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1.
FASEB J ; 35(9): e21853, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34416038

RESUMO

We highlight the ability of the tuberculosis (TB) causing bacterial pathogen, Mycobacterium tuberculosis (Mtb), to induce key characteristics that are associated with established IARC classified Group 1 and Group 2A carcinogenic agents. There is sufficient evidence from epidemiological case-control, cohort and meta-analysis studies of increased lung cancer (LC) risk in pre-existing/active/old TB cases. Similar to carcinogens and other pathogenic infectious agents, exposure to aerosol-containing Mtb sprays in mice produce malignant transformation of cells that result in squamous cell carcinoma. Convincing, mechanistic data show several characteristics shared between TB and LC which include chronic inflammation, genomic instability and replicative immortality, just to name a few cancer hallmarks. These hallmarks of cancer may serve as precursors to malignant transformation. Together, these findings form the basis of our postulate that Mtb is a complete human pulmonary carcinogen. We also discuss how Mtb may act as both an initiating agent and promoter of tumor growth. Forthcoming experimental studies will not only serve as proof-of-concept but will also pivot our understanding of how to manage/treat TB cases as well as offer solutions to clinical conundrums of TB lesions masquerading as tumors. Clinical validation of our concept may also help pave the way for next generation personalized medicine for the management of pulmonary TB/cancer particularly for cases that are not responding well to conventional chemotherapy or TB drugs.


Assuntos
Transformação Celular Neoplásica , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/microbiologia , Pulmão/microbiologia , Pulmão/patologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/microbiologia , Adolescente , Adulto , Idoso , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Carcinógenos , Transformação Celular Neoplásica/genética , Criança , Estudos de Coortes , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Mycobacterium tuberculosis/genética , Metástase Neoplásica/genética , Células-Tronco Neoplásicas/patologia , Fatores de Risco , Tuberculose Pulmonar/patologia , Adulto Jovem
2.
Mol Biol (Mosk) ; 55(4): 531-542, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34432772

RESUMO

Small SCP phosphatases CTDSP1, CTDSP2, and CTDSPL specifically dephosphorylate serine and threonine residues in protein molecules. The enzymes are involved in regulating activity of RNA polymerase II at the transition from transcription initiation to elongation, regulating expression of neuron-specific genes, and activating the key cell-cycle protein pRb at the G1/S boundary. In addition, the substrates of SCP phosphatases include SMAD transcription modulators; AKT1 protein kinase, which regulates the cell cycle, apoptosis, and angiogenesis; the TWIST1 and c-MYC transcription factors; Ras family proteins, which are involved in signaling pathways regulating the cell growth and apoptosis; CDCA3, which is associated with cell division; the cyclin-dependent kinase inhibitor p21; and the promyelocytic leukemia protein (PML), which is involved in regulation of the tumor suppressors p53, PTEN, and mTOR. Dysfunction or inactivation of SCP phosphatases leads to various diseases, including cancer. Recently the increase in interest to SCP phosphatases is due to their their tumor growth-inhibiting properties or role in the development of malignant tumors of various etiology and localization. The review discusses the properties of SCP phosphatases and their role in oncogenesis. Understanding the functions of SCP phosphatases and their regulatory mechanisms can be useful in searching for efficient targets for tumor therapy.


Assuntos
Carcinogênese , Neoplasias , Carcinogênese/genética , Ciclo Celular , Proteínas de Ciclo Celular , Transformação Celular Neoplásica/genética , Humanos , Neoplasias/genética , Fosfoproteínas Fosfatases/genética
3.
Nat Commun ; 12(1): 4878, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385447

