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1.
Cancer Lett ; 588: 216769, 2024 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-38438098

RESUMEN

Cancer-associated fibroblasts (CAFs) play an important role in a variety of cancers. However, the role of tumor stroma in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) is often neglected. Profiling the heterogeneity of CAFs can reveal the causes of malignant phenotypes in NF-PanNETs. Here, we found that patients with high stromal proportion had poor prognosis, especially for that with infiltrating stroma (stroma and tumor cells that presented an infiltrative growth pattern and no regular boundary). In addition, myofibroblastic CAFs (myCAFs), characterized by FAP+ and α-SMAhigh, were spatially closer to tumor cells and promoted the EMT and tumor growth. Intriguingly, only tumor cells which were spatially closer to myCAFs underwent EMT. We further elucidated that myCAFs stimulate TGF-ß expression in nearby tumor cells. Then, TGF-ß promoted the EMT in adjacent tumor cells and promoted the expression of myCAFs marker genes in tumor cells, resulting in distant metastasis. Our results indicate that myCAFs cause spatial heterogeneity of EMT, which accounts for liver metastasis of NF-PanNETs. The findings of this study might provide possible targets for the prevention of liver metastasis.


Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias Hepáticas , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Línea Celular Tumoral , Tumores Neuroendocrinos/patología , Fibroblastos Asociados al Cáncer/metabolismo , Neoplasias Pancreáticas/patología , Fenotipo , Factor de Crecimiento Transformador beta/metabolismo , Neoplasias Hepáticas/patología , Microambiente Tumoral
2.
J Adv Res ; 2024 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-38190940

RESUMEN

BACKGROUND: Colorectal cancer (CRC), which is mainly caused by epigenetic and lifestyle factors, is very often associated with functional plasticity during its development. In addition, the malignant plasticity of CRC cells underscores one of their survival abilities to functionally adapt to specific stresses, including inflammation, that occur during carcinogenesis. This leads to the generation of various subsets of cancer cells with phenotypic diversity and promotes epithelial-mesenchymal transition (EMT), formation of cancer cell stem cells (CSCs) and metabolic reprogramming. This can enhance cancer cell differentiation and facilitate tumorigenic potential, drug resistance and metastasis. AIM OF REVIEW: The tumor protein p53 acts as one of the central suppressors of carcinogenesis by regulating its target genes, whose proteins are involved in the plasticity of cancer cells, autophagy, cell cycle, apoptosis, DNA repair. The aim of this review is to summarize the latest published research on resveratrol's effect in the prevention of CRC, its regulatory actions, specifically on the p53 pathway, and its treatment options. KEY SCIENTIFIC CONCEPTS OF REVIEW: Resveratrol, a naturally occurring polyphenol, is a potent inducer of a variety of tumor-controlling. However, the underlying mechanisms linking the p53 signaling pathway to the functional anti-plasticity effect of resveratrol in CRC are still poorly understood. Therefore, this review discusses novel relationships between anti-cellular plasticity/heterogeneity, pro-apoptosis and modulation of tumor protein p53 signaling in CRC oncogenesis, as one of the crucial mechanisms by which resveratrol prevents malignant phenotypic changes leading to cell migration and drug resistance, thus improving the ongoing treatment of CRC.

3.
Pathogens ; 11(2)2022 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-35215208

RESUMEN

Squamous cell carcinoma of the head and neck (HNSCC) is a common malignant tumor in humans and animals. In humans, papillomavirus (PV)-induced HNSCCs have a better prognosis than papillomavirus-unrelated HNSCCs. The ability of tumor cells to switch from epithelial to mesenchymal, endothelial, or therapy-resistant stem-cell-like phenotypes promotes disease progression and metastasis. In equine HNSCC, PV-association and tumor cell phenotype switching are poorly understood. We screened 49 equine HNSCCs for equine PV (EcPV) type 2, 3 and 5 infection. Subsequently, PV-positive versus -negative lesions were analyzed for expression of selected epithelial (keratins, ß-catenin), mesenchymal (vimentin), endothelial (COX-2), and stem-cell markers (CD271, CD44) by immunohistochemistry (IHC) and immunofluorescence (IF; keratins/vimentin, CD44/CD271 double-staining) to address tumor cell plasticity in relation to PV infection. Only EcPV2 PCR scored positive for 11/49 equine HNSCCs. IHC and IF from 11 EcPV2-positive and 11 EcPV2-negative tumors revealed epithelial-to-mesenchymal transition events, with vimentin-positive cells ranging between <10 and >50%. CD44- and CD271-staining disclosed the intralesional presence of infiltrative tumor cell fronts and double-positive tumor cell subsets independently of the PV infection status. Our findings are indicative of (partial) epithelial-mesenchymal transition events giving rise to hybrid epithelial/mesenchymal and stem-cell-like tumor cell phenotypes in equine HNSCCs and suggest CD44 and CD271 as potential malignancy markers that merit to be further explored in the horse.

