BERTHA NAPITUPULU 080100151 FK USU A2

K1-Introduction to Cancer Biology

by: Dr. Suyatno SpB(K)Onk

PERSPECTIVE

Cancer is not modern disease Hippocrates ( 4oo bc): Cancer as imbalance between black humor (spleen) and three bodily humor (blood,phlegm, bile) Sir Percival Pott (1775): one of the first scientific inquiries in to the cause of the cancer observed chimney soot as carcinogen for prostate cancer

 Recenly, the most important in knowledge about the biology of cancer are understanding of moleculer genetics The current model for cancer development cells undergoing a series genetic mutations and/or alteration, which result inability to respon normally to intracellular and/or extracellular signals

Basic molecules of life

All life depends on three critical molecules: DNAs Hold information on how cell works RNAs Act to transfer short pieces of information to different parts of cell Provide templates to synthesize into protein Proteins Form enzymes that send signals to other cells and regulate gene activity Form body s major components (e.g. hair, skin, etc.)

DOGMA CENTRAL

DNA

RNA

Protein

Mathematical Biosciences Institute (Ohio State Univ), 2 October 2003

Central Dogma of Molecular Biology DNA

Translation

RNA
Transcription A gene is expressed in 3 steps: 1) Transcription: RNA synthesis 2) Splicing: removal of intron sequence from RNA 3) Translation: Protein synthesis

Protein

How much DNA do we have?

Humans have 2 x 23 chromosomes EACH cells contains 6 billion bases DNA That is 1 meter of DNA A human being has >100.000.000.000.000 cells That is 100 billion km of DNA

 Genetic alteration may arise direct or indirect from: 1. Inherited gen mutations 2. Chemical or radiation induced DNA damage and genetic instability 3. Incorporation of virus into the cell 4. Random error during DNA synthesis

Characteristic Cancer Growth

Disturbed Growth Control :
- Lose of contact inhibition, - Need of growth factor is decreased, - Anchorage independent

Fail of maturation Immortal Could to transplantation

Cancer: General Etiology and Pathogen esis

 Carcinogenesis is multi stage process: inisiation promotion progression (malignant tranformation). Inisiation and promotion cause acumulation DNA mutation reversibel eg. displasia PROGRESSION irreversibel

Step 1: Initiation
Inisiation is exposed cell by single carcinogenic agent (inisiator) Simple mutation in one or more cellular genes that control key regulatory pathways of the cell

From: Brooks, Chap. 7

Step 2: Promotion

From: Brooks, Chap. 7

Step 3: Progression
Karyotypic instability
Increased growth rates Increased invasiveness Increased hormonal reponsse Anaplasia

Interaction Inisiator and Promotor

The Future of Oncology Since increase understanding of cancer moleculer, several therapy developed with better outcome Eg ; patient with chronic myelogenous leukemia can be treated with succesfully using imatinib (specific competitive inhibitor) In the future, treatment strategies decide on genetic footprint of the cancer rather than on histopathological type.

Molecular target in cancer therapy

Anti tyrosine kinase: Gleevec, Iressa Anti VEGF: bevacizumab EGFR inhibitor : trastuzumab

Need to enhance translational research into early IRT-MTA (Interdiscilinary Research Teams) for Molecular Target assesment

Key words
Oncogenesis: 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.

Impact on Technical Operation of Breast Cancer

Ancient

CRM/MRM

BCT

NSP+TRAM

BERTHA NAPITUPULU 080100151 FK USU A2

K2-Cancer Epidemiology
Hematology Oncology Division Child Health Departement Universty of Sumatera Utara

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Epidemiology
The study of distribution and determinants of disease in human population ; why different population or group are at different risks for diferrent disease Patterns of incidence and death rates of malignant disease : sex,age,race,geography
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Childhood cancer
is rare less than 1 % of all cancer in industrialized countries Several types of cancer are virtually unique to childhood, whereas the carcinomas most frequently seen in adults Some of the most striking progress in cancer treatment has been made in paediatric oncology Investigation of childhood tumours has led to major advances in the understanding of the genetic
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Concept epidemiology

1.Disease is not randomly distributed 2.Disease causation is multifactorial

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The scope of Epidemiology

Concerned with population health Concern to clinicians Clinical researchers Laboratory scientiest

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General approach
What Who Where When

