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Experimental IgE-mediated food allergy depends on intestinal anaphylaxis driven by interleukin-9 (IL-9). However, the primary cellular source of IL-9 and the mechanisms underlying the susceptibility to food-induced intestinal anaphylaxis remain unclear. Herein, we have reported the identification of multifunctional IL-9-producing mucosal mast cells (MMC9s) that can secrete prodigious amounts of IL-9 and IL-13 in response to IL-33, and mast cell protease-1 (MCPt-1) in response to antigen and IgE complex crosslinking, respectively. Repeated intragastric antigen challenge induced MMC9 development that required T cells, IL-4, and STAT6 transcription factor, but not IL-9 signals. Mice ablated of MMC9 induction failed to develop intestinal mastocytosis, which resulted in decreased food allergy symptoms that could be restored by adoptively transferred MMC9s. Finally, atopic patients that developed food allergy displayed increased intestinal expression of Il9- and MC-specific transcripts. Thus, the induction of MMC9s is a pivotal step to acquire the susceptibility to IgE-mediated food allergy.
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Hipersensibilidade Alimentar/imunologia , Imunoglobulina E/imunologia , Interleucina-9/metabolismo , Mucosa Intestinal/imunologia , Mastócitos/imunologia , Mastocitose/imunologia , Transferência Adotiva , Anafilaxia/etiologia , Anafilaxia/imunologia , Animais , Sequência de Bases , Células da Medula Óssea/citologia , Linhagem da Célula , Quimases/biossíntese , Quimases/genética , Diarreia/etiologia , Diarreia/imunologia , Suscetibilidade a Doenças , Duodeno/imunologia , Duodeno/patologia , Hipersensibilidade Alimentar/etiologia , Hipersensibilidade Alimentar/patologia , Humanos , Hipersensibilidade Imediata/complicações , Interleucina-9/biossíntese , Interleucina-9/genética , Interleucinas/biossíntese , Interleucinas/metabolismo , Interleucinas/fisiologia , Mastócitos/metabolismo , Mastócitos/transplante , Mastocitose/patologia , Camundongos , Camundongos Endogâmicos , Dados de Sequência Molecular , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Ovalbumina/toxicidade , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Fator de Transcrição STAT6/fisiologia , Especificidade da Espécie , Linfócitos T/imunologiaRESUMO
Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a severe manifestation of CTD that leads to significant morbidity and mortality. Clinically, ILD can occur in diverse CTDs. Pathologically, CTD-ILD is characterized by various histologic patterns, such as nonspecific interstitial pneumonia, organizing pneumonia, and usual interstitial pneumonia. Abnormal immune system responses have traditionally been instrumental in its pathophysiology, and various changes in immune cells have been described, especially in macrophages. This article first briefly overviews the epidemiology, clinical characteristics, impacts, and histopathologic changes associated with CTD-ILD. Next, it summarizes the roles of various signaling pathways in macrophages or products of macrophages in ILD, helped by insights gained from animal models. In the following sections, this review returns to studies of macrophages in CTD-ILD in humans for an overall picture of the current understanding. Finally, we direct attention to potential therapies targeting macrophages in CTD-ILD in investigation or in clinical trials, as well as the future directions regarding macrophages in the context of CTD-ILD. Although the field of macrophages in CTD-ILD is still in its infancy, several lines of evidence suggest the potential of this area.
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Doenças do Tecido Conjuntivo , Pneumonias Intersticiais Idiopáticas , Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Animais , Humanos , Doenças Pulmonares Intersticiais/terapia , Doenças Pulmonares Intersticiais/complicações , Doenças do Tecido Conjuntivo/complicações , Fibrose Pulmonar Idiopática/complicações , MacrófagosRESUMO
The outbreak of COVID-19 has brought many challenges to youth development. During this specific period, adolescents have suffered from numerous behavioral problems, which will lead to more maladaptive consequences. It is necessary to explore several protective factors to prevent or reduce the occurrence of problem behaviors in adolescence. The current study combined school resources and self-control to evaluate the multiple protective effects on adolescents' problematic behaviors in a two-wave longitudinal study. A sample of 789 Chinese adolescents (Mage = 14.00 years, SD = 2.05, 418 boys) were recruited via the random cluster sampling method to participate in the survey. The results confirmed the assumptions about the multiple protective effects of school resources and self-control on adolescents' problem behaviors. Specifically, school resources could negatively predict IGD and victimization, and self-control mediated these associations. Moreover, one problematic behavior could also mediate the associations between self-control and another problematic behavior. This is the first study to focus on the multiple protective effects of positive factors on adolescents' problem behaviors during the post-pandemic period, which has made several contributions to the literature and practice.
