Role of mTORC1 and mTORC2 in Breast Cancer: Therapeutic Targeting of mTOR and Its Partners to Overcome Metastasis and Drug Resistance

Butt, G. | Shahwar, D. | Qureshi, M.Z. | Attar, Rukset | Akram, M. | Birinci, Y. | Farooqi, A.A.

Book Part | 2019 | Advances in Experimental Medicine and Biology1152 , pp.283 - 292

Based on the insights gleaned from decades of research, it seems clear that mechanistic target of rapamycin (mTOR) is an essential signaling node that integrates environmental clues for regulation of cell survival, metabolism and proliferation of the cells. However, overwhelmingly increasing scientific evidence has added a new layer of intricacy to already complicated and versatile signaling pathway of mTOR. Deregulation of spatio-temporally controlled mTOR-driven pathway played contributory role in breast cancer development and progression. Pharmacologists and molecular biologists have specifically emphasized on the identification . . .and development of mTOR-pathway inhibitors. In this chapter we have attempted to provide an overview of the most recent findings related to therapeutic targeting of mTOR-associated mTORC1 and mTORC2 in breast cancer. We have also comprehensively summarized regulation of mTOR and its partners by microRNAs in breast cancer. © 2019, Springer Nature Switzerland AG Daha fazlası Daha az

A Novel Virtue in Stem Cell Research: Exosomes and Their Role in Differentiation

Abdik, H. | Avsar Abdik, E. | Hızlı Deniz, A.A. | Taşlı, P.N. | Şahin, Fikrettin

Book Part | 2019 | Advances in Experimental Medicine and Biology1144 , pp.133 - 146

In the past decade a number of different stem cell types have entered the clinical applications increasingly as a therapeutic option, due to their tissue maintenance capacity at the site where they localize. Although it was initially thought that conferral of resilience to damaged tissue largely depends on the stem cells themselves through orchestration of signaling among the local epithelial and immune systems at the injury site, recent findings point out that the remarkable regenerative capacity of stem cells is rather due to their nanovesicular products that emerge as the new active players of tissue repair processes. Among these . . . extracellular vesicles exosomes generated particularly by stem cells have been receiving a substantial interest both in the fields of stem cell biology and extracellular vesicles. In this chapter fundamental facts about stem cell biology, biogenesis of extracellular vesicles and exosomes, their structure, and function are summarized. Moreover, properties of both tumor-derived exosomes as well as those derived from stem cells are discussed relatively in-depth in terms of their influence on proximal and distal tissue physiology. Last but not the least, among countless studies in an exploding field, we summarize those that attempt to unravel the complex signaling networks through which stem cell-derived exosomes alter the fate of differentiating stem cells as well as the molecular make-up of exosomes released from differentiating stem cells by conducting thorough proteomic and genomic analyses with the ultimate goal of identifying effector gene products mediating exosomal cues in stem cell biology. © 2019, Springer Nature Switzerland AG Daha fazlası Daha az

Dental stem cells in bone tissue engineering: Current overview and challenges

Ercal, P. | Pekozer, G.G. | Kose, G.T.

Book Part | 2018 | Advances in Experimental Medicine and Biology1107 , pp.113 - 127

The treatment of bone that is impaired due to disease, trauma or tumor resection creates a challenge for both clinicians and researchers. Critical size bone defects are conventionally treated with autografts which are associated with risks such as donor site morbidity and limitations like donor shortage. Bone tissue engineering has become a promising area for the management of critical size bone defects by the employment of biocompatible materials and the discovery of novel stem cell sources. Mesenchymal stem cells (MSCs) can be isolated with ease from various dental tissues including dental pulp stem cells, stem cells from apical p . . .apilla, dental follicle stem cells, stem cells from human exfoliated deciduous teeth, periodontal ligament stem cells, gingival stem cells and tooth germ derived stem cells. Outcomes of dental MSC mediated bone tissue engineering is explored in various in vivo and in vitro preclinical studies. However, there are still obscurities regarding the mechanisms underlying in MSC mediated bone regeneration and challenges in applications of dental stem cells. In this review, we summarized dental stem cell sources and their characterizations, along with currently used biomaterials for cell delivery and future perspectives for dental MSCs in the field of bone tissue engineering. Further efforts are necessary before moving to clinical trials for future applications. © Springer International Publishing AG 2018 Daha fazlası Daha az

