Metastatic tumors are the cause of more than 90% of cancer related deaths. Metastasis formation can be considered as a culmination of the Darwinian evolutionary process within the tumor, when ...competition of multiple clones results in the development of cell inherent traits that favor tumor dissemination. Cancer stem cells (CSC) which possess self-renewal properties and genomic instability are considered to be an engine of tumor evolution. Cancer cells which have the capacity to colonize distant organs have the features of CSC and, in addition, exert their tumor-initiating capacity under adverse microenvironmental conditions. Recent studies support an idea that metastases can be driven by the evolved and selected subpopulations of CSC. In this review we discuss the common hallmarks of CSC and metastasis initiating cells (MIC) and prospects for the development of anti-metastatic therapy.
The current preclinical and clinical findings demonstrate that, in addition to the conventional clinical and pathological indicators that have a prognostic value in radiation oncology, the number of ...cancer stem cells (CSCs) and their inherent radioresistance are important parameters for local control after radiotherapy. In this review, we discuss the molecular mechanisms of CSC radioresistance attributable to DNA repair mechanisms and the development of CSC-targeted therapies for tumor radiosensitization. We also discuss the current challenges in preclinical and translational CSC research including the high inter- and intratumoral heterogeneity, plasticity of CSCs, and microenvironment-stimulated tumor cell reprogramming.
SLC3A2/CD98hc (solute carrier family 3 member 2) and its light chain subunits constitute the heterodimeric transmembrane complexes that mediate amino acid transport and regulate MTOR and ...macroautophagy/autophagy. Despite the proven tumorigenic role of SLC3A2 in a number of cancers including head and neck squamous cell carcinomas (HNSCC), the link between SLC3A2, autophagy regulation and tumor radioresistance remained elusive. In a recently published study we demonstrated that low levels of SLC3A2 and SLC7A5/LAT1 protein expression significantly correlate with good clinical prognosis in locally advanced HNSCC treated with primary radiochemotherapy. The SLC3A2-deficient HNSCC cells show a higher radiosensitivity and increased autophagy levels. We found that autophagy activation is a tumor survival strategy to overcome nutrient stress by lack of SLC3A2 and to withstand radiation-mediated cell damage. Inhibition of the autophagy activation in SLC3A2 knockout HNSCC cells by knockdown of ATG5 expression or treatment with bafilomycin A
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results in radiosensitivity. Consequently, the expression levels of ATG5 correlates with overall survival in HNSCC patients, and autophagy inhibition in combination with SLC3A2-targeted therapy can be a promising strategy for HNSCC radiosensitization.
CD98hc: CD98 heavy chain CSC cancer stem cells; EAA: essential amino acids; GSH: glutathione; MTOR: mammalian target of rapamycin; HNSCC: head and neck squamous cell carcinoma; RCTx: primary radiochemotherapy; PORT-C: postoperative radiochemotherapy; ROS: reactive oxygen species; SLC3A2: solute carrier family 3 member 2; TCA cycle: tricarboxylic acid cycle.
Abstract Similar to normal tissue, many tumors have a hierarchical organization where tumorigenic cancer stem cells (CSCs) differentiate into non-tumorigenic progenies. A host of studies have ...demonstrated that although CSCs and their non-tumorigenic progenies within the same clone can share common genotype, they display different epigenetic profiles that results in changes of multiple signaling pathways. Many of these pathways confer cell adaptation to the microenvironmental stresses including inflammation, hypoxia, low pH, shortage in nutrients and anti-cancer therapies. Treatment strategies based on combination of conventional therapies targeting bulk tumor cells and CSC-specific pathway inhibition bear a promise to improve cancer cure compared to monotherapies. In this review we describe the mechanisms of CSC-related therapy resistance including drug efflux by ABC transporters, activation of aldehyde dehydrogenase and developmental pathways, enhanced DNA damage response, autophagy and microenvironmental conditions, and discuss possible therapeutic strategies for improving cancer treatment.
Most human tumors possess a high heterogeneity resulting from both clonal evolution and cell differentiation program. The process of cell differentiation is initiated from a population of cancer stem ...cells (CSCs), which are enriched in tumor-regenerating and tumor-propagating activities and responsible for tumor maintenance and regrowth after treatment. Intrinsic resistance to conventional therapies, as well as a high degree of phenotypic plasticity, makes CSCs hard-to-target tumor cell population. Reprogramming of CSC metabolic pathways plays an essential role in tumor progression and metastatic spread. Many of these pathways confer cell adaptation to the microenvironmental stresses, including a shortage of nutrients and anti-cancer therapies. A better understanding of CSC metabolic dependences as well as metabolic communication between CSCs and the tumor microenvironment are of utmost importance for efficient cancer treatment. In this mini-review, we discuss the general characteristics of CSC metabolism and potential metabolic targeting of CSC populations as a potent strategy to enhance the efficacy of conventional treatment approaches.
