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PubMed2005

The role of Wnt signaling in cancer and stem cells.

The Wingless-Int (Wnt) signaling pathway has been widely investigated in recent years. Initially, its role regulating cell proliferation and survival during embryogenesis aroused the interest of researchers. Later, the focus was placed on the link between aberrant Wnt pathway activation and human cancer. The improper function of Wnt signaling components can lead to aberrant cell proliferation and cancer. Mutations in the adenomatous polyposis coli and beta-catenin genes first implicated Wnt signaling in carcinogenesis. Over time, a wealth of evidence has indicated that amplification or inhibition of other components might also play a role in human cancers. In addition, Wnt signaling pathways also play a crucial role in normal tissue regeneration and stem cell self-renewal, raising the possibility of controlling immature tumor stem cells.

Animals↗
PubMed2005

miRNAs, cancer, and stem cell division.

MicroRNAs (miRNAs) are known to regulate the expression of genes involved in the control of development, proliferation, apoptosis, and the stress response. As a cluster of recent Nature papers now show, altered expression of specific miRNA genes contributes to the initiation and progression of cancer.

Animals↗
PubMed2006

Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells.

The epithelial components of the mammary gland are thought to arise from stem cells with a capacity for self-renewal and multilineage differentiation. Furthermore, these cells and/or their immediate progeny may be targets for transformation. We have used both in vitro cultivation and a xenograft mouse model to examine the role of hedgehog signaling and Bmi-1 in regulating self-renewal of normal and malignant human mammary stem cells. We show that hedgehog signaling components PTCH1, Gli1, and Gli2 are highly expressed in normal human mammary stem/progenitor cells cultured as mammospheres and that these genes are down-regulated when cells are induced to differentiate. Activation of hedgehog signaling increases mammosphere-initiating cell number and mammosphere size, whereas inhibition of the pathway results in a reduction of these effects. These effects are mediated by the polycomb gene Bmi-1. Overexpression of Gli2 in mammosphere-initiating cells results in the production of ductal hyperplasia, and modulation of Bmi-1 expression in mammosphere-initiating cells alters mammary development in a humanized nonobese diabetic-severe combined immunodeficient mouse model. Furthermore, we show that the hedgehog signaling pathway is activated in human breast "cancer stem cells" characterized as CD44+CD24-/lowLin-. These studies support a cancer stem cell model in which the hedgehog pathway and Bmi-1 play important roles in regulating self-renewal of normal and tumorigenic human mammary stem cells.

Animals↗
PubMed2004

Comprehensive genomics linking between neural development and cancer: neuroblastoma as a model.

Cancer cells are derived from their precursor cells, which normally develop to the matured cells to form individual organs. Neuroblastoma, one of the most common pediatric solid tumors, originates from possible cancer stem cells derived from the neural crest. During the development, neural crest cells segregate into several lineages such as sensory, enteric and sympathetic neurons. However, the genetic events to cause neuroblastoma occur only in the sympathetic precursor cells or cancer stem cells. Furthermore, spontaneous regression of a subset of neuroblastoma found in patients under one year of age mimics a developmentally programmed neuronal cell death that occurs in normal sympathetic neurons during the perinatal period. Thus, the genetic events to cause neuroblastoma may be programmed to occur in a lineage-specific as well as developmentally regulated manner. In this review, we discuss about the molecular link between neural development and the genesis of neuroblastoma based on our comprehensive genomics approach.

Animals↗
PubMed2006

Multiple tumor types may originate from bone marrow-derived cells.

It was believed that tumors originated from the transformation of their tissue-specific stem cells. However, bone marrow-derived cells (BMDCs), which possess an unexpected degree of plasticity and often reside in other tissues, might also represent a potential source of malignancy. To study whether BMDCs play a role in the source of other tumors, BMDCs from mice were treated with 3-methycholanthrene until malignant transformation was achieved. Here we show that transformed BMDCs could form many tumor types, including epithelial tumors, neural tumors, muscular tumors, tumors of fibroblasts, blood vessel endothelial tumors, and tumors of poor differentiation in vivo. Moreover, a single transformed BMDC has the ability to self-renew, differentiate spontaneously into various types of tumor cells in vitro, express markers associated with multipotency, and form teratoma in vivo. These data suggest that multipotent cancer stem cells seemed to originate from transformed BMDCs. Conclusively, these findings reveal that BMDCs might be a source of many tumor types, even teratoma. In addition, multipotent cancer stem cells might originate from malignant transformed BMDCs.

