k1-perspectife, blok onk defi
DESCRIPTION
oncoTRANSCRIPT
Dr, EMIR T PASARIBU SpB(K) OnkDr. SUYATNO SpB(K) Onk
Dr. Deri Edianto SpOG(K) OnkFK-USU/ RS.HAM
PERSPECTIVE
Cancer is not modern diseaseHippocrates (± 400 bc): Cancer as imbalance between black humor (spleen) and three bodily humor (blood,plegm, bile)
Sir Percival Pott (1775): one of the first scientific inquiries in to the cause of the cancer → observed chimney soot as carcinogen for cancer of the scrotal.
Virchow, 19 th century, pathologist
“every cell is born from another cell”
Cancer as a cellular disease, where was loss of normal control of the cell prolifration
Fisher: Breast cancer is systemic disease as its inception
Mormons in UtahMany type of cancer depend on
relatedness – that is, on the sharing of genes
Cancer, as a genetic disease
Basic molecules of life
All life depends on three critical molecules: 1.DNAs
Hold information on how cell works2.RNAs
Act to transfer short pieces of information to different parts of cell
Provide templates to synthesize into protein3.Proteins
Form enzymes that send signals to other cells and regulate gene activity
Form body’s major components (e.g. hair, skin, etc.)
Mathematical Biosciences Institute (Ohio State Univ), 2 October 2003
RNA
Protein
DNADOGMA CENTRAL
Central Dogma of Molecular Biology
DNA
RNA
Protein
Transcription
Translation
A gene is expressed in 3 steps:
1) Transcription: RNA synthesis
2) Splicing: removal of intron sequence from RNA
3) Translation: Protein synthesis
Genetic alteration may arise direct or indirect from:
1.Inherited gen mutations2.Chemical or radiation induced DNA
damage and genetic instability3.Incorporation of virus into the cell4.Random error during DNA synthesis
Cause of cancer? Multiple genetic abnormalities Internal factors : defect
genetic/inherited External factors :
X RAYSViral infectionsCarcinogenic compounds : food, working area, lifestyle
Cancer: General Etiology and Pathogenesis
KARSINOGENESIS Merupakan proses perubahan menjadi
kanker Melalui tahapan multi step karsinogenesis
1.TAHAP INISIASI2.TAHAP PROMOSI3.TAHAP PROGRESI (Transformasi maligna)
Inisiasi dan Promosi akibat akumulasi mutasi DNA → reversibel eg. displasia
PROGRESI → irreversibel
INTERAKSI INISIATOR DAN PROMOTOR
How does a Proto-oncogene become an Oncogene?
Proto-Oncogene Oncogene
1.Mutation 2. Abnormal Activity
3.Gene Translocation 4. Amplification
Abnormal Activity
Functions of oncogene
1. Growth Factor (ex: Epithelium growth factor EGF , and platelet derived growth factor PDGF)
2. Growth Factor Receptor (Ex: PDGFR)
3. Signal transudation (example; Ras, Raf, & MEK)
4. Transcription Factor (example; Jun, Fos, Elk-1 & myc)
Oncogenes Oncogene causes cancer by affecting:
1. Cell Proliferation: (ex: Ras, Raf, EGF)
2. Cell differentiation (ex: PML/RAR that inhibits the differentiation of promyelocyte to granulocyte which will maintain the cell in its active proliferate state)
3. Cell Survival (ex: Pl-3/AKT will activate BCL-2 inhibit Apoptosis & maintain cell survival.
Tumour Suppressor Genes Tumour Suppressor genes: are genes
that act to inhibit cell proliferation and tumour development.
