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Simple Summary: Gliomas are deleterious central nervous system tumors that harbor cellular heterogeneity and infiltrative capabilities. They are biologically aggressive and highly invasive tumors that lack efficient treatment. Glioma stem cells (GSCs) are a subpopulation of cancer stem cells (CSCs) with the ability for self-renewal that is responsible for tumor plasticity. They show tumor-initiating properties, are influenced by genetic drivers and display great migratory abilities. GSCs engage in a synergistic relationship with the surrounding tumor microenvironment to promote tumor progression and therapy resistance. A great effort is under way in order to find ways to eliminate or neutralize GSCs. On a molecular level, glioma is very diverse and presents a whole spectrum of specific genetic and epigenetic alterations. The tumors are unfortunately resistant to available therapies and the survival rate is low. The explanation of significant intra- and inter-tumor heterogeneity and the infiltrative capability of gliomas, as well as its resistance to therapy, recurrence and aggressive behavior, lies in a small subset of tumor-initiating cells that behave like stem cells and are known as glioma cancer stem cells (GCSCs). They are responsible for tumor plasticity and are influenced by genetic drivers. Additionally, GCSCs also display greater migratory abilities. A great effort is under way in order to find ways to eliminate or neutralize GCSCs. Many different treatment strategies are currently being explored, including modulation of the tumor microenvironment, posttranscriptional regulation, epigenetic modulation and immunotherapy. [ABSTRACT FROM AUTHOR]

Despite the tremendous clinical successes recorded in the landscape of cancer therapy, tumor heterogeneity remains a formidable challenge to successful cancer treatment. In recent years, the emergence of high-throughput technologies has advanced our understanding of the variables influencing tumor heterogeneity beyond intrinsic tumor characteristics. Emerging knowledge shows that drivers of tumor heterogeneity are not only intrinsic to cancer cells but can also emanate from their microenvironment, which significantly favors tumor progression and impairs therapeutic response. Although much has been explored to understand the fundamentals of the influence of innate tumor factors on cancer diversity, the roles of the tumor microenvironment (TME) are often undervalued. It is therefore imperative that a clear understanding of the interactions between the TME and other tumor intrinsic factors underlying the plastic molecular behaviors of cancers be identified to develop patient-specific treatment strategies. This review highlights the roles of the TME as an emerging factor in tumor heterogeneity. More particularly, we discuss the role of the TME in the context of tumor heterogeneity and explore the cutting-edge diagnostic and therapeutic approaches that could be used to resolve this recurring clinical conundrum. We conclude by speculating on exciting research questions that can advance our understanding of tumor heterogeneity with the goal of developing customized therapeutic solutions. [ABSTRACT FROM AUTHOR]

On a molecular level, glioma is very diverse and presents a whole spectrum of specific genetic and epigenetic alterations. The tumors are unfortunately resistant to available therapies and the survival rate is low. The explanation of significant intra- and inter-tumor heterogeneity and the infiltrative capability of gliomas, as well as its resistance to therapy, recurrence and aggressive behavior, lies in a small subset of tumor-initiating cells that behave like stem cells and are known as glioma cancer stem cells (GCSCs). They are responsible for tumor plasticity and are influenced by genetic drivers. Additionally, GCSCs also display greater migratory abilities. A great effort is under way in order to find ways to eliminate or neutralize GCSCs. Many different treatment strategies are currently being explored, including modulation of the tumor microenvironment, posttranscriptional regulation, epigenetic modulation and immunotherapy.