Cancer stem cells in metastasis therapy

Aydemir Çoban, E. | Şahin, Fikrettin

Book Part | 2018 | Advances in Experimental Medicine and Biology1089 , pp.97 - 113

Tumors consists of subpopulation of cells in which each subtype has contributes to tumor progression. Specifically one subtype known as cancer stem cells are associated with the initiation, progression, resistance to conventional therapies and metastasis. Metastasis is leading cause of cancer related deaths. Overall it is important to consider cancer as a whole in which a mutated cell proliferating indefinitely and forming its hierarchy consisting of subgroups with different molecular signatures. To be able to target this disease we need to evaluate every step including initiation, progression, survival, angiogenesis and finally mig . . .ration and repopulation. Cancer stem cells do play vital roles in each step however when metastasis can be stopped or eliminated we talk about saving a life or improving its quality. Considering how deeply these cancer stem like cells affect the tumor life and metastasis it is crucial to develop effective strategies against them. Metastatic cascade can also be directed by membrane derived vesicles specifically exosomes. Several studies show the role of exosomes in mediating cellular migration and pre-metastatic niche formation. During this chapter we wanted to explain in detail how the metastasis occur in tumor and how cancer stem cells contribute into the development of metastatic cascade and possibly suggest therapeutic approaches against cancer stem cells. © Springer Nature Switzerland AG 2018 Daha fazlası Daha az

Immunomodulatory behavior of mesenchymal stem cells

Taşlı, P.N. | Bozkurt, B.T. | Kırbaş, O.K. | Deniz-Hızlı, A.A. | Şahin, Fikrettin

Book Part | 2018 | Advances in Experimental Medicine and Biology1119 , pp.73 - 84

The use of Mesenchymal Stem Cells (MSCs) in the treatment of diseases where immunomodulation impacts therapy is increasing steadily. Recent studies aim to achieve effective use of MSCs in treatment of Graft versus Host Disease (GvHD), Crohn’s disease and organ transplantations. The molecular mechanisms governing immunomodulatory properties of MSCs have not been fully understood, although current studies are indicating progress. Especially, in vitro studies and animal models provide a major contribution to our knowledge in clinical use of MSCs. The immunosuppressive and immune-enhancer properties of MSCs are –typically- determined wi . . .th respect to type and concentrations of soluble molecules found in their physiological environment. In mammals the immune system protects the organism -not only- from certain microorganisms, but also from any entity that it recognizes as foreign, including its own cells when it is received as a threat. This protection can sometimes occur by increasing the number of immune cells and sometimes by suppressing a pathologically hyper-induced immunological response. In particular, realization of the bi-directional effect of MSCs on immune cells has placed substantial emphasis on this area of research. This chapter focuses on the interaction of MSCs with the immune cells, the bilateral role of these interactions, and whether studies that aim to understand these interactions can yield promising results in terms of developing improved use of MSCs in treatment. © Springer International Publishing AG, part of Springer Nature 2018 Daha fazlası Daha az

NEDD4 Family of E3 Ubiquitin Ligases in Breast Cancer: Spotlight on SMURFs, WWPs and NEDD4

Butt, G. | Yaylim, I. | Attar, Rukset | Aras, A. | Romero, M.A. | Qureshi, M.Z. | Farooqi, A.A.