If Tumor Suppresor Gene was
Mutated Inactivated
It will lead to cell transformation
OR
Function of Tumour Suppressor gene1. Antagonize the action of oncogene. (ex.PTEN
which converts PIPIII to PIPII because PIPIII will activate Pl-3/AKT which will activate BCL-2 that will inhibit apoptosis and induce cell transformation)
PIPII PIPIIIPTEN
AKT
BCL-2
Inhibit apoptosis & induce cell transformation
PI-3
Function of Tumour Suppressor gene
2. Transcription factorsRepressor transcription factors: exa, WT1 is a repressor that appears to suppress transcription factor ( Insulin like growth factor) which will contribute in the development of tumour
Activator transcription factors: exa,SMAD family that are activated by TGF-β, leading to inhibition of cell proliferation
Function of Tumour Suppressor gene3. Regulate cell cycle :
Rb gene: that inhibits the cell cycle in the G1 phase decrease cell proliferation
INK-4 gene: that produces P16 that inhibits cdk4/cyclin D action ( to phosphorylate Rb gene to inactivate it’s action)
P53: that produces P21 that has the same action of P16 in inhibiting the action of cdk4/cyclin D
Function of Tumour Suppressor gene
4. Induce apoptosis:P53 release will increase Bax
form holes in the mitochondria
release cytochrom c activate apoptosis
Tumor Growth number of number of cancer cellscancer cells
diagnosticdiagnosticthresholdthreshold
(1cm)(1cm)
timetime
undetectable undetectable cancercancer
detectable detectable cancercancer
limit ofclinical
detection
hostdeath
10 10 1212
10 10 99
Gompertzian Growth• Growth rates are exponential at early stages of
development and slower at later stages of development.
24
- Biological growth follows this characteristic curve.- Biological growth follows this characteristic curve.
The Future of Onccology
PreventionEarly detectionTreatment
Biomarkers and Prevention…?Folate and vit B12 – decreased breast Ca
risk (Canc Epid Biomarkers Prev 2006;15(3):443-448)
Genetic variation of Nucleotide excission repair (NER) and cancer risk ( Canc Epid Biomarkers Prev 2006;15:536-542)
Lipid profile :Monosaturates lipid elevated and low ratio w6/w3 fatty acid – decreased breast ca risk ( Canc Epid Biomarkers Prev 2006;15:416-421)
Cancer DetectionCancer detection :
Clinical detection by mammogram, coloscopy… etc
Molecular detection Serotype
Restriction fragment length polymorphism (RFLP)
PCRWestern Blot
CANCER TREATMENTSURGERYRADIATION THERAPYCHEMOTHERAPYHORMONAL THERAPYTARGETED THERAPY
Cancer Treatment Chemotherapy:
Deals with DNA damage, & has affinity to all proliferating cells not specifying if it was a cancer cell or not.
Inhibiting AngiogenesisInhibit blood flow/supply to the tumour
cellsDecrease franesylation of Ras
Decrease activation of Ras, because Ras mutation causes most cancers.
Monoclonal Antibody
Molecular target in cancer therapy
Anti tyrosine kinase: Gleevec, IressaAnti VEGFEGFR inhibitor etc
Need to enhance translational research into early IRT-MTA (Interdiscilinary Research Teams) for
Molecular Target assesment
Estrogenbiosynthesis
Tumor cell
Nucleus
Inhibition of cell
proliferation
Estrogenbiosynthesis
Antiestrogens
AIs
AIs = aromatase inhibitors.
Development of Technical Operation of Breast Cancer
Ancient → → CRM/MRM → → BCT → → NSP+TRAM
Key wordsOncogenesis: Pathogenesis of neoplasm (b/m)Carcinogenesis: Pathogenesis of cancer (m)Carcinogen - agent causing cancer.Oncogen - agent causing neoplasm.Mutagen - agent causing mutation.Tumour Suppressor genes: are genes that act to inhibit cell proliferation and tumour development.
1. Tannock IF. Introduction to Cancer Biology. In : The Basic Science of Oncology, Mc Graw-Hill Inc, Boston, 2005.
2. Devita VT, Hellman S, Rosenberg SA. Penyunting. Cancer Principlels & practice of Oncology. Edisi ke-8. Philadelphia. Lippincott William & Wilkins. 2008.
3. Sofia MH. Mutagenesis dan Transformasi, Basic Science of Oncology, Ilmu Onkologi Dasar. POI.BP FKUI, Jakarta 2010
4. Cornain S. Perangai Biologik Sel Kanker dan Onkogenesis, Basic Science of Oncology, Ilmu Onkologi Dasar, POI,BP FKUI,Jakarta 2010