RESUMO

A postprandial increase of translation mediated by eukaryotic Initiation Factor 6 (eIF6) occurs in the liver. Its contribution to steatosis and disease is unknown. In this study we address whether eIF6-driven translation contributes to disease progression. eIF6 levels increase throughout the progression from Non-Alcoholic Fatty Liver Disease (NAFLD) to hepatocellular carcinoma. Reduction of eIF6 levels protects the liver from disease progression. eIF6 depletion blunts lipid accumulation, increases fatty acid oxidation (FAO) and reduces oncogenic transformation in vitro. In addition, eIF6 depletion delays the progression from NAFLD to hepatocellular carcinoma, in vivo. Mechanistically, eIF6 depletion reduces the translation of transcription factor C/EBPß, leading to a drop in biomarkers associated with NAFLD progression to hepatocellular carcinoma and preserves mitochondrial respiration due to the maintenance of an alternative mTORC1-eIF4F translational branch that increases the expression of transcription factor YY1. We provide proof-of-concept that in vitro pharmacological inhibition of eIF6 activity recapitulates the protective effects of eIF6 depletion. We hypothesize the existence of a targetable, evolutionarily conserved translation circuit optimized for lipid accumulation and tumor progression.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Hepatopatia Gordurosa não Alcoólica/genética , Fatores de Iniciação de Peptídeos/genética , Biossíntese de Proteínas/genética , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Clofazimina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Inativação Gênica , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Fatores de Iniciação de Peptídeos/antagonistas & inibidores , Fatores de Iniciação de Peptídeos/metabolismo
4.
Cell Death Dis ; 12(7): 669, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34218261

RESUMO

Malignant transformation of gastrointestinal stromal tumors (GISTs) is correlated with poor prognosis; however, the underlying biological mechanism is not well understood. In the present study, low-risk (LR) GISTs, GISTs categorized as high-risk based on tumor size (HBS), and on mitotic rate (HBM) were collected for RNA sequencing. Candidate hub lncRNAs were selected by Oncomine analysis. Expression of a selected hub lncRNA, DNM3OS, and its correlation with patients' prognosis were analyzed using FISH staining, followed with the determination of function and underlying mechanism. Our results revealed a series of key pathways and hub lncRNAs involved in the malignant transformation of GISTs. Oncomine analysis revealed a tight association between clinical signatures and DNM3OS and suggested that DNM3OS is a hub lncRNA that is involved in the Hippo signaling pathway. In addition, DNM3OS was upregulated in HBS, HBM, and HBS/M GIST and correlated with worse prognosis in patients with GISTs. In addition, DNM3OS promoted GIST cell proliferation and mitosis by regulating the expression of GLUT4 and CD36. Collectively, these results improve our understanding of the malignant transformation of GISTs and unveil a series of hub lncRNAs in GISTs.


Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Perfilação da Expressão Gênica , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Transcriptoma , Antígenos CD36/genética , Antígenos CD36/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Bases de Dados Genéticas , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Mitose , Mapas de Interação de Proteínas , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais
6.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199046

RESUMO

Hyperglycemia may contribute to the progression of carcinomas by triggering epithelial-to-mesenchymal transition (EMT). Some proteostasis systems are involved in metastasis; in this paper, we sought to explore the mechanism of Hsp70 chaperone in EMT. We showed that knockdown of Hsp70 reduced cell migration capacity concomitantly with levels of mRNA of the Slug, Snail, and Twist markers of EMT, in colon cancer cells incubated in high glucose medium. Conversely, treatment of cells with Hsp70 inducer U-133 were found to elevate cell motility, along with the other EMT markers. To prove that inhibiting Hsp70 may reduce EMT efficiency, we treated cells with a CL-43 inhibitor of the HSF1 transcription factor, which lowered Hsp70 and HSF1 content in the control and induced EMT in carcinoma cells. Importantly, CL-43 reduced migration capacity, EMT-linked transcription factors, and increased content of epithelial marker E-cadherin in colon cancer cells of three lines, including one derived from a clinical sample. To prove that Hsp70 chaperone should be targeted when inhibiting the EMT pathway, we treated cancer cells with 2-phenylethynesulfonamide (PES) and demonstrated that the compound inhibited substrate-binding capacity of Hsp70. Furthermore, PES suppressed EMT features, cell motility, and expression of specific transcription factors. In conclusion, the Hsp70 chaperone machine efficiently protects mechanisms of the EMT, and the safe inhibitors of the chaperone are needed to hamper metastasis at its initial stage.


