Cancer stem-like cell behavior in anaplastic thyroid cancer: A challenging dilemma
Introduction
Cancer is one of the most life-threatening diseases with no conclusive therapy so far. Although there is no agreement on the factors responsible for some cancers' features such as metastasis, relapse and drug resistance, it seems that tumor heterogeneity plays the major role. Indeed, tumor is a complex environment containing tumor cells and various infiltrating cells such as endothelial, hematopoietic and stromal cells. These exterior cells affect tumor environment (TME) by changing metabolic status of tumor cells (like creating hypoxic condition) [23].
Generally, two models have been used for explaining tumor heterogeneity, stochastic and hierarchical models. In one hand, stochastic model relies on presumption that cancer is the result of mutations in cell cycle's genes that lead to cell hyperproliferation. In this model, cells that over express oncogenes or down regulate tumor-suppressor genes are capable of producing cancer. On the other hand, hierarchical theory emphasizes that tumor cells are originated from a small population of cells (CSCs) that have similar characteristics to adult stem cells (Fig. 1). According to this model, carcinogenesis occurs when an adult stem cell bypasses regulation or even when a terminally differentiated cell (with cancerous properties) is dedifferentiated (Fig. 1A, B) [35]. However, these two models are not mutually exclusive and can be harmonized by considering cellular plasticity, genetic diversity and non-genetic influences [27] [32], [35].
CSCs are tumor cells that have self-renewal, clonal tumor initiation and clonal long-term repopulation capacity (Fig. 1B) [35], [37]. Also, CSCs are able to transit between stem cell and non-stem cell states, an ability that refers as plasticity. CSCs are able to be quiescent for a long time and metastasize to different organs. These cells are resistant to usual treatments [34]. CSCs anatomically and functionally do not resemble the original organs' adult stem cells. Actually, it has been shown that CSCs lose multipotency (generation of an entire tissue) and asymmetric cell division in comparison with adult stem cells [27]. Hence, many of researchers prefer to use “tumor-initiating cells (T-ICs)” term instead of CSCs. However, phenotypes and gene-expression patterns of the cell of origin may differ considerably from that “CSCs” [35].
Most of signaling pathways that are important for maintaining stemness in stem cells, are similarly vital for CSCs such as Oct4/Sox2, Notch, and Wnt. It has been shown that disrupting CSCs' signaling pathways, leading to differentiation of them, can inhibit cancer drug resistance and relapse (known as differentiation therapy) [5], [20], [36].
First, CSCs were isolated from leukemia followed by their isolation from many solid tumors [1], [28]. Generally, techniques that are used for CSCs' isolation are based on the enrichment of CSCs via Hoechst dye or surface markers [18]. CD44 and CD133 are two common cell surface markers that have been used for the isolation of CSCs from many tumors [45], [51]. In addition, some studies have been successful in isolating CSCs from cancer cell lines [10], [18], [49]. Isolating CSCs from cell cultures can facilitate studies since they are more accessible than clinical samples.
Based on differentiation state, there are two types of thyroid cancers; differentiated thyroid cancer (papillary thyroid carcinoma and follicular thyroid carcinoma) and undifferentiated thyroid cancer (ATC). Differentiated thyroid cancers show good survival rate and are the most frequent type of thyroid cancers [7]. In contrast, ATC is an undifferentiated, aggressive and most deadly of all thyroid cancers. This type of cancer has a very low rate of cure and most patients die one year after diagnosis [24]. It is believed that chemo- and radio-resistant nature of ATC is due to the presence of stem cell-like tumor cells within the ATC. Therefore, many attempts have been done to isolate and characterize CSCs in this type of tumor [7], [26], [31]. Here, we observed that two ATC cell lines, SW1736 and C643, have SP that resembles CSCs. CD133pos cells, derived from these two cell lines, have gene expression pattern similar to CSCs and express stemness factors (Fig. 1C).
To evaluate the concept of cancer stem-like cell theory of ATC, we conducted this study to emphasize both on the concept of cancer stemness origin of these cells and target them for further therapeutic purposes.
Section snippets
Cell lines and cell culture
SW1736 and C643 are ATC cell lines (CLS Cell Lines Service GmbH, Germany) which were analyzed by STR (Supplementary Figs. 1 & 2) to confirm their cellular integrity and were subsequently cultured in RPMI high glucose (Gibco) plus Pen/Sterp 50 μg/ml (Gibco) and 10% heat-inactivated fetal bovine serum (Gibco) at 37 °C in a CO2 incubator.
The Institutional Review Board of Endocrinology and Metabolism Research Institute approved this study (IRB No. 00207-2012-07-17).
Sorting cells by MACS and evaluation of CD133pos/neg cells by flow cytometry
SW1736 and C643 cells were
CD133pos cells
SW1736 and C643 cells were sorted based on CD133 marker. CD133 (prominin-1) is a pentaspan membrane protein that was originally classified as a stem cell marker for primitive hematopoietic and neural stem cells [52]. However, it has been shown that CD133 is expressed on embryonic stem cells, adult stem cells, circulating endothelial cells and CSCs. Indeed, CD133 is commonly used for identifying and sorting of CSCs in many tumors [21], [38], [50], [52]. Our results showed that both ATC cell
Discussion
Over the last several decades, there has been a revolution in our understanding of cancer development. Sparked by the first discovery of cells with properties like stem cells in acute myeloid leukemia in 1994 [28] and then in 2003 in breast cancer [1], it has been shown that almost all cancers have CSCs [17], [19]. The incidence of random mutations in differentiated cells or adult stem cells is a prerequisite to change these cells to CSCs [14], [16]. Recently, Tomasetti and Vogelstein
Conclusion
Perhaps the most applicable feature of the CSCs concept from the clinical perspective is the ability for these stem cell-like tumor cells to keep an additional survival advantage in response to various chemotherapeutic agents. ATC is characterized by its conclusive resistance to several chemotherapies. As such, targeted therapy against SP of cells with stem cell properties within thyroid cancer, responsible for lethal clinical phenotype, would be of major clinical interest. Indeed, our data
Funding
This project has been funded by National Elite Foundation of Allameh Tabatabai grant (BN012) and Endocrinology & Metabolism Research Institute, Tehran University of Medical Sciences.
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
The authors would like to thank Stem Cell Technology Research Center and Research Institute for Hematology, Oncology and Stem Cell Transplantation at Shariati Hospital which supported some parts of the experiments. We also thank Dr. Ehsan Arefian, Dr. Naser Ahmadbeigi, Mr. Ehsan Janzamin, Mr. Majid Mosahebi, Ms. Hilda Samimi and Ms. Mahshid Akhavan for their technical assistance and advice.
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