Background: Drug resistance continues to be a major limiting factor across diverse anti-cancer therapies. Contributing to the complexity of this challenge is cancer plasticity, in which one cancer subtype switches to another in response to treatment, for example, triple-negative breast cancer (TNBC) to Her2-positive breast cancer. For optimal treatment outcomes, accurate tumor diagnosis and subsequent therapeutic decisions are vital. This study assessed a novel approach to characterize treatment-induced evolutionary changes of distinct tumor cell subpopulations to identify and therapeutically exploit anticancer drug resistance. Methods: In this research, an information-theoretic single-cell quantification strategy was developed to provide a high-resolution and individualized assessment of tumor composition for a customized treatment approach. Briefly, this single-cell quantification strategy computes cell barcodes based on at least 100,000 tumor cells from each experiment and reveals a cell-specific signaling signature (CSSS) composed of a set of ongoing processes in each cell. Results: Using these CSSS-based barcodes, distinct subpopulations evolving within the tumor in response to an outside influence, like anticancer treatments, were revealed and mapped. Barcodes were further applied to assign targeted drug combinations to each individual tumor to optimize tumor response to therapy. The strategy was validated using TNBC models and patient-derived tumors known to switch phenotypes in response to radiotherapy (RT). Conclusions: We show that a barcode-guided targeted drug cocktail significantly enhances tumor response to RT and prevents regrowth of once-resistant tumors. The strategy presented herein shows promise in preventing cancer treatment resistance, with significant applicability in clinical use. [ABSTRACT FROM AUTHOR]

At the onset, few cancer cells amidst the tumor bulk, identified as cancer stem cells (CSCs) or early disseminated cancer cells (eDCCs) are capable of survival post conventional therapy and persist as minimal residual disease (MRD). Metastatic subclones emerge both early and late in the life of primary tumor ensuing an ongoing regional clonal evolution of progenitor cells in metastatic and primary tumors. In the last decade, multiple studies proposed various identities of stem-like cells that undergo transitions to adapt to the changing microenvironment as the disease progresses. This review advocates with substantial evidence the dynamic model of tumor propagation by exploring the specific cell types, reversible phenotypic plasticity between the tumorigenic leader seeds and the supporting follower cancer cells both in circulation and in solid tissue to accurately decipher tumor promoting clones and its role in metastatic dissemination and tumor re-growth. (142 words)

Tumor plasticity refers to tumor cell's inherent property of transforming one type of cell to different types of cells. Tumor plasticity is the main cause of tumor relapse, metastasis and drug resistance. Cancer stem cell (CSC) model embodies the trait of tumor plasticity. During carcinoma progression, epithelial-mesenchymal transition (EMT) plays crucial role in the formation of CSCs and vasculogenic mimicry (VM) based on epithelial-mesenchymal plasticity. And the unique tumor microenvironment (TME) not only provides suitable niche for CSCs but promotes the building of CSCs and VM that nourishes tumor tissue together with neoplasm metabolism by affecting tumor plasticity. Therapeutic strategies targeting tumor plasticity are promising ways to treat malignant tumor. In this article, we discuss the recent developments of potential drug targets related to CSCs, EMT, TME, VM, and metabolic pathways and summarize drugs that target these areas in clinical trials.

Tumor plasticity refers to tumor cell's inherent property of transforming one type of cell to different types of cells. Tumor plasticity is the main cause of tumor relapse, metastasis and drug resistance. Cancer stem cell (CSC) model embodies the trait of tumor plasticity. During carcinoma progression, epithelial-mesenchymal transition (EMT) plays crucial role in the formation of CSCs and vasculogenic mimicry (VM) based on epithelial-mesenchymal plasticity. And the unique tumor microenvironment (TME) not only provides suitable niche for CSCs but promotes the building of CSCs and VM that nourishes tumor tissue together with neoplasm metabolism by affecting tumor plasticity. Therapeutic strategies targeting tumor plasticity are promising ways to treat malignant tumor. In this article, we discuss the recent developments of potential drug targets related to CSCs, EMT, TME, VM, and metabolic pathways and summarize drugs that target these areas in clinical trials. [ABSTRACT FROM AUTHOR]

Melanoma is one of the most aggressive and highly resistant tumors. Cell plasticity in melanoma is one of the main culprits behind its metastatic capabilities. The detailed molecular mechanisms controlling melanoma plasticity are still not completely understood. Here we combine mathematical models of phenotypic switching with experiments on IgR39 human melanoma cells to identify possible key targets to impair phenotypic switching. Our mathematical model shows that a cancer stem cell subpopulation within the tumor prevents phenotypic switching of the other cancer cells. Experiments reveal that hsa-mir-222 is a key factor enabling this process. Our results shed new light on melanoma plasticity, providing a potential target and guidance for therapeutic studies.

