REVIEW ARTICLE: Cancer stem cells and human malignant melanoma (original) (raw)
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Human malignant melanoma is a highly aggressive tumor which demonstrates heterogeneity and a propensity to drug resistance. Despite improved treatment options, patients with advanced malignant melanoma continue have a poor prognosis as measured by progression-free and overall survival. The cancer stem-like cell (CSC) hypothesis suggests that neoplastic clones are maintained by a small fraction of cells with stem cell properties. As has been demonstrated with other tumor types, melanoma progression, resistance to chemo- and radiotherapy, and recurrence can be attributed to a small fraction of cells termed melanoma stem-like cells (MSCs). These MSCs are characterized by a distinct protein patterns and aberrant signaling pathways, which are either in a causal or consequential relationship to tumor progression, drug resistance and recurrence. This review focuses on the mechanistic role of MSCs leading to tumor progression and metastasis, resistance and recurrence. Understanding the molecular mechanisms underlying MSCs migration, invasion, resistance to standard treatments, and recurrence may help to improve current therapeutic modalities and/or pave the way for the development of new therapeutical management strategy for tumor treatment.
Stem cells in melanoma development
Cancer Letters, 2009
Cutaneous melanoma is a significant health problem worldwide. Available treatments can induce objective tumor regression in a small percent of patients, but these responses are not always associated with improved long-term survival. The resistance of melanoma to therapy and its predestined recurrence are related to the genetic heterogeneity and genomic instability of the tumor. For many years these genetic alterations were thought to be linked to the accumulation of random mutations in functionally differentiated cells which transform them into malignant cells that have lost their ability to differentiate and have acquired drug resistance. In the last few years it has been largely demonstrated that melanoma as other solid tumors contains a subpopulation of cells (CSCs) considered the source of the primary tumor mass, of new tumor nodules and responsible for drug resistance and cancer recurrence.
Melanoma stem cells: targets for successful therapy?
Journal Der Deutschen Dermatologischen Gesellschaft, 2008
Increasing evidence suggests that cancer is a disease in which the persistence of the tumor relies on a small population of tumor-initiating cells, the so called tumor stem cells (TSC). Only these cells are capable of self-renewal and thereby possess the ability for unlimited proliferation. One reason for the inability of conventional tumor treatments to achieve long-term cures seems to be that TSC are resistant to many therapeutic approaches. A detailed characterization of TSC should have a substantial impact on the optimization of therapeutic protocols. While TSC in hematopoietic malignancies have been most intensively studied, subpopulations with stem cell properties have been identified in some solid tumors including breast carcinomas, gliomas and melanomas. In case of melanoma, however, a clear-cut molecular characterization is still pending. Considerable research is needed to establish standard procedures for the isolation of melanoma stem cells to facilitate determining how these cells, critical for tumor persistence and progression, can be effectively eliminated. A pressing question is if melanoma stem cells are in principle sensitive to immunotherapy.
