC's may present a challenge in the clinic. To achieve effective implementation of new therapies, physicians will require methods of determining the type (or types) of CSC's present in a given patient's tumor. It is important that agents directed against cancer stem cells discriminate between cancer stem cells and normal stem cells. However, much remains to be learned about these unique cells, which as of yet have not been identified in all tumor types. The characterization of CSCs will likely play a role in the development of novel targeted therapies designed to eradicate the most dangerous tumor cells, which may be resistant to current chemotherapy regimens, thereby providing researchers and clinicians with additional targets to alleviate the burden of cancer.
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