Tumor formation is a complex process that occurs in different steps and involves many cell types, including tumor cells, endothelial cells, and inflammatory cells, which interact to promote growth of the tumor mass and metastasization. Epigenetic alterations occurring in transformed cells result in de-regulation of miRNA expression (a class of small non-coding RNA that regulates multiple functions) which contributes to tumorigenesis. The specific miRNAs, which have an aberrant expression in tumors, are defined as oncomiRNAs, and may be either over- or under-expressed, but down-regulation is most commonly observed.Renal cell carcinoma is a frequent form of urologic tumor, associated with an alteration of multiple signaling pathways. Many molecules involved in the progression of renal cell carcinomas, such as HIF, VEGF or mTOR, are possible targets of deregulated miRNAs. Within tumor mass, the cancer stem cell population is a fundamental component that promotes tumor growth. The cancer stem cell hypothesis postulates that cancer stem cells have the unique ability to self-renew and to maintain tumor growth and metastasis. Cancer stem cells present in renal cell carcinoma were shown to express the mesenchymal stem cell marker CD105 and to exhibit self-renewal and clonogenic properties, as well as the ability to generate serially transplantable tumors. The phenotype of cancer stem cell has been related to the potential to undergo the epithelial-mesenchymal transition, which has been linked to the expression pattern of tumorigenic miRNAs or down-regulation of anti-tumor miRNAs. In addition, the pattern of circulating miRNAs may allow discrimination between healthy and tumor patients. Therefore, a miRNA signature may be used as a tumor biomarker for cancer diagnosis, as well as to classify the risk of relapse and metastasis, and for a guide for therapy.

Regenerative medicine aims to replace the lost or damaged cells in the human body through a new source of healthy transplanted cells or by endogenous repair. Although human embryonic stem cells were first thought to be the ideal source for cell therapy and tissue repair in humans, the discovery by Yamanaka and colleagues revolutionized the field. Almost any differentiated cell can be sent back in time to a pluripotency state by expressing the appropriate transcription factors. The process of somatic reprogramming using Yamanaka factors, many of which are oncogenes, offers a glimpse into how cancer stem cells may originate. In this review we discuss the similarities between tumor dedifferentiation and somatic cell reprogramming and how this may pose a risk to the application of this new technology in regenerative medicine. [ABSTRACT FROM AUTHOR]