Functional features of cancer stem cells in melanoma cell lines
Cancer Cell International, 2013
Background: Recent evidence suggests a subset of cells within a tumor with "stem-like" characteristics. These cells are able to transplant tumors in immunodeficient hosts. Distinct from non-malignant stem cells, cancer stem cells (CSC) show low proliferative rates, high self-renewing capacity, propensity to differentiate into actively proliferating tumor cells, and resistance to chemotherapy or radiation. They are often characterized by elevated expression of stem cell surface markers, in particular CD133, and sets of differentially expressed stem cell-associated genes. CSC are usually rare in clinical specimens and hardly amenable to functional studies and gene expression profiling. In this study, a panel of heterogenous melanoma cell lines was screened for typical CSC features. Methods: Nine heterogeneous metastatic melanoma cell lines including D10 and WM115 were studied. Cell lines were phenotyped using flow cytometry and clonogenic assays were performed by limiting dilution analysis on magnetically sorted cells. Spheroidal growth was investigated in pretreated flasks. Gene expression profiles were assessed by using real-time rt-PCR and DNA microarrays. Magnetically sorted tumor cells were subcutaneously injected into the flanks of immunodeficient mice. Comparative immunohistochemistry was performed on xenografts and primary human melanoma sections. Results: D10 cells expressed CD133 with a significantly higher clonogenic capacity as compared to CD133-cells. Na8, D10, and HBL cells formed spheroids on poly-HEMA-coated flasks. D10, Me39, RE, and WM115 cells expressed at least 2 of the 3 regulatory core transcription factors SOX2, NANOG, and OCT4 involved in the maintenance of stemness in mesenchymal stem cells. Gene expression profiling on CD133+ and CD133-D10 cells revealed 68 up-and 47 downregulated genes (+/-1.3 fold). Two genes, MGP and PROM1 (CD133), were outstandingly upregulated. CD133+ D10 cells formed tumors in NSG mice contrary to CD133-cells and CD133 expression was detected in xenografts and primary human melanoma sections using immunohistochemistry. Conclusions: Established melanoma cell lines exhibit, to variable extents, the typical features of CSCs. The tumorigenic cell line D10, expressing CD133 and growing in spheroids and might qualify as a potential model of melanoma CSCs.
Stem cells and targeted approaches to melanoma cure
Molecular Aspects of Medicine, 2013
Melanoma stem cells, also known as malignant melanoma-initiating cells, are identifiable through expression of specific biomarkers such as ABCB5 (ATP-binding cassette, sub-family B (MDR/TAP), member 5), NGFR (nerve growth factor receptor, CD271) and ALDH (aldehyde dehydrogenase), and drive melanoma initiation and progression based on prolonged self-renewal capacity, vasculogenic differentiation and immune evasion. As we will review here, specific roles of these aggressive subpopulations have been documented in tumorigenic growth, metastatic dissemination, therapeutic resistance, and malignant recurrence. Moreover, recent findings have provided pre-clinical proof-of-concept for the potential therapeutic utility of the melanoma stem cell concept. Therefore, melanoma stem cell-directed therapeutic approaches represent promising novel strategies to improve therapy of this arguably most virulent human cancer.
Cancers
Cancer stem cells (CSCs) have historically been defined as slow cycling elements that are able to differentiate into mature cells but without dedifferentiation in the opposite direction. Thanks to advances in genomic and non-genomic technologies, the CSC theory has more recently been reconsidered in a dynamic manner according to a “phenotype switching” plastic model. Transcriptional reprogramming rewires this plasticity and enables heterogeneous tumors to influence cancer progression and to adapt themselves to drug exposure by selecting a subpopulation of slow cycling cells, similar in nature to the originally defined CSCs. This model has been conceptualized for malignant melanoma tailored to explain resistance to target therapies. Here, we conducted a bioinformatics analysis of available data directed to the identification of the molecular pathways sustaining slow cycling melanoma stem cells. Using this approach, we identified a signature of 25 genes that were assigned to four majo...
Melanoma, Nevogenesis, and Stem Cell Biology
Journal of Investigative Dermatology, 2008
It is now well established that a subpopulation of tumor stem cells (TSCs) are present within cancer tissues. This suggests that tumors evolve from stem cells; however, the exact cell of tumor origin, the potential role of dedifferentiation, and the role of plasticity in tumor development are largely unknown. A model cancer for the study of the oncologic process is melanoma. The developmental biology of melanocytes is relatively well understood, the cells pigment as they differentiate making them easy to identify, and benign and malignant tumors develop on the skin surface allowing direct observation of growth features, early detection, and removal. This ready access to early-stage tumors will facilitate study of the early oncologic processes and the role of tissue stem cells. Melanomas, like other cancers, include a subpopulation of TSCs. These TSCs have access to embryologic developmental programs, including the capacity to differentiate along multiple cell lineages. For example, melanomas can activate germ-cell pathways with major implications for TSC self-renewal through the activation of telomerase and genomic instability through the collision of meiotic and mitotic pathways (meiomitosis). The TSC model is still evolving, but the existence of TSCs has significant ramifications for tumor development, diagnosis, prognosis, and treatment of melanoma and other cancers.
