Department of Pathology Gadjah Mada University School of ... Dasar Neoplasia Blok Biomedis... ·...

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Department of PathologyGadjah Mada University School of Medicine

Blok Biomedis, 4 Maret 2009 [11]

Neoplasia• Neoplasia new growth

• Neoplasm: abnormal tissue mass growing excessively and indefinitely without coordination with normal tissue

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coordination with normal tissue

• Behaviour: progressive, useless, independent from surrounding tissue, unrelated to host needs, parasitic, autonomic.

NEOPLASIA(BASIC SCIENCES OF ONCOLOGY)

GENERAL DIAGNOSIS

COMPREHENSION

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EPIDEMIOLOGY THERAPY

PATHOBIOLOGY MANAGEMENT

NEOPLASIA• General Comprehension of Cancer

Definition, Perspective, Nomenclature, Epidemio-logy, Hereditary Pre-neoplastic Disease

• The Pathobiology of cancer

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Molecular Basis of Cancer, Oncogenes, Apoptotic Genes, Suppressor Genes, Telomerase, Epige-netic Theory

• The Clinical Relevancies of CancerBiology of Tumor Growth, The Kinetic of Tumor, Immunology of Tumor, Clinical Features of Tumor

Related terms

• Hypertrophy• Hyperplasia• Metaplasia

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• Metaplasia• Displasia• Anaplasia

• HAMARTOMA

• Hiperplasia: an increase in the number of cells in an organ/ tissue

• Hipertrofi: an increase in the size of the cells

• Metaplasia : a reversible change in which one adult cell type is replaced by another adult cell type

ISTILAH YANG BERUBUNGAN DENGAN NEOPLASIA

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cell type is replaced by another adult cell type

• Displasia: a loss in the uniformity of the individual cells + a loss of their architectural orientation

• Anaplasia: lack of differentiation

• Hamartoma: tumor like lesion, consist of two/ more mature cell type normally found in an organ in which the lesion arises

Metaplasia

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Apocrine metaplasia of the breast Squamous metaplasia

Diferensiasi

• Suatu proses/keadaan/perkembangan sel tumor sampai tingkat tertentu di mana ada kemiripan sel-sel neoplastik dengan sel asalnya (baik, sedang, buruk tanpa

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asalnya (baik, sedang, buruk tanpa diferensiasi / anaplasi)

Anaplasia:

- pleomorfisma selular dan nuklear- peningkatan rasio inti/sitoplasma- meningkatnya kromatin inti clumping /

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- meningkatnya kromatin inti clumping / irregular

- mitosis patologik bizarre- hilangnya orientasi (polarisasi sel)- hilangnya kapasitas fungsional sel

Dysplasia

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History – 1

Cancer has become increasingly prominent in modern time

Cancer is not a modern disease

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Cancer is not a modern disease

recorded in ancient civilization: mummies from Egypt,

Ramayana history (2500 BC)

• early cultures attributed the cause of cancer

to various gods

History – 2

ancient civilization

middle agesHippocrates: ~400BC 1st theory

of natural causes of cancer: imbalance between

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of natural causes of cancer: imbalance between black humor and the three bodily humors: blood,

phlegm, bile

Cancer house, cancer family, cancer village

History – 3Sir Percival Pott (1775)

(the 1st recorded epidemiological study of cancer)

Young boy as a chimney sweeps In their twentieth had a high rate of death due to cancer of the scrotum then

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high rate of death due to cancer of the scrotum then

he suggested frequent washing and changing of clothing that trapped the soot reduce exposure to “carcinogen”

Other epidemiological study – identified major environmental factors: tobacco smoke, various

occupational exposure

History – 4Invention of microscope

Virchow every cell is born from another cell cancer is a cellular disease

Cell biology molecular genetics the advancement of

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Cell biology molecular genetics the advancement of knowledge about cancer biology cancer is

a genetic disease

Diagnostic, prognostic factors, therapy depend on the study of populations of patients

History – 5Population study of cancer patients

Recognize the presence of heterogeneity

among patients with certain tumors

Predict the probability of certain outcome (e.g. survival as function of time), based on the properties of tumors and host