Book Part | 2019 | Advances in Experimental Medicine and Biology1152 , pp.365 - 375

Massively parallel sequencing, genomic and proteomic technologies have provided near complete resolution of signaling landscape of breast cancer (BCa). NEDD4 family of E3-ubiquitin ligases comprises a large family of proteins particularly, SMURFs (SMURF1, SMURF2), WWPs and NEDD4 which are ideal candidates for targeted therapy. However, it is becoming progressively more understandable that SMURFs and NEDD4 have “split-personalities”. These molecules behave dualistically in breast cancer and future studies must converge on detailed identification of context specific role of these proteins in BCa. Finally, we provide scattered clues of . . . regulation of SMURF2 by oncogenic miRNAs, specifically considering longstanding questions related to regulation of SMURF1 and WWPs by miRNAs in BCa. SMURFS, WWPs and NEDD4 are versatile regulators and represent a fast-growing field in cancer research and better understanding of the underlying mechanisms will be helpful in transition of our knowledge from a segmented view to a more conceptual continuum. © 2019, Springer Nature Switzerland AG Daha fazlası Daha az

Mesenchymal Stem Cells as Regulators of Carcinogenesis

Hayal, T.B. | Kıratlı, B. | Şişli, H.B. | Şahin, Fikrettin | Doğan, A.

Book Part | 2019 | Advances in Experimental Medicine and Biology1144 , pp.147 - 166

Mesenchymal Stem Cells (MSCs) are adult stem cells; isolated from various body parts including bone marrow, adipose tissue and dental tissue, have been characterized well and used in regenerative medicine applications. The promising potential of MSCs makes them great candidates in many disorders. It has been well known in the literature that MSCs interact with cancer cells and regulate the carcinogenesis process at different stages. The dual role of MSCs in cancer progression should be clearly identified at the physiological and molecular level to identify clinical potential in cancer treatment. The promoting or suppressive role of . . .MSCs in cancer is controlled by various growth factors, cytokines and chemokines which affect the cell proliferation, angiogenesis and metastasis. Although many studies have been conducted to explore MSC-cancer cell interactions, it is still unclear how MSCs communicate with cancer cells and tumor microenvironment. Further studies are required to investigate secreted factors and paracrine effects, tumor stroma environment, molecular regulators and downstream pathways that are involved in MSC-cancer interaction loop. MSC type, cancer type and stage specific phenotypic and transcriptomic profile changes should be identified in detail to improve clinical use of MSCs in cancer either as a target or as a tool. In the current book chapter, we review the literature to summarize current information about the MSC-cancer cell interactions in terms of soluble factors, angiogenesis, metastasis and drug resistance. The role of MSCs in tumor progression or suppression was discussed based on the current literature. © 2018, Springer Nature Switzerland AG Daha fazlası Daha az

Stem Cells Derived from Dental Tissues

Aydin, S. | Şahin, Fikrettin

Book Part | 2019 | Advances in Experimental Medicine and Biology1144 , pp.123 - 132

Stem cells are undifferentiated cells located in different parts of the body. The major role of stem cells is to restore of injured tissues. Since the discover of stem cells, they gained a big attention due to their differentiation and regeneration capacity. The main source of stem cells was known as bone marrow. However, different sources for obtaining stem cells were discovered. Dental tissues, a new source for stem cells, provide cells having mesenchymal stem cell characteristics such as fibroblast-like structure, expression of surface antigens specific for mesenchymal stem cells, regeneration ability, multilineage differentiatio . . .n capacity and immunomodulatory features. Dental pulp stem cells (DPSCs), dental follicle progenitor cells (DFPCs), stem cells from apical papilla (SCAP), tooth germ stem cells (TGSCs) and periodontal ligament stem cells (PDLSCs) are stem cells derived from dental tissues as well as stem cells from exfoliated deciduous teeth (SHED). Dental stem cells express mesenchymal stem cell markers like Stro-1, CD146, CD106, CD90, CD73 CD29 and CD13. However, they do not express hematopoietic stem cell markers such as CD11b, CD45 and CD34. Dental stem cells are able to undergo myogenic, chondrogenic, adipogenic, neurogenic, osteogenic and odontogenic differentiation. Thanks to these differentiation ability of dental stem cells, they can easily be manipulated in regenerative medicine. Dental stem cells, that can effortlessly be transfected, can also be used in cell therapy application. Immunomodulatory features of dental stem cells make them suitable candidates for the therapy of immune-related disorders. Dental stem cells with high potentials such as ability of self-renewal, mesenchymal stem cell characteristics, multilineage differentiation and immunomodulation are promising tool for in vitro and in vivo differentiation studies as well as the therapy of immune-related diseases. © 2019, Springer Nature Switzerland AG Daha fazlası Daha az