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Understanding the host response to oncolytic viruses is important to maximize their antitumor efficacy. Despite robust cytotoxicity and high virus production of an oncolytic herpes simplex virus (oHSV) in cultured human sarcoma cells, intratumoral (ITu) virus injection resulted in only mild antitumor effects in some xenograft models, prompting us to characterize the host inflammatory response. Virotherapy induced an acute neutrophilic infiltrate, a relative decrease of ITu macrophages, and a myeloid cell-dependent upregulation of host-derived vascular endothelial growth factor (VEGF). Anti-VEGF antibodies, bevacizumab and r84, the latter of which binds VEGF and selectively inhibits binding to VEGF receptor-2 (VEGFR2) but not VEGFR1, enhanced the antitumor effects of virotherapy, in part due to decreased angiogenesis but not increased virus production. Neither antibody affected neutrophilic infiltration but both partially mitigated virus-induced depletion of macrophages. Enhancement of virotherapy-mediated antitumor effects by anti-VEGF antibodies could largely be recapitulated by systemic depletion of CD11b(+) cells. These data suggest the combined effect of oHSV virotherapy and anti-VEGF antibodies is in part due to modulation of a host inflammatory reaction to virus. Our data provide strong preclinical support for combined oHSV and anti-VEGF antibody therapy and suggest that understanding and counteracting the innate host response may help enable the full antitumor potential of oncolytic virotherapy.
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Vetores Genéticos/imunologia , Células Mieloides/imunologia , Neoplasias/imunologia , Vírus Oncolíticos/imunologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Bevacizumab , Antígeno CD11b/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Vetores Genéticos/administração & dosagem , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Células Mieloides/metabolismo , Neoplasias/metabolismo , Neoplasias/terapia , Neovascularização Patológica/terapia , Terapia Viral Oncolítica , Sarcoma/imunologia , Sarcoma/metabolismo , Sarcoma/terapia , Simplexvirus/imunologia , Células Estromais/metabolismo , Células Estromais/virologia , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/imunologia , Replicação Viral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Clinical manifestations of phlebosclerotic colitis (PC) exhibit significant variability, necessitating diverse treatment strategies depending on disease severity. However, there is limited research exploring the relationship between imaging findings and disease severity. Hence, this retrospective study aimed to analyze the correlation between computed tomography (CT) findings, colonoscopic features, and disease severity. This study compared the abdominal CT characteristics, colonoscopy findings, and treatment modalities of 45 PC patients. CT images were assessed for the severity of mesenteric venous calcification, maximum colonic wall thickness, number of involved colonic segments, and presence of pericolic inflammation. Colonoscopic images were assessed for dark purple discoloration mucosa, erosive and ulcerative lesions, mucosal edema, luminal narrowing, and the number of involved colonic segments. In addition, patients were categorized into three groups: the observation (n = 15), medical treatment (n = 19), and operation (n = 11) groups. In CT images, a significant difference in pericolic inflammation (p = 0.039) was observed among groups. Further, significant differences in dark purple discoloration mucosa (p = 0.033), erosive or ulcerative lesions (p < 0.001), mucosal edema (p < 0.001), luminal narrowing (p = 0.012), and the number of involved colonic segments (p = 0.001) were observed in colonoscopy. Moreover, we found positive correlations between CT and colonoscopy features. In conclusion, CT manifestations and colonoscopy findings exhibited correlation with disease severity in PC. When limited to one diagnostic tool, observations from that tool can infer potential manifestations of the alternative tool.