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time), based on the properties of tumors and host

Challenge in therapeutic studies: application of knowledge about:

produce overall improvements in treatment outcome

with acceptable level of toxicity

The biology of tumor

Normal cells

Malignant cells

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Changes:• Genotypic

• Phenotypic

Nomenklatur (tatanama)

Awalan yang menunjukkan asal jaringan

Skuamosa (epitel gepeng berlapis), adeno-(epitel kelenjar), transisional, fibro- (jaringan ikat fibrosa, leiomio-(otot polos), rabdomio-(otot lurik), lipo-(lemK), kondro (tulang rawan), osteo-(tulang), hemangio-(pembuluh darah), limfangio-(pembuluh limfe)

Awalan yang menunjukkan pola pertumbuhan

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Awalan yang menunjukkan pola pertumbuhan

Folikular, sistik, papilar, vilosa, kribriformis, dll.

Kata tambahan menunjukkan gambaran makroskopik

Scirrhous (keras), medular (lunak, menyerupai sumsum tulang), koloid)

Teratoma

Berasal dari lebih dari satu germ layer (jinak & ganas)

Benign epithelial tumors

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Adenomatous polyp

Benign germ cell tumors

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Benign cystic teratoma (dermoid cyst)

Benign epithelial tumor

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Squamous cell Papilloma

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Fibroadenoma of the breast

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Pleomorphic Adenoma of the salivary gland

Benign vs malignant epithelial tumor

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Adenoma Adenocarcinoma

Malignant epithelial tumor

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Carcinoma of the breast

Malignant tumor

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Cystadenocarcinoma of the ovari

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Squamous cell carcinoma

Malignant Epithelial Tumors

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Carcinoma in situ of the uterine cervix

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Colon carcinoma

Malignant Epithelial Tumors

Well differentiated

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Well differentiated adeno-carcinoma of the colon

Benign germ cell tumors

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Benign cystic teratoma (dermoid cyst)

Malignant mesenchymal tumor

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Rhabdomyosarcoma

Principal characteristics of benign and malignant tumors

Features Benign Malignant

Growth rate Slow Relatively rapid

Mitotic activity Low High

Histologic resemblance to normal tissue

Good Variable, often poor

Nuclear morphology Mostly normal Hyperchromatic,multiple nucleoli, pleomorphic

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Invasion No Yes

Metastasis never Frequent

Border Circumscribed/ encapsulated

Poorly defined/ irregular

Necrosis Rare Common

Ulceration Rare Common

Growth Often exophytic Often endophytic

Malignant Mesenchymal Tumors

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Rhabdomyosarcoma

Benign vs malignant

• Benign malignant

Circumscribed/ encapsulated

Intact surface

Exophytic growth

Ulcerated surfaceEndophytic growth

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Circumscribed/ encapsulated

Homogenous cut surface Heterogenous cut surface due to necrosis

Vascular permeation

Irregular infiltrative edge

Benign vs Malignant Tumors

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Benign vs malignant

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Benign vs malignant mesenchymal tumor

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Leiomyoma of the uteri

Spread of Malignant Tumors

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Metastatic cancer in the liver (pancreatic adenocarcinoma)

Cystic lesion of the breast

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Metastasis

1. Limfogen2. Hematogen

- Sistem venas porta hati- Sistem venosa sistemik paru- Sistem vena paru jantung kiri sirkulasi umum

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- Sistem vena paru jantung kiri sirkulasi umum- Ca uteri & abdomen limfonodi cisterna chyli ductus thoracicus sistemik

3. Trans-coelomic4. Intra-epitelial

The Pathobiology of Cancer

Molecular basis of cancer: Oncogenes and regulator genes

Carcinogenic agents and their cellular interaction: chemical, radiation, viral, bacterial carcinogenesis

Biology of tumor growth: kinetic, angiogenesis, progression and heterogeneity, invasion and metastasis

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and heterogeneity, invasion and metastasis

Host defense against tumors: tumor antigens and immunosurveillance

Clinical features of tumors: efect of tumors on host grading and staging of tumors

Epidemiologi : Faktor risiko

1. UmurMakin tua pengaruh karsinogen makin kuat

2. DietPerbedaan geografis insiden kanker mencerminkan perbedaan diet

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perbedaan dietMinuman alkohol berpengaruh terhadap karsinogenesis

3. LingkunganPolusi (rokok, pekerjaan, kendaraan, pabrik)Ativitas seksual

4. Perubahan genetik

Cancerepidemiology

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Comparison between native Japanese, Japanese immigrants and Calif.white

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HEREDITY & CANCER

Question:Is cancer inherited?