Developments in hematopoietic stem cell expansion and gene editing technologies

Yucel, D. | Kocabas, F.

Book Part | 2018 | Advances in Experimental Medicine and Biology1079 , pp.103 - 125

Hematopoietic stem cells (HSCs) are rare cells, which housed in the adult bone marrow. They maintain all types of differentiated blood cells throughout life. Due to limited availability of HSCs for transplantation, treatment of various inherited bone marrow disorders and anemia requires the development of HSC expansion and gene editing technologies. To this end, various studies addressed the use of cytokines and growth factors for HSC expansion. Major hurdle with these studies was found to be spontaneous differentiation of HSCs into different lineages during ex vivo procedure. In addition, cost efficient approaches were needed. Thus . . ., studies move on to the identification of small molecules and development of RNA interference technologies with potential to enhance cell cycle progression and block inhibitory signaling mechanisms during ex vivo HSC expansion as well as single cell expansion of HSCs following gene editing studies. This review aims to highlight developments in hematopoietic stem cells expansion and gene editing technologies. © Springer International Publishing AG 2017 Daha fazlası Daha az

Gene therapy strategies in bone tissue engineering and current clinical applications

Atasoy-Zeybek, A. | Kose, G.T.

Book Part | 2018 | Advances in Experimental Medicine and Biology1119 , pp.85 - 101

Gene therapy provides a promising approach for regeneration and repair of injured bone. Application of gene therapy has displayed increased efficiency in various animal models and preclinical trials in comparison with traditional bone grafting methods. The objective of this review is to highlight fundamental principles of gene therapy strategies in bone tissue engineering and solutions of their current limitations for the healing of bone injury. Vector types are debated for the repair of defected site due to demonstration of constraints and applications of the protocols. In recent years, the combination of gene therapy strategies an . . .d bone tissue engineering has highly gained attention. We discussed viral and non-viral mediated delivery of therapeutic protein by using scaffolds for bone tissue engineering. Although pre-clinical studies have showed that gene therapy has very promising results to heal injured bone, there are several limitations regarding with the usage of gene delivery methods into clinical applications. Choice of suitable vector, selection of transgene and gene delivery protocols are the most outstanding questions. This article also addresses current state of gene delivery strategies in bone tissue engineering for their potential applications in clinical considerations. © Springer International Publishing AG, part of Springer Nature 2018 Daha fazlası Daha az

Stem cells in regenerative cardiology

Arbatlı, S. | Aslan, G.S. | Kocabaş, F.

Book Part | 2018 | Advances in Experimental Medicine and Biology1079 , pp.37 - 53

The common prevalence of heart failure and limitations in its treatment are leading cause of attention and interest towards the induction of cardiac regeneration with novel approaches. Recent studies provide growing evidence regarding bona fide cardiac regeneration post genetic manipulations, administration of stimulatory factors and myocardial injuries in animal models and human studies. To this end, stem cells of different sources have been tested to treat heart failure for the development of cellular therapies. Endogenous and exogenous stem cells sources used in regenerative cardiology have provided a proof of concept and applica . . .bility of cellular therapies in myocardial improvement. Recent clinical studies, especially, based on the endogenous cardiac progenitor and stem cells highlighted the possibility to regenerate lost cardiomyocytes in the myocardium. This review discusses emerging concepts in cardiac stem cell therapy, their sources and route of administration, and plausibility of de novo cardiomyocyte formation. © Springer International Publishing AG 2017 Daha fazlası Daha az

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