4.
EMBO Mol Med ; 14(4): e14876, 2022 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-35119792

RESUMEN

Despite the advance and success of precision oncology in gastrointestinal cancers, the frequency of molecular-informed therapy decisions in pancreatic ductal adenocarcinoma (PDAC) is currently neglectable. We present a longitudinal precision oncology platform based on functional model systems, including patient-derived organoids, to identify chemotherapy-induced vulnerabilities. We demonstrate that treatment-induced tumor cell plasticity in vivo distinctly changes responsiveness to targeted therapies, without the presence of a selectable genetic marker, indicating that tumor cell plasticity can be functionalized. By adding a mechanistic layer to precision oncology, adaptive processes of tumors under therapy can be exploited, particularly in highly plastic tumors, such as pancreatic cancer.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Humanos , Organoides/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Medicina de Precisión , Neoplasias Pancreáticas
5.
Front Immunol ; 12: 693609, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34194441

RESUMEN

The immune checkpoint blockade therapy has completely transformed cancer treatment modalities because of its unprecedented and durable clinical responses in various cancers. With the increasing use of immune checkpoint blockades in clinical practice, a large number of patients develop acquired resistance. However, the knowledge about acquired resistance to immune checkpoint blockades is limited and poorly summarized. In this review, we clarify the principal elements of acquired resistance to immune checkpoint blockades. The definition of acquired resistance is heterogeneous among groups or societies, but the expert consensus of The Society for Immunotherapy of Cancer can be referred. Oligo-progression is the main pattern of acquired resistance. Acquired resistance can be derived from the selection of resistant cancer cell clones that exist in the tumor mass before therapeutic intervention or gradual acquisition in the sensitive cancer cells. Specifically, tumor intrinsic mechanisms include neoantigen depletion, defects in antigen presentation machinery, aberrations of interferon signaling, tumor-induced exclusion/immunosuppression, and tumor cell plasticity. Tumor extrinsic mechanisms include upregulation of other immune checkpoints. Presently, a set of treatment modalities is applied to patients with similar clinical characteristics or resistance mechanisms for overcoming acquired resistance, and hence, further research is required.


Asunto(s)
Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Proteínas de Punto de Control Inmunitario/metabolismo , Neoplasias/tratamiento farmacológico , Animales , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Transducción de Señal , Microambiente Tumoral
6.
Front Oncol ; 10: 614468, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33585241

RESUMEN

Cellular heterogeneity poses an immense therapeutic challenge in cancer due to a constant change in tumor cell characteristics, endowing cancer cells with the ability to dynamically shift between states. Intra-tumor heterogeneity is largely driven by cancer cell plasticity, demonstrated by the ability of malignant cells to acquire stemness and epithelial-to-mesenchymal transition (EMT) properties, to develop therapy resistance and to escape dormancy. These different aspects of cancer cell remodeling are driven by intrinsic as well as by extrinsic signals, the latter being dominated by factors of the tumor microenvironment. As part of the tumor milieu, chronic inflammation is generally regarded as a most influential player that supports tumor development and progression. In this review article, we put together recent findings on the roles of inflammatory elements in driving forward key processes of tumor cell plasticity. Using breast cancer as a representative research system, we demonstrate the critical roles played by inflammation-associated myeloid cells (mainly macrophages), pro-inflammatory cytokines [such as tumor necrosis factor α (TNFα) and interleukin 6 (IL-6)] and inflammatory chemokines [primarily CXCL8 (interleukin 8, IL-8) and CXCL1 (GROα)] in promoting tumor cell remodeling. These inflammatory components form a common thread that is involved in regulation of the three plasticity levels: stemness/EMT, therapy resistance, and dormancy. In view of the fact that inflammatory elements are a common denominator shared by different aspects of tumor cell plasticity, it is possible that their targeting may have a critical clinical benefit for cancer patients.

