Stem Cell and Cancer Stem Cell Games in the ECM Field (original) (raw)
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Stem cell and cancer stem cell games on the ECM field
Journal of Cancer Stem Cell Research, 2013
Stem cell (SC) and cancer stem cell (CSC) regulation is congregated around the dynamic role played by their niche that defines a domain-specific identity and functions. The major macromolecular components of any physiological niche are collectively referred to as Extra Cellular Matrix (ECM). Consequently, niche-determined governance of SC-CSC fate(s) is significantly wired by the ECM and its chemical undercurrents, which involve specific signaling cascades driving asymmetrical division and self-renewal, besides maintaining tissue and organ homeostasis. Cell transformation is often associated with variations in ECM composition and dynamics; although the distinction of whether these are a cause or an effect of the process is not clearly established. CSCs regulate altered ECM subtleties; these in turn support disease progression by providing the necessary cues to maintain CSC quiescence and regeneration yet drive cancer metastases. Further, the specific composition of altered ECM plays a critical role in metastatic dissemination and homing to specific secondary sites for tumor regeneration. The present review presents our understanding of modulation of SC and CSC interactions in their respective niche by ECM components, and a complementary focus of intonation of ECM biochemistry by these cells in developing an aberrant phenotype. ABBREVIATIONS Stem cells (SCs); extra cellular matrix (ECM); cancer stem cells (CSCs); epithelial-to-mesenchymal transitions (EMT); basement membrane (BM); interstitial matrix (IM); fibroblast growth factor (FGF); epidermal growth factor (EGF); transforming growth factor-beta (TGFb); platelet-derived growth factor (PDGF), insulin-like growth factor (IGF); tumor necrosis factor a (TNFa); epidermal growth factor receptor (EGFR); matrix metallo-proteinases (MMPs); basic fibroblast growth factor (bFGF); human embryonic stem cells (hESCs); lineage negative (Lin À); reactive oxygen species (ROS); cancer associated fibroblasts (CAFs); osteopontin (OPN), periostin (POSTN), secreted protein acidic and rich in cysteine (SPARC); thrombospondin-1 (TSP-1); hyaluronic acid (HA); sonic hedgehog (SHH); phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), mitogen activated kinase-like protein (MAPK); verb -b2 avian erthroblastic leukemia viral oncogene homolog 2 (ERBB2); hyaluronan-mediated motility receptor (HMMR). CONTENTS 1. Introduction 1.1 Transformation and emergence of CSCs 1.2 Extracellular matrix 1.3 Composition 2. Cross-talk between ECM and stem cells (SC) 2.1 Physical influences of ECM on SC 2.2 Chemical and molecular ECM dynamics governing SC fate 2.2.1 Soluble factors 2.2.2 Small molecules of ECM components 3. Interactions of ECM and CSC: A different ball game? 3.1 Synthesis and regulation 3.2 Role of ECM in cancer niche development and metastases 3.2.1 Cancer niche development 3.2.2 Role of ECM in metastases 3.3 Regulation of quiescence by ECM 3.4 Functionality of CD44, an important CSC marker 4. Concluding remarks and future perspectives References
The hitchhikers guide to cancer stem cell theory: Markers, pathways and therapy
Cytometry Part A, 2013
Cancer stem cell (CSC) biology is a rapidly developing field within cancer research. CSCs are postulated to be a unique cell population exclusively capable of infinite self renewal, multilineage differentiation and with ability to evade conventional cytotoxic cancer therapy. These traits distinguish CSCs from their more differentiated counterparts, which possess only limited or no potential for self renewal and tumor initiation. Therefore, CSCs would be the driving motor of malignant growth and therapy resistance. Accordingly, successful cancer treatment would need to eliminate this highly potent group of cells, since even small residual numbers would suffice to recapitulate the disease after therapy. Putative CSCs has been identified in a broad range of human malignancies and several cell surface markers have been associated with their stem cell phenotype. Despite all efforts, a pure CSC population has not been isolated and often in vitro clonogenic and in vivo tumorigenic potential is found in several cell populations with occasionally contradictory surface marker signatures. Here, we give a brief overview of recent advances in CSC theory, including the signaling pathways in CSCs that also appear crucial for stem cells homeostasis in normal tissues. We discuss evidence for the interaction of CSCs with the stromal tumor environment. Finally, we review the emerging potentially effective CSC-targeted treatment strategies and their future role in therapy. ' 2012 International Society for Advancement of Cytometry Key terms cancer stem cells; cancer stem cell markers; cancer stem cell niche; therapy resistance CANCER stem cell (CSC) theory hypothesizes that heterogeneity within tumors is not a mere consequence of random mutation and clonal evolution, but results from an intrinsic hierarchy of cells, with the putative CSC at the apex of the hierarchy (1,2). The CSC is thought to share several