Tumor formation is a complex process that occurs in different steps and involves many cell types, including tumor cells, endothelial cells, and inflammatory cells, which interact to promote growth of the tumor mass and metastasization. Epigenetic alterations occurring in transformed cells result in de regulation of miRNA expression (a class of small non-coding RNA that regulates multiple functions), which contributes to tumorigenesis. The specific miRNAs, which have an aberrant expression in tumors, are defined as oncomiRNAs, and may be either over or under-expressed, but down-regulation is most commonly observed. Renal cell carcinoma (RCC) is a frequent form of urologic tumor, associated with an alteration of multiple signaling pathways. Many molecules involved in the progression of RCCs, such as HIF, VEGF, or mammalian target of rapamycin, are possible targets of de-regulated miRNAs.Within tumor mass, the cancer stem cell (CSC) population is a fundamental component that promotes tumor growth. The CSC hypothesis postulates that CSCs have the unique ability to self-renew and to maintain tumor growth and metastasis. CSCs present in RCC were shown to express the mesenchymal stem cell marker CD105 and to exhibit self-renewal and clonogenic properties, as well as the ability to generate serially transplantable tumors.The phenotype of CSC has been related to the potential to undergo the epithelial mesenchymal transition, which has been linked to the expression pattern of tumorigenic miRNAs or down-regulation of anti-tumor miRNAs. In addition, the pattern of circulating miRNAs may allowdiscrimination between healthy and tumor patients.Therefore, a miRNA signature may be used as a tumor biomarker for cancer diagnosis, as well as to classify the risk of relapse and metastasis, and for a guide for therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The cancer cells in solid tumors are embedded in a complex connective tissue matrix composed of various other cell types, i.e., mesenchymal stroma/stem-like cells (MSCs) and tumor-associated macrophages (TAMs). This tumor microenvironment (TME) is considered the major cause of tumor heterogeneity, which in turn accounts for treatment failure in current cancer therapies. Physical and chemical signals from the TME as well as factors secreted by MSCs and TAMs can induce epigenetic alterations in the cancer cells that alter their phenotypic plasticity, eventually resulting in the generation of cancer stem cells (CSCs). Phenotype switching of CSCs involves processes such as epithelial-mesenchymal transition, transdifferentiation, retrodifferentiation, or spontaneous cell fusion of cancer cells with stromal cells, particularly MSCs. Principally, phenotype plasticity of cancer (stem) cells may be targeted pharmacologically to reduce tumor heterogeneity and hence resistance to therapy. Tumor heterogeneity is considered the major cause of treatment failure in current cancer therapies. This feature of solid tumors is not only the result of clonal outgrowth of cells with genetic mutations, but also of epigenetic alterations induced by physical and chemical signals from the tumor microenvironment (TME). Besides fibroblasts, endothelial and immune cells, mesenchymal stroma/stem-like cells (MSCs) and tumor-associated macrophages (TAMs) intimately crosstalk with cancer cells and can exhibit both anti- and pro-tumorigenic effects. MSCs can alter cancer cellular phenotypes to increase cancer cell plasticity, eventually resulting in the generation of cancer stem cells (CSCs). The shift between different phenotypic states (phenotype switching) of CSCs is controlled via both genetic programs, such as epithelial-mesenchymal transdifferentiation or retrodifferentiation, and epigenetic alterations triggered by signals from the TME, like hypoxia, spatial heterogeneity or stromal cell-derived chemokines. Finally, we highlight the role of spontaneous cancer cell fusion with various types of stromal cells. i.e., MSCs in shaping CSC plasticity. A better understanding of cell plasticity and phenotype shifting in CSCs is a prerequisite for exploiting this phenomenon to reduce tumor heterogeneity, thereby improving the chance for therapy success. [ABSTRACT FROM AUTHOR]

The complex and heterogeneous nature of hepatocellular carcinoma (HCC) hampers the identification of effective therapeutic strategies. Cancer stem cells (CSCs) represent a fraction of cells within tumors with the ability to self-renew and differentiate, and thus significantly contribute to the formation and maintenance of heterogeneous tumor mass. Increasing evidence indicates high plasticity in tumor cells, suggesting that non-CSCs could acquire stem cell properties through de-differentiation or reprogramming processes. In this paper, we reveal KLF4 as a transcription factor that can induce a CSC-like phenotype in non-CSCs through upregulating the EpCAM and E-CAD expression. Our studies indicated that KLF4 could directly bind to the promoter of EpCAM and increase the number of EpCAM+/CD133+ liver cancer stem cells (LCSCs) in the HuH7 HCC cell line. When KLF4 was overexpressed in EpCAM−/CD133− non-stem cells, the expressions of hepatic stem/progenitor cell genes such as CK19, EpCAM and LGR5 were significantly increased. KLF4 overexpressing non-stem cells exhibited greater cell viability upon sorafenib treatment, while the cell migration and invasion capabilities of these cells were suppressed. Importantly, we detected an increased membranous expression and colocalization of β-CAT, E-CAD and EpCAM in the KLF4-overexpressing EpCAM−/CD133− non-stem cells, suggesting that this complex might be required for the cancer stem cell phenotype. Moreover, our in vivo xenograft studies demonstrated that with a KLF4 overexpression, EpCAM−/CD133− non-stem cells attained an in vivo tumor forming ability comparable to EpCAM+/CD133+ LCSCs, and the tumor specimens from KLF4-overexpressing xenografts had increased levels of both the KLF4 and EpCAM proteins. Additionally, we identified a correlation between the KLF4 and EpCAM protein expressions in human HCC tissues independent of the tumor stage and differentiation status. Collectively, our data suggest a novel function for KLF4 in modulating the de-differentiation of tumor cells and the induction of EpCAM+/CD133+ LCSCs in HuH7 HCC cells. [ABSTRACT FROM AUTHOR]