The SLC3A2 gene encodes for a cell-surface transmembrane protein CD98hc (4F2). CD98hc serves as a chaperone for LAT1 (SLC7A5), LAT2 (SLC7A8), y
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LAT1 (SLC7A7), y
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LAT2 (SLC7A6), xCT (SLC7A11) and ...Asc1 (SLC7A10) providing their recruitment to the plasma membrane. Together with the light subunits, it constitutes heterodimeric transmembrane amino acid transporters. CD98hc interacts with other surface molecules, such as extracellular matrix metalloproteinase inducer CD147 (EMMPRIN) and adhesion receptors integrins, and regulates glucose uptake. In this way, CD98hc connects the signaling pathways sustaining cell proliferation and migration, biosynthesis and antioxidant defense, energy production, and stem cell properties. This multifaceted role makes CD98hc one of the critical regulators of tumor growth, therapy resistance, and metastases. Indeed, the high expression levels of CD98hc were confirmed in various tumor tissues, including head and neck squamous cell carcinoma, glioblastoma, colon adenocarcinoma, pancreatic ductal adenocarcinoma, and others. A high expression of CD98hc has been linked to clinical prognosis and response to chemo- and radiotherapy in several types of cancer. In this mini-review, we discuss the physiological functions of CD98hc, its role in regulating tumor stemness, metastases, and therapy resistance, and the clinical significance of CD98hc as a tumor marker and therapeutic target.
Prostate cancer (PCa) is heterogeneous, harboring phenotypically diverse cancer cell types. PCa cell heterogeneity is caused by genomic instability that leads to the clonal competition and evolution ...of the cancer genome and by epigenetic mechanisms that result in subclonal cellular differentiation. The process of tumor cell differentiation is initiated from a population of prostate cancer stem cells (PCSCs) that possess many phenotypic and functional properties of normal stem cells. Since the initial reports on PCSCs in 2005, there has been much effort to elucidate their biological properties, including unique metabolic characteristics. In this Review, we discuss the current methods for PCSC enrichment and analysis, the hallmarks of PCSC metabolism, and the role of PCSCs in tumor progression. Stem Cells 2018;36:1457–1474
Prostate cancer development is an evolutionary process that reflects an evolving of prostate cancer stem cells (PCSCs) possessing self‐renewal properties and genomic instability. Tumor metastases might be driven by the constantly evolving populations of PCSCs. This is evidenced by the fact that circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) express many PCSC markers, and metastasis‐initiating cells (MICs) also share key PCSC features including ability to self‐renew, establish tumors and activate PCSC‐specific signaling pathways. In this review, we discuss the current methods for PCSC enrichment and analysis, the hallmarks of PCSC biology and the role of PCSCs in therapy resistance, tumor progression and metastases.
Abstract Radiotherapy has a proven potential to eradicate cancer stem cells which is reflected by its curative potential in many cancer types. Considerable progress has been made in identification ...and biological characterisation of cancer stem cells during the past years. Recent biological findings indicate significant inter- and intratumoural and functional heterogeneity of cancer stem cells and lead to more complex models which have potential implications for radiobiology and radiotherapy. Clinical evidence is emerging that biomarkers of cancer stem cells may be prognostic for the outcome of radiotherapy in some tumour entities. Perspectives of cancer stem cell based research for radiotherapy reviewed here include their radioresistance compared to the mass of non-cancer stem cells which form the bulk of all tumour cells, implications for image- and non-image based predictive bio-assays of the outcome of radiotherapy and a combination of novel systemic treatments with radiotherapy.
Abstract Tumors are known to be heterogeneous containing a dynamic mixture of phenotypically and functionally different tumor cells. The two concepts attempting to explain the origin of intratumor ...heterogeneity are the cancer stem cell hypothesis and the clonal evolution model. The stochastic model argues that tumors are biologically homogenous and all cancer cells within the tumor have equal ability to propagate the tumor growth depending on continuing mutations and selective pressure. By contrast, the stem cells model suggests that cancer heterogeneity is due to the hierarchy that originates from a small population of cancer stem cells (CSCs) which are biologically distinct from the bulk tumor and possesses self-renewal, tumorigenic and multilineage potential. Although these two hypotheses have been discussed for a long time as mutually exclusive explanations of tumor heterogeneity, they are easily reconciled serving as a driving force of cancer evolution and diversity. Recent discovery of the cancer cell plasticity and heterogeneity makes the CSC population a moving target that could be hard to track and eradicate. Understanding the signaling mechanisms regulating CSCs during the course of cancer treatment can be indispensable for the optimization of current treatment strategies.
Ovarian cancer (OC) is one of the most lethal gynecologic malignancies. Due to the lack of specific symptoms and screening methods, this disease is usually diagnosed only at an advanced and ...metastatic stage. The gold-standard treatment for OC patients consists of debulking surgery followed by taxane combined with platinum-based chemotherapy. Most patients show complete clinical remission after first-line therapy, but the majority of them ultimately relapse, developing radio- and chemoresistant tumors. It is now proposed that the cause of recurrence and reduced therapy efficacy is the presence of small populations of cancer stem cells (CSCs). These cells are usually resistant against conventional cancer therapies and for this reason, effective targeted therapies for the complete eradication of CSCs are urgently needed. In this review article, we highlight the mechanisms of CSC therapy resistance, epithelial-to-mesenchymal transition, stemness, and novel therapeutic strategies for ovarian CSCs.
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