key features with normal stem cells: unlimited capacity for self renewal, including maintenance of the CSC population through asymmetric division, the ability to differentiate into several cell lineages and intrinsic resistance against cytotoxic therapies through drug-efflux mechanisms and slow cell cycling (2). CSC theory postulates that not all tumor cells are equal with regard to self-renewal, tumor initiation, and maintenance potential, these traits being reserved for the CSC population. Additionally, cellular heterogeneity and hierarchy within the tumor originates from CSCs, which give rise to daughter cells that proliferate and differentiate into the cell mass that compromises a significant portion of the bulk tumor (1). Further, CSCs are thought to be responsible for therapy resistance, minimal residual disease and relapse after initial successful therapy, their stem-like features making them able to evade conventional treatment modalities (3). It has also been implied that these stem cell traits allow CSCs to play a leading role in metastasis (4-6).
Stemness in Cancer: Stem Cells, Cancer Stem Cells, and Their Microenvironment
Stem Cells International, 2017
Stemness combines the ability of a cell to perpetuate its lineage, to give rise to differentiated cells, and to interact with its environment to maintain a balance between quiescence, proliferation, and regeneration. While adult Stem Cells display these properties when participating in tissue homeostasis, Cancer Stem Cells (CSCs) behave as their malignant equivalents. CSCs display stemness in various circumstances, including the sustaining of cancer progression, and the interaction with their environment in search for key survival factors. As a result, CSCs can recurrently persist after therapy. In order to understand how the concept of stemness applies to cancer, this review will explore properties shared between normal and malignant Stem Cells. First, we provide an overview of properties of normal adult Stem Cells. We thereafter elaborate on how these features operate in CSCs. We then review the organization of microenvironment components, which enables CSCs hosting. We subsequent...
Cancer stem cells maintain a hierarchy of differentiation by creating their niche
International Journal of Cancer, 2014
The self-renewal and differentiation properties of cancer stem cells (CSCs) are regulated and maintained by the CSC niche. However, the mechanism of this maintenance, especially the maintenance contributed by differentiated cancer cells, remains to be fully elucidated. Recently, we have established a model of CSCs, miPS-LLCcm, from mouse induced pluripotent stem cells (miPSCs). In vitro cultured miPS-LLCcm cells were autonomously balanced with stem-like cells and differentiated cells including vascular endothelial cells. Under these conditions, the CSC properties appeared to be stable in the presence of the factor(s) secreted by the differentiated cells. The factor(s) activated Notch signaling and promoted self-renewal of CSCs. In addition, the secreted factor(s) appeared to regulate the differentiation lineage of CSCs. Our results indicate that the differentiated progenies of CSCs containing vascular endothelium play important roles for regulating the CSC's properties. Therefore, miPS-LLCcm cells create their own in vitro niche to maintain themselves in the hierarchy of differentiating CSCs. Cancer stem cells (CSCs) are unique subpopulation of tumor cells that possess self-renewal and differentiation capacity, that can give rise to the entire heterogeneous population of the tumor tissue. 1-3 With regard to differentiation capacity, three independent groups have demonstrated that vascular endothelial cells are one of the types of cells that differentiate from CSCs. 4-6 For example, CD133-positive (CD133 1) glioblastoma (GBM) stem-like cells were found to differentiate into vascular endothelial cells that could contribute to tumor angiogenesis in vivo. Interestingly, the capacity to differentiate into CD133 1 /vascular endothelial cadherin (VE-cadherin, also known as CD144 1) endothelial progenitors from CD133 1 /VE-cadherin-negative(VE-cadherin 2) GBM stem-like cells was acquired during co-culture with tumor cells. 4 This suggested that CSCs possess plasticity which could be regulated by cell-to-cell interaction or environmental factors within the differentiated component of the tumor tissue. Similar to normal stem cells, CSCs reside in unique microenvironment called the niche. The fate of stem cells appears to be regulated by the communication between adjacent cells and components within the niche. 7-9 It has also been shown that vascular endothelial cells within GBM tumor tissue can activate the Notch signaling pathway in GBM stem-like cells and that this activation of canonical Notch signaling was required for self-renewal of GBM stemlike cells. 10,11 Given the fact that GBM stem-like cells differentiate into vascular endothelial cells, it raises the possibility that these differentiated cells which arise from CSCs might generate a CSC niche. However, direct contribution of the
Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence
Cancers, 2022
Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future ...