Assuntos
Glicemia , Transição Epitelial-Mesenquimal , Glucose/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Biomarcadores , Caderinas/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glucose/farmacologia , Humanos , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Ligação Proteica , Fatores de Transcrição da Família Snail/metabolismo
7.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209703

RESUMO

The M1/M2 macrophage paradigm plays a key role in tumor progression. M1 macrophages are historically regarded as anti-tumor, while M2-polarized macrophages, commonly deemed tumor-associated macrophages (TAMs), are contributors to many pro-tumorigenic outcomes in cancer through angiogenic and lymphangiogenic regulation, immune suppression, hypoxia induction, tumor cell proliferation, and metastasis. The tumor microenvironment (TME) can influence macrophage recruitment and polarization, giving way to these pro-tumorigenic outcomes. Investigating TME-induced macrophage polarization is critical for further understanding of TAM-related pro-tumor outcomes and potential development of new therapeutic approaches. This review explores the current understanding of TME-induced macrophage polarization and the role of M2-polarized macrophages in promoting tumor progression.


Assuntos
Ativação de Macrófagos/imunologia , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Animais , Biomarcadores , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Citocinas/metabolismo , Humanos , Hipóxia/genética , Hipóxia/imunologia , Hipóxia/metabolismo , Imunofenotipagem , Inflamação/etiologia , Inflamação/metabolismo , Ativação de Macrófagos/genética , Metástase Neoplásica , Estadiamento de Neoplasias , Transdução de Sinais , Macrófagos Associados a Tumor/patologia
8.
Nat Commun ; 12(1): 4130, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226546

RESUMO

Chromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10PZP-dependent CALM-AF10-mediated leukemogenesis.


Assuntos
Doença Aguda , Leucemia Mieloide Aguda/genética , Fatores de Transcrição/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Translocação Genética/genética , Animais , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Cromatina , Células HEK293 , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Metilação , Camundongos , Modelos Moleculares , Proteínas Monoméricas de Montagem de Clatrina/genética , Proteínas Monoméricas de Montagem de Clatrina/metabolismo , Nucleossomos , Conformação Proteica
9.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200790

RESUMO

Exosomes released from tumor cells are instrumental in shaping the local tumor microenvironment to allow cancer progression. Recently, it has been shown that tumor exosomes carry large fragments of dsDNA, which may reflect the mutational status of parental cells. Although it has been described that a stressful microenvironment can influence exosomal cargo, the effects on DNA packing and its transfer into recipient cells have yet to be investigated. Here, we report that exosomes derived from SW480 (human colorectal adenocarcinoma cell line) cells can carry dsDNA fragments containing the entire coding sequence of both TP53 and KRAS genes, harboring the SW480-related TP53 c.818G > A and KRAS c.35G > T typical mutations. We also report the following: that cell stimulation with lipopolysaccharides (LPS) promotes the selective packaging of the TP53 gene, but not the KRAS gene; that exosomes secreted by SW480 cells efficiently transfer the mutated sequences into normal CCD841-CoN colon epithelial and THLE-2 hepatic cells; that this mechanism is more efficient when the cells had been previously incubated with pro-inflammatory cytokines; that the TP53 gene appears actively transcribed in both recipient cells; and that mutated mRNA levels are not influenced by cytokine treatment. Our data strongly suggest that pro-inflammatory stimulation promotes the horizontal transfer of an oncogene by exosomes, although this remains a rare event. Further studies are needed to assess the impact of the oncogenic transfer by exosomes in malignant transformation and its role in tumor progression.