Descriptive epidemiology

Analytic epidemiology
Why How
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Types of epidemilogical
Occupational epidemiology : effects of workplace exposures on workers Clinical epidemiology : outcome the patients Genetic epidemiology: focus on familes or high risk individual, concerned with determinants of disease in families and on inherited causes of cancer in population Nutritional or environmental epidemiology Molecular epidemiology
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Application epidemiology Planning Evaluation of cancer control Primary prevention Early detection Scope of cancer epidemiology: broad concern causes of cancer identification of population where risk reduced prevention
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Cancer statistic
When a patient is diagnosed with cancer one of the first questions an oncologist will be asked: how long do I have Survival based statistics : observational studies : 1.relative 5-year survival rates 2.Overall survival 3.Median survival

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Cancer trends
- Relatifve 5-year survival rate for all cancer: 1975 - 1977 : 51% 1996 - 2002 : 66% The reason: Multifactorial: Increasing:1. diagnostic test:mammogram,Pap smears,prostate specific antigen 2.immunosupression 3.the aging of population
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Leading cancer types in Indonesia 1.Cervix cancer 2.Breast cancer 3.Colorectal cancer 4.Lung cancer 5.Nasopharyng cancer

( POI=Perhimpunan Onkologi Indonesia)

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Leading cancer types among African American

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Male
Prostate Lung and bronchus Colon and rectum NHL Oral cavity Kidney Urinary bladder Pancreas Stomach liver
Basic science of Oncology 2011

Female
Breast Lung and bronchus Colon and rectum Uterine corpus Pancreas Ovary NHL Kidney Multiple Myeloma

Leading cancer in children

Leukemia Lymphoma and Reticuloendothelial neoplasms CNS tumours Retinoblastoma Renal Tumours Hepatic Tumours
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.cancer in children

Malignant Bone tumours Soft Tissue sarcomas Germ Cell, trophoblastic and other gonadal neoplasms Carcinomas and other malignant epithelial neoplasms Other and unspecified malignant neoplasms

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Etiology
Chemical carcinogens Environmental and industrial carcinogens Drug induced cancers Radiation carcinogenesis Viral and immunologic mechanisms

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Etiology
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A.Chemical carcinogens 1.Industrial exposure 2-Naphthylamine Benzidine Bis(chloromethyl)ether Bis(2-chloroethyl)sulfide (mustard gas) Vinyl chloride Certain tars,soots,oils
Basic science of Oncology 2011

Chromium compounds Nickel compounds Asbestos Benzene

Chemicals
pesticides (CNS tumors) solvents (eg, CNS tumors, leukemia, neuroblastoma, hepatoblastoma) metals (hepatoblastoma) petroleum products (eg, Wilms tumor, leukemia, hepatoblastoma) lead (Wilms tumor) boron (Wilms tumor) furnaces (lymphoma) chemotherapy (leukemia)

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2.Medical exposure N,N-bis(2-chloroethyl)-2naphthylamine (Chlornaphazin) Diethylstilbestrol Inorganic arsenic comp. Mephalan,cyclophospha mide Azathioprine,Phenytoin
Basic science of Oncology 2011

3.Societal exposure Cigarette smoke Betel nut and tobacco quid

2.Radiation carcinogenesis:medical x-rays,atomic weapon,radon in house

3.Viral and immunologic mechanisms -Epstein-Barr virus -Hepatitis-B -HIV 4.Environmental: ultraviolet
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 Environmental Factors
Ionizing radiation Data derived from the atomic bomb exposures at Hiroshima and Nagasaki Leukemia Electromagnetic fields Published reports have suggested that electromagnetic fields have some potential effect on the promotion of leukemia
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Cancers 7 warning signals

1.Change in bowel or bladder habits 2.A sore that does not heal 3.Unusual bleeding or discharge 4.Thickening or lump in breast or elsewhere 5.Indigestionor difficulty in swallowing 6.Obvious change in wart or mole 7.Nagging cough or hoarseness If you have a warning signal ,see your doctor
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Role of infection
Epstein-Barr virus (EBV) Underdeveloped country rate infection in infancy , high the age of onset HD -EBV is present in 40 60% of cases -chronic viral infection activation of cellular oncogenes, loss of tumour suppressor genes and deregulation of several cytin

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 Epstein-Barr virus (EBV) African Burkitt lymphoma Hodgkin lymphoma Nasopharyngeal carcinoma HIV-induced immunosuppression CNS lymphoma Leiomyosarcoma