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Colite Ulcerativa , Colite , Humanos , Estudos Retrospectivos , Relevância Clínica , Colonoscopia/métodos , Colite/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Inflamação , EdemaRESUMO
Different human leukocyte antigen (HLA) genotypes have been known to be associated with the risk of development of Sjögren's syndrome in different populations, but this association has never been reported in Taiwan. We enrolled 1044 subjects (673 patients, 371 controls) and tested their HLA-DR genotypes. We found an increased risk of Sjögren's syndrome in patients carrying HLA-DR8. DR1 and DR14 were associated with increased risk of eye involvement (uveitis, scleritis or optic neuritis), while DR15 was associated with increased risk of interstitial lung disease. DR8 was associated with increased risk of formation of multiple antibodies: anti-Ro, rheumatoid factor and antinuclear antibodies (ANA) reaching titer 1:80 or above. DR9 was associated with decreased risk of formation of anti-La antibodies and increased risk of formation of antithyroglobulin antibodies. DR10 was associated with risk of formation of anticyclic citrullinated peptide (anti-CCP) antibodies, and DR11 was associated with increased risk of formation of anti-La antibodies. Oral ulcer was found to be negatively associated with anti-Ro antibodies and with anti-ENA antibodies. Skin lesions were associated with ANA antibody titer elevation to 1:80 or above. Malignancies of any kind were associated with the presence of cryoglobulin. Females were more likely to be diagnosed at a younger age than males. There was no statistically significant relationship between HLA-DR genotype and age at disease diagnosis. In patients with Sjögren's syndrome in Taiwan, the presence of HLA-DR8 appeared to be a risk factor. In addition, we found several associations between HLA-DR genotype, clinical presentation, and autoantibody status among them.
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[This corrects the article DOI: 10.3389/fimmu.2024.1384623.].
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Modelos Animais de Doenças , Terapia Viral Oncolítica , Animais , Terapia Viral Oncolítica/métodos , Camundongos , Imunoterapia/métodos , Humanos , Vírus Oncolíticos/imunologia , Vírus Oncolíticos/genética , Terapia CombinadaRESUMO
Introduction: Malignant peripheral nerve sheath tumors (MPNST) pose a significant therapeutic challenge due to high recurrence rates after surgical resection and a largely ineffective response to traditional chemotherapy. An alternative treatment strategy is oncolytic viroimmunotherapy, which can elicit a durable and systemic antitumor immune response and is Food and Drug Administration (FDA)-approved for the treatment of melanoma. Unfortunately, only a subset of patients responds completely, underscoring the need to address barriers hindering viroimmunotherapy effectiveness. Methods: Here we investigated the therapeutic utility of targeting key components of the MPNST immunosuppressive microenvironment to enhance viroimmunotherapy's antitumor efficacy in three murine models, one of which showed more immunogenic characteristics than the others. Results: Myelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model. However, tumor regressions or shrinkages were not observed. Depletion experiments confirmed that the enhanced survival benefit relied on a T cell response. Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment. Discussion: In summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation.
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Modelos Animais de Doenças , Terapia Viral Oncolítica , Microambiente Tumoral , Animais , Terapia Viral Oncolítica/métodos , Camundongos , Microambiente Tumoral/imunologia , Vírus Oncolíticos/imunologia , Vírus Oncolíticos/genética , Linhagem Celular Tumoral , Imunoterapia/métodos , Humanos , Terapia Combinada , Feminino , Camundongos Endogâmicos C57BL , Neoplasias de Bainha Neural/terapia , Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/genética , Aminopiridinas , PirróisRESUMO
We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular anti-viral response which increases viral transcript spread throughout the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing immunosuppressive macrophages and stimulating granzyme expression in infiltrating T and NK cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients.