Animals↗
PubMed2004

Granulocyte-macrophage-colony-stimulating factor and other cytokines: as adjuncts to cancer immunotherapy, stem cell transplantation, and vaccines.

A new role for myeloid-acting cytokines in regulating immune responses has been proposed based upon their activity on dendritic cell (DC) maturation and activation. Subsets of DCs may augment or inhibit cellular immune responses. Enhanced DC1 activity has been associated with enhanced cytotoxic immune responses. Granulocyte-macrophage-colony-stimulating factor (GM-CSF) and granulocyte-colony- stimulating factor (G-CSF) differ by their effects on enhancing the numbers or activity of DC1 or DC2 subsets of DCs, respectively. The increase in DC1 content and activity following local and systemic GM-CSF administration support a role for GM-CSF as an immune stimulant and vaccine adjuvant in cancer patients. The clinical activity of GM-CSF in anti-tumor immune responses has been documented in its use in tumor cell and DC vaccines, but a significant anti-tumor effect of parenterally administered GM-CSF in a randomized clinical study has yet to be consistently demonstrated. The successful use of myeloid acting cytokines to enhance anti-tumor responses will likely require targeting these drugs or activating DCs directly into the tumor microenvironment.

Cancer Vaccines↗
PubMed2026

Third-generation whole-genome sequencing reveals the role of CNTNAP2 as a tumor suppressor gene in high-risk neuroblastomas.

BACKGROUND: Neuroblastoma is a common and aggressive pediatric sympathetic nervous system tumor. Genomic structural variants (SVs) contribute substantially to neuroblastoma, yet remain under-characterized in high-risk neuroblastomas. We aimed to elucidate neuroblastoma pathogenesis using third-generation whole-genome sequence high-risk cases to identify driver aberrations and explore potential therapeutic strategies. METHODS: We analyzed third-generation whole-genome sequencing data of 20 high-risk neuroblastoma samples and combined the findings with those obtained from the analysis of clinical samples, in vitro models, and public datasets. RESULTS: The contactin-associated protein-like 2 (CNTNAP2) gene was observed to be frequently aberrated because of structural variants in high-risk neuroblastoma samples. CNTNAP2 expression was significantly correlated with favorable histology and could be used to predict prognosis using clinical samples and neuroblastoma datasets. Overexpression and knockdown experiments and transcriptomic analysis revealed that CNTNAP2 was primarily involved in neuronal differentiation and axon guidance pathways; moreover, CNTNAP2 was required for neuroblastoma differentiation and affected cancer stemness. Immunoprecipitation and mass spectrometry revealed that CNTNAP2 interacted with cytoskeletal proteins like drebrin 1 (DBN1) and myosin-heavy chain 9 (MYH9). CNTNAP2 dynamically reorganises actin and microtubules for DBN1-mediated neuronal differentiation. CNTNAP2 also reduces CTNNB1 transcription and β-catenin pathway activation by inhibiting MYH9 nuclear translocation. CNTNAP2 overexpression in neuroblastoma cell lines resulted in cell cycle arrest, decreased cell proliferation and metastasis. CONCLUSIONS: The recurrent loss of CNTNAP2 in neuroblastoma contributes to an aggressive phenotype by impairing neuronal differentiation and increasing cancer stemness. These findings may serve as a foundation for developing therapeutic strategies to overcome barriers to differentiation.

Humans↗
PubMed1997

Telomerase: a promising marker of biological immortality of germ, stem, and cancer cells. A review.

This review will describe the current state of knowledge of telomerase as it relates to human malignancies, focusing primarily on published measurements of this enzymes activity in benign and malignant neoplasms and their normal tissue counterparts. Key questions concerning the potential clinical utility of assaying for telomerase activity will be addressed and the implications of recent findings discussed.

Biomarkers↗
PubMed1976

Should curative surgery be attempted in patients with cancer of the main stem bronchus?

Among tumors of the lung, main stem bronchial cancer offers a particularly unfavorable prognosis, probably because of its rapid extension to the segmental bronchi, trachea, and extrapulmonary structures. However, analysis of data gathered by the End Results Group indicates that survival among those patients with main stem bronchial cancer whose tumor was resected was virtually the same as that of patients with resectable lung cancer of other sites. From these data it is impossible to assess what role, if any, the resection itself played, and a randomized trial would be necessary to determine whether resection improves the probability of patient survival. On the other hand, it is not now advisable to deny resection to patients with operable main stem bronchial tumors (except oat cell tumors) on the basis of the available nonexperimental evidence alone.