Cancer stem cell niche: the place to be
Cancer research, 2011
Tumors are being increasingly perceived as abnormal organs that, in many respects, recapitulate the outgrowth and differentiation patterns of normal tissues. In line with this idea is the observation that only a small fraction of tumor cells is capable of initiating a new tumor. Because of the features that these cells share with somatic stem cells, they have been termed cancer stem cells (CSC). Normal stem cells reside in a "stem cell niche" that maintains them in a stem-like state. Recent data suggest that CSCs also rely on a similar niche, dubbed the "CSC niche," which controls their self-renewal and differentiation. Moreover, CSCs can be generated by the microenvironment through induction of CSC features in more differentiated tumor cells. In addition to a role in CSC maintenance, the microenvironment is hypothesized to be involved in metastasis by induction of the epithelial-mesenchymal transition, leading to dissemination and invasion of tumor cells. The localization of secondary tumors also seems to be orchestrated by the microenvironment, which is suggested to form a premetastatic niche. Thus, the microenvironment seems to be of crucial importance for primary tumor growth as well as metastasis formation. Combined with its role in the protection of CSCs against genotoxic insults, these data strongly put forward the niche as an important target for novel therapies. Cancer Res; 71(3); 634-9. Ó2011 AACR.
Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity
Connective tissue research, 2015
Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a "proliferating" cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the ...
Cancer Cell Microenvironment, 2014
The critical features of cancer stem cells (CSCs) are tumorigenicity, self-renewal and differentiation, which are considered to be responsible for tumor maintenance. It has been proposed that CSCs generate a heterogenetic population in tumor by giving rise to diverse progenies in the apex of differentiation hierarchy. Our newest results indicate that differentiated cells from CSCs secreted soluble factors to keep the balance between selfrenewal and differentiation of CSCs, partially via activation of Notch signaling pathway. The cellular population of tumor could be varied in response to the dynamic cellular communications in CSC niche, which is produced by CSCs themselves.
Intrinsic and Extrinsic Factors Impacting Cancer Stemness and Tumor Progression
Cancers, 2022
Tumor heterogeneity represents an important limitation to the development of effective cancer therapies. The presence of cancer stem cells (CSCs) and their differentiation hierarchies contribute to cancer complexity and confer tumors the ability to grow, resist treatment, survive unfavorable conditions, and invade neighboring and distant tissues. A large body of research is currently focusing on understanding the properties of CSCs, including their cellular and molecular origin, as well as their biological behavior in different tumor types. In turn, this knowledge informs strategies for targeting these tumor initiating cells and related cancer stemness. Cancer stemness is modulated by the tumor microenvironment, which influences CSC function and survival. Several advanced in vitro models are currently being developed to study cancer stemness in order to advance new knowledge of the key molecular pathways involved in CSC self-renewal and dormancy, as well as to mimic the complexity o...