Assuntos
Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/patologia , Exossomos/genética , Mediadores da Inflamação/imunologia , Mutação , Microambiente Tumoral/imunologia , Proteína Supressora de Tumor p53/genética , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Humanos , Células Tumorais Cultivadas
10.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188576, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34090932

RESUMO

Hematopoietic PBX interacting protein (HPIP or pre-B-cell leukemia transcription factor interacting protein (PBXIP1) was discovered two decades ago as a corepressor of pre-B-cell leukemia homeobox (PBX) 1 with a vital functional role in hematopoiesis. Later it emerged as a potential biomarker of poor prognosis and tumorigenesis for more than a dozen different cancers. It regulates aggressive cancer phenotypes, cell proliferation, metastasis, EMT, etc. The anomaly in the regulation of HPIP is linked with physiological disorders like renal fibrosis, chronic kidney disease and osteoarthritis. Scientists have unraveled more than twenty interacting proteins of HPIP and its functional role in various physiological and cellular processes that involves normal neuronal development, embryogenesis, endometrium decidualization, and germ cell proliferation. Over the past 20 years, we have witnessed the emerging role of HPIP and its association with a myriad of cellular activities ranging from germ cell proliferation to cancer aggressiveness, modulating multitude of signaling cascades like TGF-ß1, PI3K/AKT, Wnt, mTOR, and Sonic hedgehog signaling pathways. This review will give the current understanding of HPIP, in terms of its diverse functions, theoretical ideas, and further explore cellular links and promising areas that need to be investigated. We also provide a comprehensive overview of the transcript variants of HPIP and distinct sets of transcription factors regulating their expression, which may help to understand the role of HPIP in various cellular or physiological conditions.


Assuntos
Transformação Celular Neoplásica/metabolismo , Proteínas Correpressoras/metabolismo , Células Germinativas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Sítios de Ligação , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Proteínas Correpressoras/genética , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Invasividade Neoplásica , Neoplasias/genética , Neoplasias/patologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais
11.
J Cancer Res Clin Oncol ; 147(8): 2199-2207, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34115239

RESUMO

Colorectal cancer is an important public health concern leading to significant cancer associate mortality. A vast majority of colon cancer arises from polyp which later follows adenoma, adenocarcinoma, and carcinoma sequence. This whole process takes several years to complete and recent genomic and proteomic technologies are identifying several targets involved in each step of polyp to carcinoma transformation in a large number of studies. Current text presents interaction network of targets involved in polyp to carcinoma transformation. In addition, important targets involved in each step according to network biological parameters are also presented. The functional overrepresentation analysis of each step targets and common top biological processes and pathways involved in carcinoma indicate several insights about this whole mechanism. Interaction networks indicate TP53, AKT1, GAPDH, INS, EGFR, and ALB as the most important targets commonly involved in polyp to carcinoma sequence. Though several important pathways are known to be involved in CRC, the central common involvement of PI3K-AKT indicates its potential for devising CRC management strategies. The common and central targets and pathways involved in polyp to carcinoma progression can shed light on its mechanism and potential management strategies. The data-driven approach aims to add valuable inputs to the mechanism of the years-long polyp-carcinoma sequence.


Assuntos
Carcinoma/prevenção & controle , Transformação Celular Neoplásica , Neoplasias do Colo/prevenção & controle , Pólipos do Colo/terapia , Terapia de Alvo Molecular/métodos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Adenoma/prevenção & controle , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patologia , Pólipos Adenomatosos/prevenção & controle , Antineoplásicos/uso terapêutico , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Pólipos do Colo/genética , Pólipos do Colo/metabolismo , Pólipos do Colo/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/fisiologia , Genes de Troca/efeitos dos fármacos , Humanos , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Proteômica , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
12.
Development ; 148(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34180969