7.
Glia ; 68(6): 1228-1240, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31868967

RESUMEN

Glioblastoma (GBM) is the most frequent and deadly primary malignant brain tumor. Hallmarks are extensive intra-tumor and inter-tumor heterogeneity and highly invasive growth, which provide great challenges for treatment. Efficient therapy is lacking and the majority of patients survive less than 1 year from diagnosis. GBM progression and recurrence is caused by treatment-resistant glioblastoma stem cells (GSCs). GSC cultures are considered important models in target identification and drug screening studies. The current state-of-the-art method, to isolate and maintain GSC cultures that faithfully mimic the primary tumor, is to use serum-free (SF) media conditions developed for neural stem cells (NSCs). Here we have investigated the outcome of explanting 218 consecutively collected GBM patient samples under both SF and standard, serum-containing media conditions. The frequency of maintainable SF cultures (SFCs) was most successful, but for a subgroup of GBM specimens, a viable culture could only be established in serum-containing media, called exclusive serum culture (ESC). ESCs expressed nestin and SOX2, and displayed all functional characteristics of a GSC, that is, extended proliferation, sustained self-renewal and orthotopic tumor initiation. Once adapted to the in vitro milieu they were also sustainable in SF media. Molecular analyses showed that ESCs formed a discrete group that was most related to the mesenchymal GBM subtype. This distinct subgroup of GBM that would have evaded modeling in SF conditions only provide unique cell models of GBM inter-tumor heterogeneity.


Asunto(s)
Neoplasias Encefálicas/patología , Glioblastoma/patología , Células Madre Neoplásicas/patología , Células-Madre Neurales/patología , Animales , Técnicas de Cultivo de Célula/métodos , Línea Celular Tumoral , Proliferación Celular/fisiología , Ratones Transgénicos
8.
Cancer Lett ; 444: 147-161, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30583074

RESUMEN

Overall survival of patients with metastatic non-small cell lung cancer (NSCLC) has significantly improved with platinum-based salt treatments and recently with targeted therapies and immunotherapies. However, treatment failure occurs due to acquired or emerging tumor resistance. We developed a monoclonal antibody against the proform of neurotensin (LF-NTS mAb) that alters the homeostasis of tumors overexpressing NTSR1. Neurotensin is frequently overexpressed along with its high affinity receptor (NTSR1) in tumors from epithelial origins. This ligand/receptor complex contributes to the progression of many tumor types by activation of the cellular effects involved in tumor progression (proliferation, survival, migration, and invasion). We demonstrate that LF-NTS mAb operates on the plasticity of tumor cells overexpressing NTSR1 and lowers their aggressiveness. The mAb enables the restoration of platinum-based therapies responsiveness, while also decreasing metastatic processes. Efficacy dosage with long-term treatment showed no obvious adverse events, while demonstrating improvement in the performance status. Our data suggests that LF-NTS mAb is an ideal candidate to be safely added to the conventional standard of care in order to improve its efficacy.


Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Anticuerpos Monoclonales/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/farmacología , Resistencia a Antineoplásicos , Neurotensina/antagonistas & inhibidores , Receptores de Neurotensina/antagonistas & inhibidores , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Animales , Antineoplásicos/farmacología , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Neurotensina/inmunología , Neurotensina/metabolismo , Pronóstico , Receptores de Neurotensina/inmunología , Receptores de Neurotensina/metabolismo , Estudios Retrospectivos , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
9.
FEBS J ; 285(12): 2161-2181, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29582565

RESUMEN

Nuclear factor κB (NF-κB) transcription factors are the central hubs of signaling pathways connecting proinflammatory signals to cell survival, proliferation and cytokine production. In cancers, NF-κB signaling influences many aspects of tumor development, from initiation to metastasis. These functions are mediated by tumor-induced plasticity that allows tumor cells to adapt and survive in changing conditions within the tumor microenvironment. Tumor cell plasticity is shaped by the inflammatory microenvironment in tumors. This review focuses on inhibitor of NF-κB kinases, the direct upstream elements of NF-κB regulation, specifically on their conventional and non-conventional functions in animal models of tumorigenesis from the recent literature.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Quinasa I-kappa B/genética , FN-kappa B/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Microambiente Tumoral/genética , Animales , Carcinogénesis , Transición Epitelial-Mesenquimal/genética , Redes Reguladoras de Genes , Humanos , Quinasa I-kappa B/metabolismo , FN-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Especificidad de Órganos , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Transducción de Señal
10.
J Mol Med (Berl) ; 95(2): 133-142, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-28013389