Adenocarcinoma↗
PubMed2006

Update on management of infections in cancer and stem cell transplant patients.

Infections are the most important causes of morbidity and mortality in patients with aggressive malignancies and those undergoing allogeneic stem cell transplantation. The introduction of new therapeutic approaches including the use of nucleoside analogs and of monoclonal antibodies to CD20 and CD52 and the increased use of matched unrelated stem cell donors has resulted in new challenges with regard to systemic viral and fungal infections. In patients with bacterial infections, emergence of resistance to formerly widely used antibiotics as well as a shift of causative pathogens towards a predominance of multi-resistant gram-positive cocci has to be taken into consideration. In high-risk neutropenic patients with fever of unknown origin, prompt empiric monotherapy with piperacillin-tazobactam, cefepime, ceftazidime, or a carbapenem is mandatory. In patients with lung infiltrates, early preemptive intervention with an antifungal active against aspergilli is recommended, whereas in patients with catheter-related, skin or soft tissue infections, preemptive addition of a glycopeptide shows a high response rate. The prompt preemptive use of ganciclovir or foscarnet in allogeneic stem cell transplant recipients can reliably be guided by serial monitoring of cytomegalovirus antigen and polymerase chain reaction monitoring.

Algorithms↗
PubMed2025

Notch pathway defines an aggressive and immune-suppressive phenotype associated with checkpoint inhibitor resistance in pan-gastrointestinal adenocarcinomas.

The Notch pathway regulates the homeostasis and tumorigenesis of gastrointestinal epithelium. Given its roles in cancer stem cell capacity and cancer immunity, we hypothesized that Notch activation can predict poor prognosis and resistance to immune checkpoint inhibitors (ICIs) in gastrointestinal adenocarcinoma (GIAC). The mRNA expression and genomic alterations of Notch pathway were characterized in esophagus (ESAD), stomach (STAD), colon (COAD), or rectum (READ) adenocarcinomas from The Cancer Genome Atlas (TCGA) dataset. The prognostic model (mRNA-score) was constructed using the TCGA dataset (the training set) and was validated in 3 independent sets (GSE19417 [ESAD], GSE84437 [STAD], and GSE40967 [COAD]). The associations of the mRNA-score with drug sensitivity, immune cell infiltration, and immunotherapy efficacy were, respectively, analyzed using the Genomics of Drug Sensitivity in Cancer (GDSC) database, the TCGA dataset, and multiple clinical cohorts including GSE165252, PRJEB25780, IMvigor210, and CheckMate-009/010/025. Notch pathway genes exhibited conserved genomic/transcriptomic features across four GIAC subtypes. Three pan-GIAC clusters were determined by unsupervised clustering, and the cluster with higher expression of the Notch pathway genes had shorter overall survival (OS), immunosuppressive microenvironment, and higher scores of the signatures concerning angiogenesis, cell cycle, PI3K-AKT-mTOR, TGF-&#x3b2;, glycolysis, etc. A prognostic algorithm (mRNA-score) was constructed, which was correlated with poor OS in the training set (TCGA, P&#x2009;<&#x2009;0.001) and three validation sets (GSE19417, P&#x2009;=&#x2009;0.025; GSE84437, P&#x2009;=&#x2009;0.001, GSE40967, P&#x2009;=&#x2009;0.007). A high mRNA-score was linked with more "resting"/ "anti-inflammatory" rather than "activated"/ "pro-inflammatory" tumor-infiltrating immune cells and ICI resistance in GIACs (GSE165252, P&#x2009;=&#x2009;0.047; PRJEB25780, P&#x2009;=&#x2009;0.047) and other solid tumors such as urothelial carcinoma and clear cell renal cell carcinoma. Our findings demonstrate the utility of the Notch pathway in predicting prognosis and ICI resistance. Further studies are warranted to explore the efficacy of Notch inhibitors as immunotherapeutic adjuvants to overcome ICI resistance.

Humans↗
PubMed2004

Fetal human neural progenitors can be the target for tumor transformation.

