Cellular Senescence What is it? What causes it? Why is it important (cancer and aging)?
Cancer biology senescence & imortalisation
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Transcript of Cancer biology senescence & imortalisation
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By
Dr. Gaurav KumarPGT, Radiation OncologyMedical College, Kolkata
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In Order to effectively combat cancers we must underatand the process.
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~ 1% neonatal Cord blood Collection contains malignant clones
1/3rd of Adults possess-IgH-BCL2 translocationResponsible for follicular leukemia
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Its Tumor Suppressor Mechanisms
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By- 1) Apoptosis 2) Senescence
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P 16-Rb pathwayARF- P53 pathway
Telomeres
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Senescence It Is the process by which a primary cultured cell undergo permanent growth arrest after a f inite replicative l i fespan or in response to certain stressor.
Causes•*Telomere Erosion•* DNA damage•* Activat ion of Oncogene
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Chromosome – 9p21
INH 4a/ARF/INH 4b locus
p16 , p15 ,ARF
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Telomere dysfunction - Principle effector of tumor suppressor mechanism.
Telomeres – * TTAGGG (G-rich repeats) * 5-15 bp at end of each
chromosome. * Forms T-LOOPS near
chromosomal ends.
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T – loops
Capping of chromosomal ends
Prevents from DNA-DNA interaction&
Genetic alteration
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NUTLINS -Stabilises ARF & Mdm2, prevents p53 degradation
Reactvation of p53 – Growth Arrest (Sarcoma & HCC)
DNA Methy transferase Inhibitors – Reactivates
P15 & p16 (Induce Senescence)
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Telomerase directed Immunotherapy
Telomerase peptide vaccines
(GV 1001 & HR 2822) – Metastatic lung Ca Advanced pancreatic Ca Advanced HCC
Telomerase deficient Cells – More sensitive to Ionising radiation & DNA DSB CT agents
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CT induced senescence – Responsible for long term toxicities of therapy
Lymphocyte telomere length – Predicts risk of Atherosclerosis Alzheimer Premature MI CAD
Germline Telomere mutation – Risk of early BM failure (Aplastic Anemia)
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