Cancer stem cells and evolving novel therapies: a paradigm shift (original) (raw)

Cancer Stem Cells: Formidable Allies of Cancer

Indian Journal of Surgical Oncology, 2015

Cancer stem cells (CSC) represent the subpopulation of cells within a tumour showing two fundamental properties of stem cellsself-renewal (the ability to make more of their own kind) and differentiation (the ability to generate diverse cell types present within a tissue). The CSC hypothesis posits that CSCs play an important role in tumour initiation, maintenance and progression. Furthermore, owing to their intrinsic drug resistance, they remain refractory to currently used therapy, thereby contributing to tumour relapse. Thus, targeting or taming CSCs can lead to more effective cancer treatment in the coming decades. In this review, we will discuss about the origin of CSC hypothesis, evidence showing their existence, clinical relevance and translational significance.

Cancer stem cells (CSCs) in cancer progression and therapy

Journal of Cellular Physiology, 2018

Cancer stem cells (CSCs) are self-renewable cell types that are identified in most types of liquid and solid cancers and contributed to tumor onset, expansion, resistance, recurrence, and metastasis after therapy. CSCs are identified from the expression of cell surface markers, which is tumor-type dependent. The transition between CSCs with cancer cells and other non-CSCs occurs in cancers, which is possibly under the control of signals from CSCs and tumor microenvironment (TME), including CSC niche. Cancer-associated fibroblasts are among the most influential cells for promoting both differentiation of CSCs and dedifferentiation of non-CSCs toward attaining a CSC-like phenotype. WNT/β-catenin, transforming growth factor-β, Hedgehog, and Notch are important signals for maintaining self-renewal in CSCs. An effective therapeutic strategy relies on targeting both CSCs and non-CSCs to remove a possible chance of tumor relapse. There are multiple ways to target CSCs, including immunotherapy, hormone therapy, (mi)siRNA delivery, and gene knockout. Such approaches can be designed for suppressing CSC stemness, tumorigenic cues from TME, CSC extrinsic and/or intrinsic signaling, hypoxia or for promoting differentiation in the cells. Because of sharing a range of characteristics to normal stem/progenitor cells, CSCs must be targeted based on their unique markers and their preferential expression of antigens.

Cancer stem cells: the development of new cancer therapeutics

Expert Opinion on Biological Therapy, 2011

Introduction: Cancer stem cells (CSCs) are a subpopulation of tumor cells with indefinite proliferative potential that drive the growth of tumors. CSCs seem to provide a suitable explanation for several intriguing aspects of cancer pathophysiology. Areas covered: An explosion of therapeutic options for cancer treatment that selectively target CSCs has been recorded in the recent years. These include the targeting of cell-surface proteins, various activated signalling pathways, different molecules of the stem cell niche and various drug resistance mechanisms. Importantly, approaching cancer research by investigating the pathogenesis of these intriguing cancer cells is increasing the knowledge of the pathophysiology of the disease, emphasizing certain molecular mechanisms that have been partially neglected. Expert opinion: The characterization of the molecular phenotype of these cancer stem-like cells, associated with an accurate definition of their typical derangement in cell differentiation, can represent a fundamental advance in terms of diagnosis and therapy of cancer. Preliminary results seem to be promising but further studies are required to define the therapeutic index of this new anticancer treatment. Moreover, understanding the pathogenetic mechanisms of CSCs can expand the therapeutic applications of normal adult stem cells by reducing the risk of uncontrolled tumorigenic stem cell differentiation.

Cancer stem cells: emerging actors in both basic and clinical cancer research

TURKISH JOURNAL OF BIOLOGY, 2014

Introduction Over the past 50 years, many disease that cause death have dramatically decreased. Nevertheless, cancer deaths continue (Leaf, 2013). The International Agency for Research on Cancer, the specialized cancer agency of the World Health Organization, released the latest data on cancer incidence, mortality, and prevalence worldwide (Ferlay et al., 2013). According to GLOBOCAN 2012, an estimated 14.1 million new cancer cases and 8.2 million cancer-related deaths occurred in 2012, compared with 12.7 million and 7.6 million in 2008, respectively. The most commonly diagnosed cancers worldwide were those of the lung (13% of the total), breast (11.9%), and colorectum (9.7%). The most common causes of cancer death were cancers of the lung (19.4% of the total), liver (9.1%), and stomach (8.8%). GLOBOCAN 2012 predicted a substantive increase to 19.3 million new cancer cases per year by 2025 due to growth and aging of the global population (Ferlay et al., 2013). Despite these statistics, the ability to specifically target pathways altered in cancer raises the hope of developing therapies with high specificity and low toxicity. Therefore, it is important to target the 'right cells' (Wicha et al., 2006). A large body of evidence is accumulating to indicate that most, if not all, malignancies can be viewed as abnormal organs with a stem cell compartment that drives the growth. Furthermore, besides tumor initiation, these tumor-initiating cells, also referred to as cancer stem cells (CSCs), are thought to be responsible for metastasis, recurrence, and drug resistance (Chen K et al., 2013). The CSC hypothesis has fundamental implications for understanding the biology of carcinogenesis as well as for developing new strategies for cancer prevention and eradication of malignancies. 2. Characteristics of CSCs CSCs are cancer cells that possess characteristics associated with normal stem cells. At the molecular level, CSCs and normal stem cells share some common features, including the capacity for self-renewal (Reya et al., 2001), the ability to differentiate, active telomerase expression, activation of antiapoptotic pathways, increased membrane transporter activity, and the ability to migrate and metastasize (Wicha et al., 2006). In addition to these properties, they display an anchorage-independent survival, active DNA-repair capacity, and relative quiescence (slow cell cycling) (Dean et al., 2005; Wicha et al., 2006). 2.1. Concept of CSCs Where CSCs come from is an intensely researched question. Some researchers suggest that CSCs may originate from mutated normal stem cells upon aberrant alteration of the self-renewal pathways (Reya et al., 2001). An alternative hypothesis is that CSCs originate from differentiated cells that have acquired stem-like features following Abstract: Cancer stem cells (CSCs) are a small subset of cancer cells within a tumor that are responsible for tumorigenesis and contribute to drug resistance. The CSC displays an anchorage-independent survival, active DNA-repair capacity, and relative quiescence and is capable of self-renewing and maintaining tumor growth and heterogeneity. At the molecular level, there are several signaling pathways (e.g., Wnt/β-catenin, Notch, and Hedgehog) to control CSC properties and alteration of these pathways has been recognized as an essential step for CSC transformation. Emerging evidence suggests that CSCs are clinically relevant. These cells are resistant to conventional chemotherapy and radiation treatment. Therefore, CSCs are thought to be the most important targets for anticancer therapy. In this review, we describe the characteristics of CSCs and how to isolate them based on some of their properties, as well as their importance in oncology.