Increased expression of stem cell markers in malignant melanoma
Modern Pathology, 2007
The potential role of stem cells in neoplasia is a subject of recent interest. Three markers of melanocytic stem cells have been described recently. CD166 is expressed on the surface of mesenchymal stem cells and has been found on human melanoma cell lines. CD133 is expressed on the surface of dermal-derived stem cells that are capable of differentiating into neural cells. Nestin is an intermediate filament expressed in the cytoplasm of neuroepithelial stem cells. In this study, we evaluate the expression of these markers and possible differences among banal nevi, primary melanoma, and metastastic melanoma. Tissue microarrays containing normal tissue and 226 melanocytic lesions (71 banal nevi, 71 in situ and invasive melanomas, and 84 metastatic melanomas) were studied by immunohistochemistry using monoclonal antibodies CD166, CD133, and nestin. A significantly greater percentage of melanomas (combined primary and metastatic) contained cells that expressed CD166 (P ¼ 0.005), CD133 (P ¼ 0.003), and nestin (P ¼ 0.03) than banal nevi. Only nestin showed a statistical difference when comparing primary and metastatic melanoma (P ¼ 0.05). A stepwise increase in the proportion of lesions expressing all three markers was observed from banal nevi (2/19) to primary melanomas (8/17) to metastatic melanoma (19/28), P ¼ 0.0005. All cases of metastatic melanoma expressed at least one stem cell marker. The increased expression of CD166, CD133, and nestin in melanoma suggests that progression to malignant melanoma likely involves genetic pathways instrumental to stem cell biology and normal tissue development. Further studies and characterization of these pathways may also reveal new prognostic markers for a disease whose prognosis in advanced stages is dismal.
Conservation of Genetic Alterations in Recurrent Melanoma Supports the Melanoma Stem Cell Hypothesis
Cancer Research, 2008
It is generally accepted that human cancers derive from a mutated single cell. However, the genetic steps characterizing various stages of progression remain unclear. Studying a unique case of metastatic melanoma, we observed that cell lines derived from metachronous metastases arising over a decade retained a central core of genetic stability in spite of divergent phenotypes. In the present study, we expanded our previous observations comparing these autologous cell lines of clonal derivation with allogeneic ones and correlated array comparative genomic hybridization (aCGH) with gene expression profiling to determine their relative contribution to the dynamics of disease progression. aCGH and gene expression profiling were performed on autologous cell lines and allogeneic melanoma cell lines originating from other patients. A striking correlation existed between total extent of genetic imbalances, global transcriptional patterns, and cellular phenotypes. They did not follow a strict temporal progression but stemmed independently at various time points from a central core of genetic stability best explained according to the cancer stem cell hypothesis. Although their contribution was intertwined, genomic imbalances detectable by aCGH contributed only 25% of the transcriptional traits determining autologous tumor distinctiveness. Our study provides important insights about the dynamics of cancer progression and supports the development of targeted anticancer therapies aimed against stable genetic factors that are maintained throughout the end stage of disease.
Tumor Initiation in Human Malignant Melanoma and Potential Cancer Therapies
Anti-Cancer Agents in Medicinal Chemistry, 2010
Cancer stem cells (CSCs), also known as tumor-initiating cells, have been identified in several human malignancies, including human malignant melanoma. The frequency of malignant melanoma-initiating cells (MMICs), which are identified by their expression of ATP-binding cassette (ABC) family member ABCB5, correlates with disease progression in human patients. Furthermore, targeted MMIC ablation through ABCB5 inhibits tumor initiation and growth in preclinical xenotransplantation models, pointing to potential therapeutic promise of the CSC concept. Recent advances also show that CSCs can exert pro-angiogenic roles in tumor growth and serve immunomodulatory functions related to the evasion of host anti-tumor immunity. Thus, MMICs might initiate and sustain tumorigenic growth not only as a result of CSC-intrinsic self-renewal, differentiation and proliferative capacity, but also based on pro-tumorigenic interactions with the host environment.