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Our previous work identified one region upstream human UGT2B4 (UDP glucuronosyltransferase family 2 member B4) which is associated with breast cancer and under balancing selection. However, the distribution, functional variation and molecular mechanism underlying breast cancer and balancing selection remain unclear. In current study, the two haplotypes with deep divergence are described by analyzing 1000 genomes project data and observed to be with high frequencies in all human populations. Through population genetics analysis and genome annotation, the potential functional region is identified and verified by reporter gene assay. Further mutagenesis indicates that the functional mutations are rs66862535 and rs68096061. Both SNPs can alter the interaction efficiency of transcription factor POU2F1 (POU class 2 homeobox 1). Through chromosome conformation capture, it is identified that the enhancer containing these two SNPs can interact with UGT2B4 promoter. Expression quantitative trait loci analysis indicates that UGT2B4 expression is dependent on the genotype of this locus. The common haplotype in human is lost in four genomes of archaic hominins, which suggests that Neanderthal and Denisovan should present relatively lower UGT2B4 expression and further higher steroid hormone level. This study provides new insight into the contribution of ancient population structure to human phenotypes.
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Genética Populacional , Glucuronosiltransferase , Animais , Feminino , Humanos , Neoplasias da Mama/genética , Genoma Humano , Glucuronosiltransferase/genética , Hominidae/genética , Homem de Neandertal/genética , FenótipoRESUMO
BACKGROUND: Different human leukocyte antigen (HLA)-DR genotypes have been known to be associated with the risk of development of systemic lupus erythematosus (SLE) in different populations, although Lu et al. have reported previously that no correlation exists between the HLA-DR genotype and disease manifestation in SLE patients in Taiwan. We investigated the effects different HLA-DR genotypes had on SLE incidence in Taiwanese patients as to whether risk alleles were associated with different clinical manifestations, and the effects risk alleles had on the age of disease onset. METHODS: Two hundred thirty-four SLE patients and 346 healthy controls were enrolled. HLA-DR genotyping was performed with the HLA FluoGene DRDQ kit for each subject. Chi-square tests and t tests were performed for statistical analysis. RESULTS: HLA-DR2 was significantly more frequently found in SLE patients than in controls (odds ratio [OR] = 2.05, 95% CI, 1.44-2.92, p < 0.001). Notably, HLA-DR6 appeared to trend toward negative correlation with SLE, whereas HLA-DR8 appeared to trend toward positive correlation. HLA-DR2 patients had an earlier onset of disease as well as a higher prevalence of oral ulcer, avascular necrosis of bone, and renal involvement (lupus nephritis). CONCLUSION: HLA-DR2 was associated with SLE susceptibility in this Taiwanese population as well as lower age of disease onset and more severe clinical manifestations.
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Antígeno HLA-DR2 , Lúpus Eritematoso Sistêmico , Humanos , Antígeno HLA-DR2/genética , Taiwan , Predisposição Genética para Doença , Antígenos HLA-DR/genética , Lúpus Eritematoso Sistêmico/genética , GenótipoRESUMO
Lymphocyte-rich hepatocellular carcinoma (HCC) represents the rarest subtype among the various subgroups of HCC, and limited clinical data are available for this particular subtype. It is commonly observed as a solitary lesion and tends to present at an early stage. Histopathological examination typically reveals tumor cells infiltrated by a lymphocyte-rich background, leading to its designation as lymphoepithelioma-like HCC. Unlike other lymphoepithelioma-like tumors associated with the Epstein-Barr virus (EBV), lymphocyte-rich HCC is predominantly negative for EBV. This subtype is characterized by more favorable clinical outcomes and prognosis compared to conventional HCC. Here, we present a case of lymphocyte-rich hepatocellular carcinoma (HCC) characterized by the presence of bilateral hepatic tumors and concurrent multiple lymphadenopathy. Interestingly, contrary to previous literature, the examination for the Epstein-Barr virus (EBV) revealed a positive result in this particular case.