Cancer stem cells (CSCs) in cancer progression and therapy.pdf

Cancer stem cells (CSCs) are self‐renewable cell types that are identified in most types of liquid and solid cancers and contributed to tumor onset, expansion, resistance, recurrence, and metastasis after therapy. CSCs are identified from the expression of cell surface markers, which is tumor‐type dependent. The transition between CSCs with cancer cells and other non‐CSCs occurs in cancers, which is possibly under the control of signals from CSCs and tumor microenvironment (TME), including CSC niche. Cancer‐associated fibroblasts are among the most influential cells for promoting both differentiation of CSCs and dedifferentiation of non‐CSCs toward attaining a CSC‐like phenotype. WNT/β‐catenin, transforming growth factor‐β, Hedgehog, and Notch are important signals for maintaining self‐renewal in CSCs. An effective therapeutic strategy relies on targeting both CSCs and non‐CSCs to remove a possible chance of tumor relapse. There are multiple ways to target CSCs, including immunotherapy, hormone therapy, (mi)siRNA delivery, and gene knockout. Such approaches can be designed for suppressing CSC stemness, tumorigenic cues from TME, CSC extrinsic and/or intrinsic signaling, hypoxia or for promoting differentiation in the cells. Because of sharing a range of characteristics to normal stem/progenitor cells, CSCs must be targeted based on their unique markers and their preferential expression of antigens.

Cancer Stem Cells: Current Status and Evolving Complexities

Cell Stem Cell, 2012

The cancer stem cell (CSC) model has been established as a cellular mechanism that contributes to phenotypic and functional heterogeneity in diverse cancer types. Recent observations, however, have highlighted many complexities and challenges: the CSC phenotype can vary substantially between patients, tumors may harbor multiple phenotypically or genetically distinct CSCs, metastatic CSCs can evolve from primary CSCs, and tumor cells may undergo reversible phenotypic changes. Although the CSC concept will have clinical relevance in specific cases, accumulating evidence suggests that it will be imperative to target all CSC subsets within the tumor to prevent relapse.

The implications of cancer stem cells for cancer therapy

International journal of molecular sciences, 2012

Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Recent studies have showed that cancer stem cells (CSCs), a small subpopulation of tumor cells, can generate bulk populations of nontumorigenic cancer cell progeny through the self-renewal and differentiation processes. As CSCs are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors, development of CSC-targeted therapeutic strategies holds new hope for improving survival and quality of life in patients with cancer. Therapeutic innovations will emerge from a better understanding of the biology and environment of CSCs, which, however, are largely unexplored. This review summarizes the characteristics, evidences and development of CSCs, as well as implica...

Cancer stem cells - from initiation to elimination, how far have we reached? (Review)

International journal of oncology, 2009

Cancer stem cells (CSCs) are rare tumor cells that have the potential to proliferate, self-renew and induce tumorigenesis. Over the past few years, CSCs have been isolated from several different tumors and when implanted into immune-deficient mice, generate tumors that are identical to the parental tumors. In this review, we summarize the current literature on CSCs, which suggests that since these cells have the ability to drive tumor formation, specifically targeting them may lead to more effective therapies against tumors.

The clinical and therapeutic implications of cancer stem cell biology

Expert Review of Anticancer Therapy, 2011

Cancer stem cells (CSCs) have provided new insights into the tumorigenesis and metastatic potential of cancer. The discovery of CSCs has provided many new insights into the complexities of cancer therapy: tumor initiation, treatment resistance, metastasis, recurrence, assessment of prognosis and prediction of clinical course. Recent rapid advances in molecular ana lysis have contributed to the better understanding of the molecular attributes and pathways that give CSCs their unique attributes. Use of these molecular techniques has facilitated elucidation of specific surface markers and pathways that favor propagation of CSCs -allowing for targeted therapy. Furthermore, it has been discovered that a specific microenvironment, or niche, is essential for the genesis of tumors from CSCs. Therapeutic strategies that alter these microenvironments compromise CSC proliferation and constitute another method of targeted cancer therapy. We review the clinical and therapeutic implications of CSCs, with a focus on treatment resistance and metastasis, and the emerging approaches to target CSCs and their microenvironments in order to attain improved outcomes in cancer. It is noteworthy that CSCs are the only cells capable of sustaining tumorigenesis; however, the cell of origin of cancer, in which tumorigenesis is initiated, may be distinct from CSCs that propagate the tumor.