RESUMO
The Ninth Annual Conference of "Anticancer Innovative Therapy", organized by Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (Fondazione IRCCS INT) and hosted by Hotel Michelangelo, was held in Milan on 25 January 2019. Cutting-edge science was presented in two main scientific sessions: i) pre-clinical evidences and new targets, and ii) clinical translation. The Keynote lecture entitled "Cancer stem cells (CSCs): metabolic strategies for their identification and eradication" presented by M. Lisanti, was one of the highlights of the conference. One key concept of the meeting was how the continuous advances in our knowledge about molecular mechanisms in various fields of research (cancer metabolism reprogramming, epigenetic regulation, transformation/invasiveness, and immunology, among others) are driving cancer research towards more effective personalized antineoplastic strategies. Specifically, recent preclinical data on the following topics were discussed: 1. Polycomb group proteins in cancer; 2. A d16HER2 splice variant is a flag of HER2 addiction across HER2-positive cancers; 3. Studying chromatin as a nexus between translational and basic research; 4. Metabolomic analysis in cancer patients; 5. CDK4-6 cyclin inhibitors: clinical activity and future perspectives as immunotherapy adjuvant; and 6. Cancer stem cells (CSCs): metabolic strategies for their identification and eradication. In terms of clinical translation, several novel approaches were presented: 1. Developing CAR-T cell therapies: an update of preclinical and clinical development at University of North Carolina; 2. Vγ9Vδ2 T-cell activation and immune suppression in multiple myeloma; 3. Predictive biomarkers for real-world immunotherapy: the cancer immunogram model in the clinical arena; and 4. Mechanisms of resistance to immune checkpoint blockade in solid tumors. Overall, the pre-clinical and clinical findings presented could pave the way to identify novel actionable therapeutic targets to significantly enhance the care of persons with cancer.
Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia , Neoplasias/terapia , Terapias em Estudo , Animais , Biomarcadores Tumorais , Congressos como Assunto , Epigênese Genética , Humanos , Itália , Camundongos , Mutação , Células-Tronco NeoplásicasRESUMO
Cellular senescence is an irreversible arrest of proliferation. It is activated when a cell encounters stress such as DNA damage, telomere shortening or oncogene activation. Like apoptosis, it impedes tumour progression and acts as a barrier that pre-neoplastic cells must overcome during their evolution toward the full tumourigenic state. This review focuses on the role of transcriptional regulators in the control of cellular senescence, explores how their function is perturbed in cancer and discusses the potential to harness this knowledge for future cancer therapies.
Assuntos
Senescência Celular/genética , Regulação da Expressão Gênica/fisiologia , Fatores de Ribosilação do ADP/genética , Fatores de Ribosilação do ADP/metabolismo , Fatores de Ribosilação do ADP/fisiologia , Animais , Apoptose/genética , Apoptose/fisiologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/fisiologia , Loci Gênicos/genética , Loci Gênicos/fisiologia , Humanos , Modelos Biológicos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Transcrição Gênica/fisiologiaRESUMO
The generation of different cell types from stem cells containing identical genetic information and their organization into tissues and organs during development is a highly complex process that requires defined transcriptional programs. Maintenance of such programs is epigenetically regulated and the factors involved in these processes are often essential for development. The activities required for cell-fate decisions are frequently deregulated in human tumors, and the elucidation of the molecular mechanisms that regulate these processes is therefore important for understanding both developmental processes and tumorigenesis.
Assuntos
Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Histona-Lisina N-Metiltransferase/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Células-Tronco/citologia , Células-Tronco/enzimologia , Animais , Metilação de DNA , Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Humanos , Modelos Biológicos , Oxirredutases N-Desmetilantes/genética , Proteínas do Grupo Polycomb , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transcrição GênicaRESUMO
The retinoblastoma protein (pRB) and its two relatives, p107 and p130, regulate development and cell proliferation in part by inhibiting the activity of E2F-regulated promoters. We have used high-density oligonucleotide arrays to identify genes in which expression changed in response to activation of E2F1, E2F2, and E2F3. We show that the E2Fs control the expression of several genes that are involved in cell proliferation. We also show that the E2Fs regulate a number of genes involved in apoptosis, differentiation, and development. These results provide possible genetic explanations to the variety of phenotypes observed as a consequence of a deregulated pRB/E2F pathway.
Assuntos
Apoptose/genética , Proteínas de Transporte , Proteínas de Ciclo Celular , Diferenciação Celular/genética , Proteínas de Ligação a DNA , Regulação da Expressão Gênica , Fatores de Transcrição/fisiologia , Northern Blotting , Ciclo Celular/genética , Divisão Celular/genética , Replicação do DNA , Fatores de Transcrição E2F , Fator de Transcrição E2F1 , Fator de Transcrição E2F2 , Fator de Transcrição E2F3 , Perfilação da Expressão Gênica , Marcação de Genes , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Isoformas de Proteínas/fisiologia , Proteína do Retinoblastoma/fisiologia , Proteína 1 de Ligação ao Retinoblastoma , Fator de Transcrição DP1 , Células Tumorais CultivadasRESUMO
The process of mRNA splicing is sensitive to in vivo thermal inactivation, but can be protected by pretreatment of cells under conditions that induce heat-shock proteins (Hsps). This latter phenomenon is known as "splicing thermotolerance". In this article we demonstrate that the small nuclear ribonucleoprotein particles (snRNPs) are in vivo targets of thermal damage within the splicing apparatus in heat-shocked yeast cells. Following a heat shock, levels of the tri-snRNP (U4/U6.U5), free U6 snRNP, and a pre-U6 snRNP complex are dramatically reduced. In addition, we observe multiple alterations in U1, U2, U5, and U4/U6 snRNP profiles and the accumulation of precursor forms of U4- and U6-containing snRNPs. Reassembly of snRNPs following a heat shock is correlated with the recovery of mRNA splicing and requires both Hsp104 and the Ssa Hsp70 family of proteins. Furthermore, we correlate splicing thermotolerance with the protection of a subset of snRNPs by Ssa proteins but not Hsp104, and show that Hsp70 directly associates with U4- and U6-containing snRNPs in splicing thermotolerant cells. In addition, our results show that Hsp70 plays a role in snRNP assembly under normal physiological conditions.