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BACKGROUND: Diabetic foot ulcers (DFUs) are common in patients with diabetes, especially those undergoing hemodialysis. In severe cases, these ulcers can cause damage to the lower extremities and lead to amputation. Traditional treatments such as flap transposition and transfemoral amputation are not always applicable in all cases. Therefore, there is a need for alternative treatment methods. CASE SUMMARY: This report describes a 62-year-old female patient who was admitted to the hospital with plantar and heel ulcers on her left foot. The patient had a history of renal failure and was undergoing regular hemodialysis. Digital subtraction angiography showed extensive stenosis and occlusion in the left superficial femoral artery, left peroneal artery and left posterior tibial artery. Following evaluation by a multidisciplinary team, the patient was diagnosed with type 2 DFUs (TEXAS 4D). Traditional treatments were deemed unsuitable, and the patient was treated with endovascular surgery in the affected area, in addition to supportive medical treatment, local debridement, and sequential repair using split-thickness skin and tissue-engineered skin grafts combined with negative pressure treatment. After four months, the wound had completely healed, and the patient was able to walk with a walking aid. CONCLUSION: This study demonstrates a new treatment method for DFUs was successful, using angioplasty, skin grafts, and negative pressure.
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Abundant evidence has demonstrated that cumulative family risk is associated with cyberbullying. However, few studies to date have investigated how cumulative family risk links to cyberbullying. To fill in these gaps, the present study examined the mediating role of school connectedness and cyber victimization in the relation between cumulative family risk and cyberbullying. A sample of 1,804 Chinese adolescents was recruited to complete measures of cumulative family risk, cyberbullying, school connectedness, cyber victimization, and demographic variables through convenience sampling. There were 813 boys and 991 girls, aged from 13 to 18, with an average age of 16 years (SD = 1.71). Correlational analyses and SPSS macro PROCESS (Model 6) were used for major data analysis. Results indicated that cumulative family risk was positively associated with cyberbullying, and this link could be mediated by school connectedness and cyber victimization. The present study identifies the potential underlying mechanism by which cumulative family risk is associated with adolescent cyberbullying, which has important implications for theory and prevention.
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Comportamento do Adolescente , Vítimas de Crime , Cyberbullying , Adolescente , China/epidemiologia , Feminino , Humanos , Masculino , Instituições AcadêmicasRESUMO
T cells redirected to cancer cells either via a chimeric antigen receptor (CAR-T) or a bispecific molecule have been breakthrough technologies; however, CAR-T cells require individualized manufacturing and bispecifics generally require continuous infusions. We created an off-the-shelf, single-dose solution for achieving prolonged systemic serum levels of protein immunotherapeutics via adeno-associated virus (AAV) gene transfer. We demonstrate proof of principle in a CD19+ lymphoma xenograft model using a single intravenous dose of AAV expressing a secreted version of blinatumomab, which could serve as a universal alternative for CD19 CAR-T cell therapy. In addition, we created an inducible version using an exon skipping strategy and achieved repeated, on-demand expression up to at least 36 weeks after AAV injection. Our system could be considered for short-term and/or repeated expression of other transgenes of interest for noncancer applications.
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Receptores de Antígenos Quiméricos , Antígenos CD19/genética , Terapia Genética , Humanos , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genéticaRESUMO
BACKGROUND: Oncolytic virotherapy (OV) is an immunotherapy that incorporates viral cancer cell lysis with engagement of the recruited immune response against cancer cells. Pediatric solid tumors are challenging targets because they contain both an inert immune environment and a quiet antigenic landscape, making them more resistant to conventional OV approaches. Further complicating this, herpes simplex virus suppresses host gene expression during virotherapy infection. METHODS: We therefore developed a multimodal oncolytic herpes simplex virus (oHSV) that expresses ephrin A2 (EphA2), a shared tumor-associated antigen (TAA) expressed by many tumors to improve immune-mediated antitumor activity. We verified the virus genotypically and phenotypically and then tested it in an oHSV-resistant orthotopic model (including immunophenotypic analysis), in flank and in T cell-deficient mouse models. We then assessed the antigen-expressing virus in an unrelated peripheral tumor model that also expresses the shared tumor antigen and evaluated functional T-cell response from the treated mice. RESULTS: Virus-based EphA2 expression induces a robust acquired antitumor immune responses in both an oHSV-resistant murine brain and peripheral tumor model. Our new multimodal oncolytic virus (1) improves survival in viroimmunotherapy resistant tumors, (2) alters both the infiltrating and peripheral T-cell populations capable of suppressing tumor growth on rechallenge, and (3) produces EphA2-specific CD8 effector-like populations. CONCLUSIONS: Our results suggest that this flexible viral-based platform enables immune recognition of the shared TAA and improves the immune-therapeutic response, thus making it well suited for low-mutational load tumors.