RESUMEN

Epithelial-to-Mesenchymal Transition (EMT) is a complex process that supports the migratory capacity of epithelial tumor cells and is thought to play a crucial role in promoting cancer metastasis. Despite the wealth of experimental data, the exact role of EMT in cancer patients remains more controversial. Over the past 10 years, sensitive technologies that allow the detection and molecular characterization of circulating tumor cells (CTCs) in the peripheral blood of tumor patients have been developed. These analyses help to shed new light into the importance of EMT for human tumor cell dissemination. CTCs with mesenchymal features can be attributed in some clinical studies (in particularly on breast cancer) to higher disease stages, presence of metastases, and even to therapy response and worse outcome. However, the published studies addressing the impact of mesenchymal-like CTCs show heterogeneity with regard to assay specificity, size of cancer and control groups, and endpoint parameters. In the present review, we present the key features of the biology of CTCs in relation to epithelial-to-mesenchy-mal plasticity, describe the current technologies for enrichment and detection of CTCs with high epithelial-mesenchymal plasticity, and discuss the clinical studies that have assessed the relevance of mesenchymal CTCs in carcinoma patients.


Asunto(s)
Neoplasias de la Mama/patología , Carcinoma/patología , Plasticidad de la Célula , Transición Epitelial-Mesenquimal , Células Neoplásicas Circulantes/patología , Biomarcadores de Tumor/sangre , Separación Celular/métodos , Progresión de la Enfermedad , Femenino , Humanos
11.
Front Oncol ; 7: 309, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29376024
12.
Trends Cancer ; 2(8): 429-442, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27868104

RESUMEN

To survive inhospitable environments, tumor cells are forced to remodel their signaling pathways by altering transcription, translation, and post-translational modifications. This adaptation is regulated in a spatial and temporal manner and gives rise to individual tumor cells with distinct gene expression and metabolic signatures. Such phenotypic heterogeneity is the result of tumor cell plasticity, which-together with the genetic background of the tumor-determines whether cells resist environmental stress, enter dormancy, or metastasize. This review summarizes our understanding of how tumor cells exploit the cellular stress response to balance proliferation, differentiation, and survival signals, and to remodel local and distant environments. We focus in particular on tumor metastasis, which is the greatest impediment to clinical management of cancers today.


Asunto(s)
Plasticidad de la Célula/fisiología , Metástasis de la Neoplasia , Neoplasias/fisiopatología , Animales , Humanos , Metástasis de la Neoplasia/patología , Neoplasias/metabolismo , Neoplasias/patología , Estrés Fisiológico , Respuesta de Proteína Desplegada
13.
Pharmacol Ther ; 159: 83-92, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26808163

RESUMEN

In 1999, the American Journal of Pathology published an article, entitled "Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry" by Maniotis and colleagues, which ignited a spirited debate for several years and earned the journal's distinction of a "citation classic" (Maniotis et al., 1999). Tumor cell vasculogenic mimicry (VM), also known as vascular mimicry, describes the plasticity of aggressive cancer cells forming de novo vascular networks and is associated with the malignant phenotype and poor clinical outcome. The tumor cells capable of VM share the commonality of a stem cell-like, transendothelial phenotype, which may be induced by hypoxia. Since its introduction as a novel paradigm for melanoma tumor perfusion, many studies have contributed new findings illuminating the underlying molecular pathways supporting VM in a variety of tumors, including carcinomas, sarcomas, glioblastomas, astrocytomas, and melanomas. Of special significance is the lack of effectiveness of angiogenesis inhibitors on tumor cell VM, suggesting a selective resistance by this phenotype to conventional therapy. Facilitating the functional plasticity of tumor cell VM are key proteins associated with vascular, stem cell, extracellular matrix, and hypoxia-related signaling pathways--each deserving serious consideration as potential therapeutic targets and diagnostic indicators of the aggressive, metastatic phenotype. This review highlights seminal findings pertinent to VM, including the effects of a novel, small molecular compound, CVM-1118, currently under clinical development to target VM, and illuminates important molecular pathways involved in the suppression of this plastic, aggressive phenotype, using melanoma as a model.