RESUMO

Ets homologous factor (EHF) is a member of the epithelial-specific Ets (ESE) family of transcription factors. To investigate its role in development and epithelial homeostasis, we generated a series of novel mouse strains in which the Ets DNA-binding domain of Ehf was deleted in all tissues (Ehf-/-) or specifically in the gut epithelium. Ehf-/- mice were born at the expected Mendelian ratio, but showed reduced body weight gain, and developed a series of pathologies requiring most Ehf-/- mice to reach an ethical endpoint before reaching 1 year of age. These included papillomas in the facial skin, abscesses in the preputial glands (males) or vulvae (females), and corneal ulcers. Ehf-/-mice also displayed increased susceptibility to experimentally induced colitis, which was confirmed in intestinal-specific Ehf knockout mice. Gut-specific Ehf deletion also impaired goblet cell differentiation, induced extensive transcriptional reprogramming in the colonic epithelium and enhanced Apc-initiated adenoma development. The Ets DNA-binding domain of EHF is therefore essential for postnatal homeostasis of the epidermis and colonic epithelium, and its loss promotes colonic tumour development.


Assuntos
Transformação Celular Neoplásica/genética , Neoplasias do Colo/etiologia , Epiderme/metabolismo , Genes APC , Homeostase , Mucosa Intestinal/metabolismo , Fatores de Transcrição/genética , Animais , Reprogramação Celular/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Regulação da Expressão Gênica , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Masculino , Camundongos , Camundongos Knockout , Fatores de Transcrição/metabolismo
14.
J Cell Sci ; 134(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34085695

RESUMO

Tumor suppressor p53 mutations are associated with more than 50% of cancers. Aggregation and amyloid formation of p53 is also implicated in cancer pathogenesis, but direct evidence for aggregated p53 amyloids acting as an oncogene is lacking. Here, we conclusively demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to non-cancerous cells. p53 amyloid aggregates were transferred through cell generations, contributing to enhanced survival, apoptotic resistance with increased proliferation and migration. The tumorigenic potential of p53 amyloid-transformed cells was further confirmed in mouse xenografts, wherein the tumors showed p53 amyloids. p53 disaggregation rescued the cellular transformation and inhibited tumor development in mice. We propose that wild-type p53 amyloid formation contributes to tumorigenesis and can be a potential target for therapeutic intervention. This article has an associated First Person interview with the first author of the paper.


Assuntos
Neoplasias , Príons , Amiloide/metabolismo , Animais , Transformação Celular Neoplásica/genética , Camundongos , Mutação , Príons/genética , Príons/metabolismo , Proteína Supressora de Tumor p53/genética
15.
Commun Biol ; 4(1): 660, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34079055

RESUMO

The female mammary epithelium undergoes reorganization during development, pregnancy, and menopause, linking higher risk with breast cancer development. To characterize these periods of complex remodeling, here we report integrated 50 K mouse and 24 K human mammary epithelial cell atlases obtained by single-cell RNA sequencing, which covers most lifetime stages. Our results indicate a putative trajectory that originates from embryonic mammary stem cells which differentiates into three epithelial lineages (basal, luminal hormone-sensing, and luminal alveolar), presumably arising from unipotent progenitors in postnatal glands. The lineage-specific genes infer cells of origin of breast cancer using The Cancer Genome Atlas data and single-cell RNA sequencing of human breast cancer, as well as the association of gland reorganization to different breast cancer subtypes. This comprehensive mammary cell gene expression atlas ( https://mouse-mammary-epithelium-integrated.cells.ucsc.edu ) presents insights into the impact of the internal and external stimuli on the mammary epithelium at an advanced resolution.


