RESUMEN
Exosomes derived from solid tumour cells are involved in immune suppression, angiogenesis and metastasis; however, the role of leukaemia-derived exosomes has less been investigated. Hence, changes in immune response-related genes and human T cells apoptosis co-incubated with exosomes isolated from patients' pre-B cell acute lymphoblastic leukaemia were evaluated in this in vitro study. Vein blood sample was obtained from each newly diagnosed acute lymphoblastic leukaemia (ALL) patient prior any therapy. ALL serum exosomes were isolated by ultrafiltration and characterized using Western blotting and transmission electron microscopy. Exosomes were then co-incubated with T lymphocytes and the gene expressions, as well as functions of human T cells were quantified by qRT-PCR. Apoptosis and caspase-3 and caspase-9 protein expression were also evaluated by flowcytometry and Western blotting analysis, respectively. Exosomes isolated from ALL patients affected T lymphocytes and elevated the apoptosis. Moreover, these exosomes altered the T cells profile into regulatory type by increasing the expression of FOXP3 and Tregs-related cytokines, including TGF-B and IL-10. The expression level of Th17-related transcription factors (RoRγt) and interleukins (IL-17 and IL-23) decreased after this treatment. According to our findings, exosomes derived from ALL patients' sera carry immunosuppressive molecules, indicating the possible effect of exosomes as liquid biomarkers for cancer staging.
Asunto(s)
Exosomas , Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Niño , Exosomas/metabolismo , Humanos , Inmunidad , Neoplasias/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Linfocitos T Reguladores , Células Th17RESUMEN
Mitosis is the process of cell division and is regulated by checkpoints in the cell cycle. G1-S, S, and G2-M are the three main checkpoints that prevent initiation of the next phase of the cell cycle phase until previous phase has completed. DNA damage leads to activation of the G2-M checkpoint, which can trigger a downstream DNA damage response (DDR) pathway to induce cell cycle arrest while the damage is repaired. If the DNA damage cannot be repaired, the replication stress response (RSR) pathway finally leads to cell death by apoptosis, in this case called mitotic catastrophe. Many cancer treatments (chemotherapy and radiotherapy) cause DNA damages based on SSBs (single strand breaks) or DSBs (double strand breaks), which cause cell death through mitotic catastrophe. However, damaged cells can activate WEE1 kinase (as a part of the DDR and RSR pathways), which prevents apoptosis and cell death by inducing cell cycle arrest at G2 phase. Therefore, inhibition of WEE1 kinase could sensitize cancer cells to chemotherapeutic drugs. This review focuses on the role of WEE1 kinase (as a biological macromolecule which has a molecular mass of 96 kDa) in the cell cycle, and its interactions with other regulatory pathways. In addition, we discuss the potential of WEE1 inhibition as a new therapeutic approach in the treatment of various cancers, such as melanoma, breast cancer, pancreatic cancer, cervical cancer, etc.
Asunto(s)
Neoplasias , Proteínas Tirosina Quinasas , Ciclo Celular , Proteínas de Ciclo Celular , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Daño del ADN , Puntos de Control de la Fase G2 del Ciclo Celular , Humanos , Mitosis/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
Due to its high occurrence and mortality rate, breast cancer has been studied from various aspects as one of the cancer field's hot topics in the last decade. Epigenetic alterations are spoused to be highly effective in breast cancer development. Enhancer of zeste homolog 2 (EZH2) is an enzymatic epi-protein that takes part in most vital cell functions by its different action modes. EZH2 is suggested to be dysregulated in specific breast cancer types, particularly in advanced stages. Mounting evidence revealed that EZH2 overexpression or dysfunction affects the pathophysiology of breast cancer. In this review, we discuss biological aspects of the EZH2 molecule with a focus on its newly identified action mechanisms. We also highlight how EZH2 plays an essential role in breast cancer initiation, progression, metastasis, and invasion, which emerged as a worthy target for treating breast cancer in different approaches.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/fisiopatología , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , ADN/metabolismo , Progresión de la Enfermedad , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/fisiología , Femenino , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Histonas/metabolismo , Humanos , Invasividad Neoplásica/genética , Metástasis de la Neoplasia/patologíaRESUMEN
Hematologic malignancies include various diseases that develop from hematopoietic stem cells of bone marrow or lymphatic organs. Currently, conventional DNA-damage-based chemotherapy drugs are approved as standard therapeutic regimens for these malignancies. Although many improvements have been made, patients with relapsed or refractory hematological malignancies have a poor prognosis. Therefore, novel and practical therapeutic approaches are required for the treatment of these diseases. Interestingly several studies have shown that targeting Wee1 kinase in the Hematological malignancies, including AML, ALL, CML, CLL, DLBCL, BL, MCL, etc., can be an effective therapeutic strategy. It plays an essential role in regulating the cell cycle process by abrogating the G2-M cell-cycle checkpoint, which provides time for DNA damage repair before mitotic entry. Consistently, Wee1 overexpression is observed in various Hematological malignancies. Also, in healthy normal cells, repairing DNA damages occurs due to G1-S checkpoint function; however, in the cancer cells, which have an impaired G1-S checkpoint, the damaged DNA repair process depends on the G2-M checkpoint function. Thus, Wee1 inhibition could be a promising target in the presence of DNA damage in order to potentiate multiple therapeutic drugs. This review summarized the potentials and challenges of Wee1 inhibition combined with other therapies as a novel effective therapeutic strategy in Hematological malignancies.
Asunto(s)
Puntos de Control de la Fase G2 del Ciclo CelularRESUMEN
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway has been known to be involved in cell growth, cellular differentiation processes development, immune cell survival, and hematopoietic system development. As an important member of the STAT family, STAT3 participates as a major regulator of cellular development and differentiation-associated genes. Prolonged and persistent STAT3 activation has been reported to be associated with tumor cell survival, proliferation, and invasion. Therefore, the JAK-STAT pathway can be a potential target for drug development to treat human cancers, e.g., hematological malignancies. Although STAT3 upregulation has been reported in hematopoietic cancers, protein-level STAT3 mutations have also been reported in invasive leukemias/lymphomas. The principal role of STAT3 in tumor cell growth clarifies the importance of approaches that downregulate this molecule. Epigenetic modifications are a major regulatory mechanism controlling the activity and function of STAT3. So far, several compounds have been developed to target epigenetic regulatory enzymes in blood malignancies. Here, we discuss the current knowledge about STAT3 abnormalities and carcinogenic functions in hematopoietic cancers, novel STAT3 inhibitors, the role of epigenetic mechanisms in STAT3 regulation, and targeted therapies, by focusing on STAT3-related epigenetic modifications.