Epithelial plasticity, cancer stem cells, and the tumor-supportive stroma in bladder carcinoma

High recurrence rates and poor survival rates of metastatic bladder cancer emphasize the need for a drug that can prevent and/or treat bladder cancer progression and metastasis formation. Accumulating evidence suggests that cancer stem/progenitor cells are involved in tumor relapse and therapy resistance in urothelial carcinoma. These cells seem less affected by the antiproliferative therapies, as they are largely quiescent, have an increased DNA damage response, reside in difficult-to-reach, protective cancer stem cell niches and express ABC transporters that can efflux drugs from the cells. Recent studies have shown that epithelial-to-mesenchymal transition (EMT), a process in which sessile, epithelial cells switch to a motile, mesenchymal phenotype may render cancer cells with cancer stem cells properties and/or stimulate the expansion of this malignant cellular subpopulation. As cancer cells undergo EMT, invasiveness, drug resistance, angiogenesis, and metastatic ability seem to increase in parallel, thus giving rise to a more aggressive tumor type. Furthermore, the tumor microenvironment (tumor-associated stromal cells, extracellular matrix) plays a key role in tumorigenesis, tumor progression, and metastasis formation. Taken together, the secret for more effective cancer therapies might lie in developing and combining therapeutic strategies that also target cancer stem/progenitor cells and create an inhospitable microenvironment for highly malignant bladder cancer cells. This review will focus on the current concepts about the role of cancer stem cells, epithelial plasticity, and the supportive stroma in bladder carcinoma. The potential implications for the development of novel bladder cancer therapy will be discussed. Mol Cancer Res; 10(8); 995-1009. ?2012 AACR.     

Obesity and cancer stem cells: Roles in cancer initiation,progression and therapy resistance

Obesity, the global pandemic since industrialization, is the number one lifestyle-related risk factor for premature death, which increases the incidence and mortality of various diseases and conditions, including cancer. In recent years, the theory of cancer stem cells (CSCs), which have the capacity for self-renewal, metastasis and treatment resistance, has been bolstered by increasing evidence. However, research on how obesity affects CSCs to facilitate cancer initiation, progression and therapy resistance is still in its infancy, although evidence has already begun to accumulate. Regarding the ever-increasing burden of obesity and obesity-related cancer, it is pertinent to summarize evidence about the effects of obesity on CSCs, as elucidating these effects will contribute to the improvement in the management of obesity-related cancers. In this review, we discuss the association between obesity and CSCs, with a particular focus on how obesity promotes cancer initiation, progression and therapy resistance through CSCs and the mechanisms underlying these effects. In addition, the prospect of preventing cancer and targeting the mechanisms linking obesity and CSCs to reduce cancer risk or to improve the survival of patients with cancer is considered.     

Role of stem cells in cancer therapy and cancer stem cells: a review

For over 30 years, stem cells have been used in the replenishment of blood and immune systems damaged by the cancer cells or during treatment of cancer by chemotherapy or radiotherapy. Apart from their use in the immuno-reconstitution, the stem cells have been reported to contribute in the tissue regeneration and as delivery vehicles in the cancer treatments. The recent concept of 'cancer stem cells' has directed scientific communities towards a different wide new area of research field and possible potential future treatment modalities for the cancer. Aim of this review is primarily focus on the recent developments in the use of the stem cells in the cancer treatments, then to discuss the cancer stem cells, now considered as backbone in the development of the cancer; and their role in carcinogenesis and their implications in the development of possible new cancer treatment options in future.     

Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy

Mesenchymal stem cells (MSCs) are a pleiotropic population of cells that are self-renewing and capable of differentiating into canonical cells of the mesenchyme, including adipocytes, chondrocytes, and osteocytes. They employ multi-faceted approaches to maintain bone marrow niche homeostasis and promote wound healing during injury. Biomedical research has long sought to exploit their pleiotropic properties as a basis for cell therapy for a variety of diseases and to facilitate hematopoietic stem cell establishment and stromal reconstruction in bone marrow transplantation. Early results demonstrated their usage as safe, and there was little host response to these cells. The discovery of their immunosuppressive functions ushered in a new interest in MSCs as a promising therapeutic tool to suppress inflammation and down-regulate pathogenic immune responses in graft-versus-host and autoimmune diseases such as multiple sclerosis, autoimmune diabetes, and rheumatoid arthritis. MSCs produce a large number of soluble and membrane-bound factors, some of which inhibit immune responses. However, the full range of MSC-mediated immune-modulation remains incompletely understood, as emerging reports also reveal that MSCs can adopt an immunogenic phenotype, stimulate immune cells, and yield seemingly contradictory results in experimental animal models of inflammatory disease. The present review describes the large body of literature that has been accumulated on the fascinating biology of MSCs and their complex effects on immune responses.     