Assuntos
Neoplasias da Mama/etiologia , Mama/citologia , Mama/metabolismo , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/etiologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinogênese/genética , Linhagem da Célula/genética , Transformação Celular Neoplásica/genética , Bases de Dados de Ácidos Nucleicos/estatística & dados numéricos , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Gravidez , RNA-Seq/estatística & dados numéricos
16.
Viruses ; 13(5)2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069114

RESUMO

The incidence of Human-papillomavirus-positive (HPV+) tonsillar and base-of-tongue squamous cell carcinoma (TSCC and BOTSCC, respectively) is increasing epidemically, but they have better prognosis than equivalent HPV-negative (HPV-) cancers, with roughly 80% vs. 50% 3-year disease-free survival, respectively. The majority of HPV+ TSCC and BOTSCC patients therefore most likely do not require the intensified chemoradiotherapy given today to head and neck cancer patients and would with de-escalated therapy avoid several severe side effects. Moreover, for those with poor prognosis, survival has not improved, so better-tailored alternatives are urgently needed. In line with refined personalized medicine, recent studies have focused on identifying predictive markers and driver cancer genes useful for better stratifying patient treatment as well as for targeted therapy. This review presents some of these endeavors and briefly describes some recent experimental progress and some clinical trials with targeted therapy.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas/etiologia , Oncogenes , Infecções por Papillomavirus/complicações , Neoplasias da Língua/etiologia , Neoplasias Tonsilares/etiologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/terapia , Transformação Celular Neoplásica/genética , Transformação Celular Viral , Expressão Gênica , Humanos , Imuno-Histoquímica , Terapia de Alvo Molecular , Mutação , Infecções por Papillomavirus/virologia , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Língua/diagnóstico , Neoplasias da Língua/metabolismo , Neoplasias da Língua/terapia , Neoplasias Tonsilares/diagnóstico , Neoplasias Tonsilares/metabolismo , Neoplasias Tonsilares/terapia , Resultado do Tratamento
17.
Mutat Res Rev Mutat Res ; 787: 108361, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083051

RESUMO

Approximately 165,000 and 311,000 individuals die annually from urothelial (UC) and cervical (CC) cancer. The therapeutic success of these cancers depends strongly on their early detection and could be improved by use of additional diagnostic tools. We evaluated the current knowledge of the use of micronucleus (MN) assays (which detect structural and numerical chromosomal aberrations) with urine- (UDC) and cervix-derived (CDC) cells for the identification of humans with increased risks and for the diagnosis of UC and CC. Several findings indicate that MN rates in UDC are higher in individuals with inflammation and schistosomiasis that are associated with increased prevalence of UC; furthermore, higher MN rates were also found in CDC in women with HPV, Candidiasis and Trichomonas infections which increase the risks for CC. Only few studies were published on MN rates in UDS in patients with UC, two concern the detection of recurrent bladder tumors. Strong correlations were found in individuals with abnormal CC cells that are scored in Pap tests and histopathological abnormalities. In total, 16 studies were published which concerned these topics. MN rates increased in the order: inflammation < ASC-US/ASC-H < LSIL < HSIL < CC. It is evident that MNi numbers increase with the risk to develop CC and with the degree of malignant transformation. Overall, the evaluation of the literature indicates that MNi are useful additional biomarkers for the prognosis and detection of CC and possibly also for UC. In regard to the diagnosis/surveillance of UC, further investigations are needed to draw firm conclusions, but the currently available data are promising. In general, further standardization of the assays is needed (i.e. definition of optimal cell numbers and of suitable stains as well as elucidation of the usefulness of parameters reflecting cytotoxicity and mitotic activity) before MN trials can be implemented in routine screening.