Asunto(s)
Melanoma/patología , Animales , Plasticidad de la Célula , Humanos , Neovascularización Patológica , Transducción de Señal
14.
Trends Cancer ; 2(8): 429-442, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28741495

RESUMEN

To survive inhospitable environments, tumor cells are forced to remodel their signaling pathways by altering transcription, translation, and post-translational modifications. This adaptation is regulated in a spatial and temporal manner and gives rise to individual tumor cells with distinct gene expression and metabolic signatures. Such phenotypic heterogeneity is the result of tumor cell plasticity, which-together with the genetic background of the tumor-determines whether cells resist environmental stress, enter dormancy, or metastasize. This review summarizes our understanding of how tumor cells exploit the cellular stress response to balance proliferation, differentiation, and survival signals, as well as to remodel local and distant environments. We focus in particular on tumor metastasis, which is the greatest impediment to clinical management of cancers today.

15.
Melanoma Manag ; 2(2): 179-188, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26594315

RESUMEN

Tumors are incredibly diverse and contain many different subpopulations of cells. The cancer stem cell (CSC) subpopulation is responsible for many aspects of tumorigenesis and has been shown to play an important role in melanoma development, progression, drug resistance and metastasis. However, it is becoming clear that tumor cell populations are dynamic and can be influenced by many factors, such as signals from the tumor microenvironment and somatic evolution. This review will present the current understanding of CSCs and the challenges of identifying and characterizing this dynamic cell population. The known characteristics and functions of melanoma stem cells, and the potential for therapeutic targeting of these cells in melanoma, will be discussed.

16.
EMBO Mol Med ; 7(1): 1-11, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25398926

RESUMEN

Cancer metastasis is the main cause of cancer-related death, and dissemination of tumor cells through the blood circulation is an important intermediate step that also exemplifies the switch from localized to systemic disease. Early detection and characterization of circulating tumor cells (CTCs) is therefore important as a general strategy to monitor and prevent the development of overt metastatic disease. Furthermore, sequential analysis of CTCs can provide clinically relevant information on the effectiveness and progression of systemic therapies (e.g., chemo-, hormonal, or targeted therapies with antibodies or small inhibitors). Although many advances have been made regarding the detection and molecular characterization of CTCs, several challenges still exist that limit the current use of this important diagnostic approach. In this review, we discuss the biology of tumor cell dissemination, technical advances, as well as the challenges and potential clinical implications of CTC detection and characterization.


Asunto(s)
Neoplasias/diagnóstico , Células Neoplásicas Circulantes/patología , Animales , Movimiento Celular , Humanos , Metástasis de la Neoplasia , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/fisiopatología
17.
Front Oncol ; 4: 370, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25566507

RESUMEN

Androgens regulate biological pathways to promote proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen receptor (AR) targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression. Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or AR function. Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens (androgen deprivation) has been shown to activate both epithelial-to-mesenchymal transition (EMT) and neuroendocrine transdifferentiation (NEtD) programs. EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy) in multiple human cancer types. NEtD in prostate cancer is associated with resistance to therapy, visceral metastasis, and aggressive disease. Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK, and Aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications. Understanding tumor cell plasticity will be important in further defining the rational use of androgen-targeted therapies clinically and provides an opportunity for intervention to prolong survival of men with metastatic prostate cancer.

18.
Front Oncol ; 2: 82, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22891161

RESUMEN

We describe a novel form of tumor cell plasticity characterized by reversible adaptive plasticity in murine and human neuroblastoma. Two cellular phenotypes were defined by their ability to exhibit adhered, anchorage dependent (AD) or sphere forming, anchorage independent (AI) growth. The tumor cells could transition back and forth between the two phenotypes and the transition was dependent on the culture conditions. Both cell phenotypes exhibited stem-like features such as expression of nestin, self-renewal capacity, and mesenchymal differentiation potential. The AI tumorspheres were found to be more resistant to chemotherapy and proliferated slower in vitro compared to the AD cells. Identification of specific molecular markers like MAP2, ß-catenin, and PDGFRß enabled us to characterize and observe both phenotypes in established mouse tumors. Irrespective of the phenotype originally implanted in mice, tumors grown in vivo show phenotypic heterogeneity in molecular marker signatures and are indistinguishable in growth or histologic appearance. Similar molecular marker heterogeneity was demonstrated in primary human tumor specimens. Chemotherapy or growth factor receptor inhibition slowed tumor growth in mice and promoted initial loss of AD or AI heterogeneity, respectively. Simultaneous targeting of both phenotypes led to further tumor growth delay with emergence of new unique phenotypes. Our results demonstrate that neuroblastoma cells are plastic, dynamic, and may optimize their ability to survive by changing their phenotype. Phenotypic switching appears to be an adaptive mechanism to unfavorable selection pressure and could explain the phenotypic and functional heterogeneity of neuroblastoma.

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