Epithelial stem cells

New molecular markers for epidermal stem cells have enabled their isolation both in vitro and from the epidermis lying between hair follicles. Micro-dissection experiments have localised a second population of stem cells within hair follicles. Epidermal stem cells have a patterned distribution in vivo. The patterning can be reconstituted in vitro, showing that it is generated by interactions between keratinocytes and that the differentiation of epidermal stem cells is regulated by signals from other keratinocytes. Recent evidence from transgenic mice suggests that stem cell behaviour in the gut may be regulated by similar cell-cell interactions in vivo. Candidate genes for mediating these interactions are the homologues of Drosophila cell fate patterning genes such as Notch and Wingless and the Cadherin family of cell-cell adhesion molecules. The roles of stem cells and of mutations of the Patched gene in epithelial carcinogenesis are discussed.     

Neural stem cells in inflammatory CNS diseases: mechanisms and therapy

Autoimmune inflammatory diseases of the central nervous system (CNS) are highly complex in their interaction of different cell populations. The main therapy focus in the last years has been the inhibition of the immune system. Recent progress has shown that endogenous as well as transplanted neural stem cells might positively influence the outcome of such diseases. In this review, we discuss the current concept of the underlying pathogenesis with a specific focus on local CNS cells and potential treatment options.     

Oxidative stress in cervical cancer pathogenesis and resistance to therapy

Cervical cancer (CC) is one of the most common cancers among females, and it is most notable in developing countries. The exact etiology of CC is poorly understood; but, smoking, oral contraceptives, immunosuppression, and infection with human papillomavirus (HPV) may increase the risk of CC. There is also an association between CC and oxidative stress. Oxidative stress is caused by a disturbed oxidant-antioxidant balance in favor of the former, leading to an excessive generation of free radicals, particularly reactive oxygen species (ROS), and subsequently to biological damages. Thus, redox enzymatic and nonenzymatic regulators are required to maintain the redox homeostasis. Dysregulated antioxidants system and the pathogenic role of oxidative stress in CC have been investigated in several clinical and preclinical studies. In this study, we reviewed studies that have addressed the cross-talk between oxidative stress and CC pathogenesis and resistance to therapy.     

Convergent mechanisms in pluripotent stem cells and cancer: Implications for stem cell engineering

Stem cells and cancer cells share certain characteristics, including the capacity to self-renew, differentiatie, and undergo epithelial-to-mesenchymal transition (EMT). The mechanisms underlying tumorigenesis retain similarities with processes in normal stem cell development. Comprehensive analysis and comparison of cancer cell and stem cell development will advance the study of cancer progression, enabling development of effective strategies for cancer treatment. In this review article, we first examine the convergence of outcome, cellular communication, and signaling pathways active in pluripotent stem cells and cancer cells. Next, we detail how stem cell engineering is able to mimic in vivo microenvironments. These efforts can help better identify stem cell-cancer cell interactions, elucidated dysregulated pluripotent signaling pathways occurring in cancer, revealed new factors that restrict tumorigenesis and metastasis potential, and reprogrammed cancer cells to a less aggressive phenotype. The potential of stem cell engineering to enhance cancer research is tremendous and may lead to alternative therapeutic options for aggressive cancers.     

Neural stem cells: plasticity and therapeutic potential

Previous studies have suggested that human umbilical cord blood (HUCB) may serve as a rich source of hematopoietic and nonhematopoietic stem cells and that conditions exist that can coax hematopoietic cells to express neural characteristics. In our laboratory, these cells were tested for several models of neurodegenerative diseases and spinal cord injuries. Through a series of transplantation studies we have begun to uncover the properties of HUCB‐derived cells in neuropoietic regions of the neonatal (1) and aging rodent brain. The systematic application of phenotyping approaches to characterize survival, migratory potential and morphologic properties of the differentiated HUCB progeny within normal/unaffected brain will serve as a base for understanding the potential effect of these cells in the diseased brain. Acknowledgements: Supported in part by R01 6155039 (TZ). HUCB cells were obtained from Saneron CCEL Therapeutics, Inc. and BioWhittaker, Inc.     

Colon cancer stem cells: implications for prevention and therapy

The recent identification of colon cancer tumor-initiating cells adds further support to the cancer stem cell hypothesis. Ongoing basic and translational research efforts are aimed at gaining an increased understanding of the biology of these cells, as well as methods of targeting them. In addition, the relationship between colon carcinogenesis and inflammatory conditions, such as longstanding colitis and inherited syndromes, might be linked to the effect of the processes on stem cells in the colon. This review summarizes current literature on colon cancer stem cells and proposes strategies aimed at targeting these cells for colon cancer prevention and therapy.     

Targeting pancreatic cancer stem cells for cancer therapy

Pancreatic cancer (PC) is the fourth most frequent cause of cancer death in the United States. Emerging evidence suggests that pancreatic cancer stem cells (CSCs) play a crucial role in the development and progression of PC. Recently, there is increasing evidence showing that chemopreventive agents commonly known as nutraceuticals could target and eliminate CSCs that have been proposed as the root of the tumor progression, which could be partly due to attenuating cell signaling pathways involved in CSCs. Therefore, targeting pancreatic CSCs by nutraceuticals for the prevention of tumor progression and treatment of PC may lead to the development of novel strategy for achieving better treatment outcome of PC patients. In this review article, we will summarize the most recent advances in the pancreatic CSC field, with particular emphasis on nutraceuticals that target CSCs, for fighting this deadly disease.     