The hypothesis that stem cells may seed cancer has emerged from the cancer stem cells concept. However, the experimental systems necessary to provide more direct evidence to support the hypothesis have been lacking. We have used fetal neural progenitor cells (hNPC) transduced with the telomerase hTERT gene to investigate the neoplastic potential of hNPCs. The hTERT-transduced line, hNPCs-G3 lost normal diploid karyotype, showed loss of contact inhibition, anchorage independence, and formed neuroblastoma-like tumours in all of 10 mice. These data suggest that hNPCs have the potential for neoplastic transformation. These data have implications for providing a novel tool to test the feasibility of new anticancer treatment strategies and raise the possibility of a risk for the use of hNPCs in cell transplantation.

Animals↗
PubMed1997

Cancers after stem cell transplantation in children: a cost of cure?

There have been many advances in the field of stem cell transplantation over the past few years. Newer preparative regimens and better supportive care measures are allowing more children to survive and lead long lives after stem cell transplantation. We are only now beginning to see what the cost of this success may be in regard to the long-term effects of this treatment. Most long-term follow up studies have been reported in the adult literature and there is very little information on the pediatric population. Children who undergo stem cell transplantation will have a long period of observation in which new and different complications can occur. This article looks at the current literature on secondary malignancies and lymphoproliferative disorders after stem cell transplantation in children, with particular focus on risk factors, possible strategies for prevention, and treatment.

Child↗
PubMed2005

Acute myeloid leukemia stem cells.

A fundamental problem in cancer research is identification of the cells within a tumor that sustain the growth of the neoplastic clone. The concept that only a subpopulation of rare cancer stem cells (CSCs) is responsible for maintenance of the neoplasm emerged nearly 50 years ago; however, conclusive proof for the existence of a CSC was obtained only relatively recently. The evidence for the existence of CSCs was first derived from the study of human acute myeloid leukemia (AML), largely because of the availability of quantitative stem cell assays for the leukemic stem cell (LSC). These studies showed that only rare cells within the leukemic clone had the capacity to initiate AML growth after transplant into NOD/SCID mice, establishing the hierarchical organization of AML. Recent clonal-tracking studies showed that the LSC compartment is composed of different classes of LSCs, which can be distinguished on the basis of self-renewal potential. These findings have important implications for our understanding of the leukemogenic process as well as the design of more effective therapies to eliminate AML based on eradication of the LSCs. These studies are briefly reviewed here.

Animals↗
PubMed2006

Lung cancer and lung stem cells: strange bedfellows?

Lung cancer is a significant disease with survival rates remaining poor despite numerous therapeutic advances during the last 30 years. Understanding lung cancer pathogenesis through murine modeling may improve future human therapies, and new data indicate that mutations within different endogenous stem cells situated throughout airways can drive cancer formation. Airway stem cells maintain prototumorigenic characteristics, including high proliferative capacity, multipotent differentiation, and a long lifespan relative to other cells. These cells localize to proximal airway submucosal glands/intercartilagenous rings, neuroepithelial bodies, and terminal bronchioles/bronchoalveolar duct junctions. Recent studies suggest that endogenous stem cell signaling and differentiation pathways are maintained within distinct cancer types, and that destabilization of this signaling machinery may initiate region-specific lung cancers. A better understanding of this relationship among stem cell regulation, cellular mutation, and lung cancer oncogenesis is critical for developing the next wave of lung cancer therapies.

Animals↗
PubMed2004

[Prostate stem cell antigen and related cancers].

Prostate stem cell antigen (PSCA) is a cell surface antigen expressed in normal prostate and overexpressed in cancers associated with prostate, bladder and pancreas. The sensitivity of PSCA labeling is higher than PSA in prostate cancer. PSCA can be used in the preparation of protein vaccine and nucleic acid vaccine. Further studies are required to confirm its safety and efficacy as a diagnostic means.

Antigens, Neoplasm↗
PubMed2006

Human neuroblastoma stem cells.

Human neuroblastoma is an embryonic cancer of the neural crest. Cellular heterogeneity is a characteristic feature of both tumors and derived cell lines. Recent studies have revealed that both cell lines and tumors contain cancer stem cells. In culture, these cells are self-renewing, multipotent, and highly malignant; in tumors their frequency correlates with a worse prognosis. Their identification and characterization should now permit a targeted approach to more effective treatment of this often fatal childhood cancer.

Humans↗