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BERTHA NAPITUPULU 080100151 FK USU A2

K2B-CARCINOGENESIS
Hematology-Oncology Division Child Health Dept. University of Sumatera Utara

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Normal human cell populate specific areas of the body:function,grow,divide in response to signals (i.e,growth factors) die ( checkpoints cell growth death ) Malignancy : cell develop genetic defects DNA change lose growth pattern resistent to celullar mechanism , ability to acoid programmed cell death , leave their usual site travel blood stream, lymphatic system grow in new location
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Principal genes

Oncogenes Tumor suppressor genes Apoptosis ( programmed cell death )

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Oncogenes :genes whose normal function involves promoting the growth and reproduction of cells in regulated When uncontrolled malignant transformation of cell Tumor suppressor genes :normal to stop cell proliferation p53 P53 lost DNA damage not repair mutation malignant transformation
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 Genesis of malignant tumor : multistep process , involves derangement of multiple genes normal function of cells Most malignancy do not have a clear hereditary genetic basis

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Genetic cancer syndromes Familial Retinoblastoma Li-Fraumeni syndrome Wilms Tumor Neurofibromatosis Type I Familial Adenomatous polyposis Multiple endocrine neoplasia Hereditary nonpolyposis colon cancer
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Carcinogenesis :multistage process that leads to uncontrolled clonal cell growth evolution of normal cells into malignant cells Stage carcinogenesis: 1.Transformation 2.Growth 3.Local invasion 4.Metastasis

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Carcinogen: any subtance when exposed to living tissue potential to lead cancer 1.Radiation : ultraviolet, ionizing 2.Infection agents: virus,bacteria,flatworms 3.Chemical : -direct acting initiators: vinyl chloride -indirect initiators (procarcinogen ) : polycyclic aromatic hydrocarbon 4.Foreign body reaction :asbestos, silica

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What are intervals between exposure to a carcinogen and the development of cancer?
from a few years to decade Epidemiologic studies very complicated Smoking related cancers : after 15 years of exposure Asbestos related cancer : 25 40 years Ionizing radiation related skin cancer and leukemia : few years Malignancies of connective tissue , and adenocarcinoma : 15 30 years
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Exposure in children Appear more dangerous Carcinogenic interval : shorter Increased overall exposure concentration Increased level of replicating cells

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How can prevent or minimized carcinogenesis

Minimize exposure to carcinogen Dont smoke Maintain healthy diet : adequate fiber , antioxidant Use sunscreen and limit intense sun exposure Childhood Immunization: avoid viral infection associated with cancer ( Hepatitis B) Hereditary risk cancer : intensive screening Treatment pre-cancerous lesion (e.g.excision) Avoid excessive iatrogenic drug (antineoplastic, estrogen,oral contraceptive,diethylstilbestrol )
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How can we prevent or minimize carcinogenesis?

Choose cancer free abcestors Minimize exposure to carcinogens Dont smoke Maintain a nutritious diet with antioxidant Use sunscreen and limit intense sun exposure Immunization: avoid viral infection associated with cancer Intensive screening: for hereditary risk Treatment of pre-cancerous lesions Avoid excessive iatrogenic drugs and hormones
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BERTHA NAPITUPULU 080100151 FK USU A2

K3-4 BLOK ONCOLOGY

Biochemistry Department Medical Faculty USU

TUMOR GENETICS
PROTOONCOGENES ONCOGENES TUMORSUPPRESSOR GENES CARCINOGENESIS: MOLECULAR MECHANISM OF TUMOR CELLULAR TRANSFORMATION

TUMOR MECHANISM
HOW TO DETECT A TUMOR HOW TO DIAGNOSED HOW TO UNDERSTAND THE MECHANISM HOW ARE THE MOLECULAR PATHWAY IN WHAT CONDITION COULD WE TREAT THE TUMOR WHAT KIND OF TREATMENT

THE NEW TUMOR DRUGS

Proto Oncogen and Oncogen

Oncogen
Genes that possess the ability to cause cellular transformation. Act in a dominant fashion, either overexpression or activating mutations. Cellular transformation. morphologic changes, loss of contact inhibition, anchorage independent growth, ability to form tumors when transplanted into nude mice.