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Herpes Simples/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/virologia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/metabolismo , Animais , Modelos Animais de Doenças , Imunoterapia/métodos , CamundongosRESUMO
Osteosarcoma remains one of the deadliest cancers in pediatrics and young adults. We administered two types of immunotherapies, oncolytic virotherapy and immune checkpoint inhibition, to two murine osteosarcoma models and observed divergent results. Mice bearing F420 showed no response, whereas those with K7M2 showed prolonged survival in response to combination therapy. K7M2 had higher expression of immune-related genes and higher baseline immune cell infiltrates, but there were no significant differences in tumor mutational burden or predicted MHC class I binding of nonsynonymous mutations. Instead, we found several mouse endogenous retrovirus sequences highly expressed in K7M2 compared with F420. T cell tetramer staining for one of them, gp70, was detected in mice with K7M2 but not F420, suggesting that endogenous retrovirus proteins are targets for the anti-tumor immune reaction. Given prior observations of endogenous retrovirus expression in human osteosarcomas, our findings may be translatable to human disease.
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Recent reports have shown that upon expression of appropriate oncogenes, both stem cells and more differentiated progenitor populations can serve as leukemia-initiating cells. These studies suggest that oncogenic mutations subvert normal development and induce reacquisition of stem-like features. However, no study has described how specific mutations influence the ability of differentiating cell subsets to serve as leukemia-initiating cells and if varying such cellular origins confers a functional difference. We have examined the role of the tumor suppressor gene p19(ARF) in a murine model of acute lymphoblastic leukemia and found that loss of p19(ARF) changes the spectrum of cells capable of tumor initiation. With intact p19(ARF), only hematopoietic stem cells (HSCs) can be directly transformed by BCR/ABL expression. In a p19(ARF)-null genetic background expression of the BCR/ABL fusion protein renders functionally defined HSCs, common lymphoid progenitors (CLP), and precursor B-lymphocytes competent to generate leukemia stem cells. Furthermore, we show that leukemias arising from p19(ARF)-null HSC versus pro-B cells differ biologically, including relative response to drug insult. Our observations elucidate a unique mechanism by which heterogeneity arises in tumor populations harboring identical genetic lesions and show that activity of p19(ARF) profoundly influences the nature of tumor-initiating cells during BCR/ABL-mediated leukemogenesis.
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Transformação Celular Neoplásica/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteínas de Fusão bcr-abl/metabolismo , Células Progenitoras Linfoides/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Modelos Animais de Doenças , Proteínas de Fusão bcr-abl/genética , Células Progenitoras Linfoides/patologia , Camundongos , Camundongos Transgênicos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
Recent studies in a variety of leukemias and solid tumors indicate that there is significant heterogeneity with respect to tumor-forming ability within a given population of tumor cells, suggesting that only a subpopulation of cells is responsible for tumorigenesis. These cells have been commonly referred to as cancer stem cells (CSCs) or cancer-initiating cells (CICs). CICs have been shown to be relatively resistant to conventional anticancer therapies and are thus thought to be responsible for disease relapse. As such, they represent a potentially critical therapeutic target. Oncolytic viruses are in clinical trials for cancer and kill cells through mechanisms different from conventional therapeutics. Because these viruses are not susceptible to the same pathways of drug or radiation resistance, it is important to learn whether CICs are susceptible to oncolytic virus infection. Here we review the available data regarding the ability of several different oncolytic virus types to target CICs for destruction.