Assuntos
Testes para Micronúcleos/métodos , Neoplasias do Colo do Útero/genética , Transformação Celular Neoplásica/genética , Dano ao DNA/genética , Feminino , Humanos , Urotélio/patologia
18.
Hematol Oncol ; 39 Suppl 1: 88-93, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34105811

RESUMO

Follicular lymphoma (FL) is a common disease with clinically indolent behavior, and a long natural history for the majority of patients. Despite excellent therapeutic strategies currently available for FL, approximately 10%-20% of patients will experience early disease progression, defined as occurring within two years of diagnosis. These patients have poor outcomes, with overall survival at 5 years ranging between 37% and 50%. Much of the biology driving early progression and inferior survival is attributed to early transformation events; however, transformation alone does not account for all the observed clinical heterogeneity and survival differences among patients. Several clinical, genetic, and molecular alterations in FL have been discovered that help define subsets of patients at risk for multiply relapses and refractory disease, and are slowly making their way into risk calculators to be used in daily practice. Additionally, the role of functional imaging with PET scan, as well as circulating and cell free tumor DNA are being evaluated as tools to define high-risk subsets of patients with FL. This review seeks to provide an over view of current and evolving biomarkers that define high-risk FL at diagnosis. The goal is for these tools to assist clinicians in integrating these rapidly evolving prognosis models into clinical practice, in the hopes of risk-stratifying treatments and improving outcomes for patients.


Assuntos
Transformação Celular Neoplásica/genética , Linfoma Folicular , Modelos Biológicos , Tomografia por Emissão de Pósitrons , Intervalo Livre de Doença , Humanos , Linfoma Folicular/diagnóstico por imagem , Linfoma Folicular/genética , Linfoma Folicular/mortalidade , Linfoma Folicular/terapia , Taxa de Sobrevida
19.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072237

RESUMO

In this review, we focus on bioinformatic oncology as an integrative discipline that incorporates knowledge from the mathematical, physical, and computational fields to further the biomedical understanding of cancer. Before providing a deeper insight into the bioinformatics approach and utilities involved in oncology, we must understand what is a system biology framework and the genetic connection, because of the high heterogenicity of the backgrounds of people approaching precision medicine. In fact, it is essential to providing general theoretical information on genomics, epigenomics, and transcriptomics to understand the phases of multi-omics approach. We consider how to create a multi-omics model. In the last section, we describe the new frontiers and future perspectives of this field.


Assuntos
Epigenômica , Genômica , Neoplasias/etiologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Aberrações Cromossômicas , Biologia Computacional/métodos , Suscetibilidade a Doenças , Epigenômica/métodos , Predisposição Genética para Doença , Genômica/métodos , Humanos , Aprendizado de Máquina , Medicina de Precisão , Proteômica/métodos , Transcriptoma
20.
Curr Hematol Malig Rep ; 16(3): 286-303, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33945086

RESUMO

PURPOSE OF REVIEW: Monocytosis is a distinct but non-specific manifestation of various physiologic and pathologic conditions. Among hematopoietic stem cell neoplasms, depending on the criteria used for disease classification, monocytosis may be a consistent and integral component of diseases such as chronic myelomonocytic leukemia or acute myeloid leukemia with monocytic differentiation, or it may represent an inconsistent finding that often provides a clue to the underlying genetic changes driving the neoplasm. The purpose of this review is to provide the readers with a laboratory-based approach to neoplastic monocytosis. RECENT FINDINGS: In-depth elucidation of the genomic landscape of myeloid neoplasms within the past few years has broadened our understanding of monocytosis and its implications for diagnosis and prognosis. Genetic findings also shed light on potential disease response - or lack thereof - to various therapeutic agents used in the setting of myeloid neoplasms. In this review, we provide our approach to diagnose neoplastic monocytosis in the context of case-based studies while incorporating the most recent literature on this topic.


Assuntos
Leucemia Mieloide/diagnóstico , Leucemia Mielomonocítica Crônica/diagnóstico , Fatores Etários , Biomarcadores , Medula Óssea/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Gerenciamento Clínico , Progressão da Doença , Suscetibilidade a Doenças , Predisposição Genética para Doença , Variação Genética , Humanos , Leucemia Mieloide/etiologia , Leucemia Mieloide/mortalidade , Leucemia Mielomonocítica Crônica/etiologia , Leucemia Mielomonocítica Crônica/mortalidade , Monócitos/metabolismo , Monócitos/patologia
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