CAR-T therapy: Prospects in targeting cancer stem cells

Cancer stem cells (CSCs), a group of tumour cells with stem cell characteristics, have the ability of self-renewal, multi-lineage differentiation and tumour formation. Since CSCs are resistant to conventional radiotherapy and chemotherapy, their existence may be one of the root causes of cancer treatment failure and tumour progression. The elimination of CSCs may be effective for eventual tumour eradication. Because of the good therapeutic effects without major histocompatibility complex (MHC) restriction and the unique characteristics of CSCs, chimeric antigen receptor T-cell (CAR-T) therapy is expected to be an important method to eliminate CSCs. In this review, we have discussed the feasibility of CSCs-targeted CAR-T therapy for cancer treatment, summarized current research and clinical trials of targeting CSCs with CAR-T cells and forecasted the challenges and future direction from the perspectives of toxicity, persistence and potency, trafficking, infiltration, immunosuppressive tumour microenvironment, and tumour heterogeneity.     

Immunobiology and signaling pathways of cancer stem cells: implication for cancer therapy

Cancer stem cells (CSCs) need to survive cancer treatments with a specific end goal to provide new, more differentiated, metastatic-prone cancerous cells. This happens through diverse signals delivered within the tumor microenvironment where ample evidence indicates that altered developmental signaling pathways play an essential role in maintaining CSCs and accordingly the survival and the progression of the tumor itself. This review summarizes findings on the immunobiological properties of CSCs as compared with cancerous non-stem cells involving the expression of immunological molecules, cytokines and tumor antigens as well as the roles of the Notch, Wnt and Hedgehog pathways in the brain, breast and colon CSCs. We concluded that if CSCs are the main driving force behind tumor support and growth then understanding the molecular mechanisms and the immunological properties directing these cells for immune tolerance is of great clinical significance. Such knowledge will contribute to designing better targeted therapies that could prevent tumor recurrence and accordingly significantly improve cancer treatments and patient survival.     

Epithelial stem cells: turning over new leaves

Most epithelial tissues self-renew throughout adult life due to the presence of multipotent stem cells and/or unipotent progenitor cells. Epithelial stem cells are specified during development and are controlled by epithelial-mesenchymal interactions. Despite morphological and functional differences among epithelia, common signaling pathways appear to control epithelial stem cell maintenance, activation, lineage determination, and differentiation. Additionally, deregulation of these pathways can lead to human disorders including cancer. Understanding epithelial stem cell biology has major clinical implications for the diagnosis, prevention, and treatment of human diseases, as well as for regenerative medicine.     

Epithelial cell plasticity defines heterogeneity in lung cancer

Lung cancer is the leading cause of cancer death for both men and women and accounts for almost 18.4% of all deaths due to cancer worldwide, with the global incidence increasing by approximately 0.5% per year. Lung cancer is regarded as a devastating type of cancer owing to its high prevalence, reduction in the health-related quality of life, frequently delayed diagnosis, low response rate, high toxicity, and resistance to available therapeutic options. The highly heterogeneous nature of this cancer with a proximal-to-distal distribution throughout the respiratory tract dramatically affects its diagnostic and therapeutic management. The diverse composition and plasticity of lung epithelial cells across the respiratory tract are regarded as significant factors underlying lung cancer heterogeneity. Therefore, definitions of the cells of origin for different types of lung cancer are urgently needed to understand lung cancer biology and to achieve early diagnosis and develop cell-targeted therapies. In the present review, we will discuss the current understanding of the cellular and molecular alterations in distinct lung epithelial cells that result in each type of lung cancer.     

MicroRNAs and breast cancer stem cells: Potential role in breast cancer therapy

MicroRNAs (miRNAs) can control cancer and cancer stem cells (CSCs), and this topic has drawn immense attention recently. Stem cells are a tiny population of a bulk of tumor cells that have enormous potential in expansion and metastasis of the tumor. miRNA have a crucial role in the management of the function of stem cells. This role is to either promote or suppress the tumor. In this review, we investigated the function and different characteristics of CSCs and function of the miRNAs that are related to them. We also demonstrated the role and efficacy of these miRNAs in breast cancer and breast cancer stem cells (BCSC). Eventually, we revealed the metastasis, tumor formation, and their role in the apoptosis process. Also, the therapeutic potential of miRNA as an effective method for the treatment of BCSC was described. Extensive research is required to investigate the employment or suppression of these miRNAs for therapeutics approached in different cancers in the future.     

Neural stem cells: mechanisms and modeling

In the adult brain, neural stem cells have been found in two major niches: the hippocampus and the olfactory bulb. Neurons derived from these stem cells contribute to learning, memory, and the autonomous repair of the brain under pathological conditions. Hence, the physiology of adult neural stem cells has become a significant component of research on synaptic plasticity and neuronal disorders. In addition, the recently developed induced pluripotent stem cell technique provides a powerful tool for researchers engaged in the pathological and pharmacological study of neuronal disorders. In this review, we briefly summarize the research progress in neural stem cells in the adult brain and in the neuropathological application of the induced pluripotent stem cell technique.