 Proto-oncogene.
Potential to become activated into a cancer causing oncogene. Have been found in all multicellular organisms. Would be involved : basic essential functions of the cell related to control of cell proliferation and differentiation. In normal cell : expression is tightly controlled.

Protooncogen products
SIS ABL

SRC RAS

FMS Orga nella

Nucleus FOS MYC JUN

FMS

MOS

ERB-B1

Cell Cycle

 Cell-cycle control system is based on cyclically activated protein kinases : -Cdks (cyclin dependent kinases) -Cyclins (cdk regulator protein), without cyclins cdk is inactive.

Proto-oncogenes
1.Growth Factors
Stimulate cells in stationary stage to enter the cell cycle. Occurs in a two stage process :
Stimulation to proceed into G1 provided by PDGF,EGF,followed by progression factors :IGF to progress through the cell cycle.

Action via autocrine and paracrine model.

 2.Growth factor receptors

Link the information from extracellular environment (GF) to a number of different intracellular signaling pathways. The most important : transmembrane receptor tyrosine kinases.

 3. Signal transducers.
Cytoplasmic nonreceptor tyrosine kinases. Proteins with enzyme activity such as phospholipase C , PI3-K Adaptor proteins : Grb2 SH2 and SH3 domain. Three major pathways : PI3-kinase (PI3-K/AKT pathway, RAS/mitogen-activated protein kinase (MAPK) pathway, JAK/STAT pathway.

 4. Nuclear proto-oncogene and transcription factors.

Involved in the control of gene expression by their action on DNA itself Final site of action for messages sent from GF. Level at which control of growth and proliferation.

 G-Protein and Signal transduction

CARCINOGENESIS

MOLECULAR MECHANISM OF TUMOR CELLULAR TRANSFORMATION

Mechanisms of oncogene activation

1. Structural alteration.
Point mutations Chromosomal translocation Truncated form of protein (transition mutation)

2. Amplification 3. Deregulated expression

Insertional mutagenesis Translocation.

Tumor suppressor genes

Play an important role in tumorigenesis. Involved in the control of abnormal cell proliferation. Loss or inactivation : association with the development of malignancy.

Viral Oncogene
Three major mechanisms by which an infectious agent can cause cancer 1. Persistent infection chronic inflammation repeated cycles of cell damage and cellular proliferation accumulate genetic mutations initiation and promotion of cancer .

CHRONIC INFLAMMATION AFFECTS MULTIPLE PATHWAYS

Chronic Inflammation
Cytokines Free radicals

DNA Damage ATM ATM NFOB Pathway p53 Pathway MEK/ERK ATM p14ARF RB Pathway

Cell Survival

Cell cycle arrest

DNA Apoptosis Repair

Cytokines, e.g., TNF, IL-1, IL-6, IL-8

 2.Direct participation of infectious agents in the transformation of the cell through activation of cellular oncogene pathway. 3. Relevant to HIV : infection may result in immunosuppression and decreased recognition of infected or transformed cell by host immune system.

Gene
TRANSCRIPTION

Primary transcript NUCLEUS

Degradation

MODIFICATION / PROCESSING

mRNA

Degradation Transport

mRNA CYTOPLASM

Active degradation

inactive

TRANSLATION

Protein

Degradation

Mechanisms of retroviral oncogenesis.

1. Slowly transforming viruses.
Insertional mutagenesis

2. Acutely transforming viruses.

Oncogene transduction

3. Trans-acting retroviruses.
Affect expression or function of cellular growth and differentiation genes.
HTLV1 ( the only human retrovirus known to directly cause cancer).

FREE RADICALS AND INFLAMMATION

ROS OH O2-
(Hydroxyl (Superoxide) radical)

NO

(Nitric Oxide) (Peroxynitrite)

RNS ONOO- N2O3

Protein Damage
(DNA Repair Enzymes, Caspases)

Lipid Peroxidation MDA

(malondialdehyde)

DNA Damage and Mutation

Nitrosamines/Deamination 8--oxo-dG 8-nitroguanine Etheno Adducts M1G Adduct S-nitrosothiol SSBs DSBs

4HNE
(4-hydroxynonenal)

Arachidonic Acid Cascade Eicosanoids Cell Proliferation

1760-CH

Apoptosis
Programmed cell death Intracellular machinery responsible for apoptosis is called caspases. Caspases
Synthesized in the cell as inactive precursor called procaspases Usually activated by cleavage at aspartic acids by other caspases.