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