Evidence:Lung cancer in most instances clearly related to

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Lung cancer in most instances clearly related to cigarette smoking, yet,

mortality to lung cancer has been shown to be four times greater among non-smoking relatives

(parents & siblings) of lung cancer patients than non-smoking relatives of controls

Hereditary forms of cancers canbe divided into 3 categories:

1. Inherited Cancer Syndromes (autosomal dominant)

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2. Familial Cancers3. Autosomal Recessive Syndromes of

Defective DNA Repair

• Inheritance of a single mutant gene greatly increases the risk of developing a tumor

• The predisposition of these tumors shows an

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• The predisposition of these tumors shows an autosomal dominant pattern of inheritance

• Inherited predisposition is indicated by strong family history of uncommon cancer and/or associated marker phenotype

Contoh tumor• Familial retinoblastoma• Familial adenomatous polyposis

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• Familial adenomatous polyposis of the colon

• Multiple endocrine neoplasia syndromes (MEN)

• Neurofibromatosis type 1 and 2• Von Hippel–Lindau Syndromes

Inherited Cancer Syndromes

RETINOBLASTOMA• Carriers of mutant Rb

gene have a 10,000 fold increased risk of

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increased risk of developing retinoblastoma (familial type)

• greatly increased of developing second cancer (ostreosarcoma)

Multiple endocrine neoplasia (MEN)- The familial occurrence of the combination of:

medullary thyroid Ca, bilateral pheochromocy-tomas, hyperparathyroidism (due to tumor)

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tomas, hyperparathyroidism (due to tumor)- Mutation of ret proto-oncogene that is transmitted

in the germline

Von Recklinghausen neurofibromatosis type 1 and 2- multiple benign neurofibromas, cafe au laitspot, iris hamartoma, increased risk of

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spot, iris hamartoma, increased risk of developing fibrosarcomas

- mutation of NF-1 and NF-2 (tumor suppressorgenes which functions as a GAP protein that inactivates ras)

Familial Adenomatous Polyposis Coli• Another hereditary disorder marked by

an extraordunarily high risk of cancer

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an extraordunarily high risk of cancer • Autosomal dominant mutation from

birth innumerable polypoid adenomas mostly develop colon Ca by age of 50

Adenoma-Carcinoma Sequence

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Von Hippel-Lindau Syndrome

• Germ line mutation of VHN gene on chromosome 3p hereditary renal cell

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chromosome 3p hereditary renal cell cancer, phaeochromocytoma, hemangioblastoma of the CNS, retinal angioma, renal cyst

2. Familial Cancers

Evident familial clustering of cancer but role of inherited predisposition may not be clear in an individual case

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– Breast Cancer

– Ovarian cancer

– Colon cancer other than familial adenomatous polyps

3. Autosomal Recessive Syndromes of Defective DNA Repair

Xeroderma pigmentosum

Ataxia telangiectasia

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Ataxia telangiectasia

Bloom syndrome

Fancony anemia

- autosomal recessive disorder hypersensitive to UV

Xeroderma pigmentosum

Autosomal Recessive Syndromes of Defective DNA Repair

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- increased incidence of skin cancers- defect in genes that function in nucleotide

excision repair, which is required for repair of UV-induced pyrimidine dimers

Ataxia Telangiectasia AT gene (mutation in single gene)

– Gradual loss of Purkinje cells

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– Immunodeficiency

– Acute sensitivity to ionizing radiation

– Profound susceptibility to lymphoid malignancies

Bloom Syndrome• Hypersensitivity to ionizing

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• Hypersensitivity to ionizing radiation

• Developmental defects

• Predisposition to cancer

Fanconi anemia• Hypersensitivity to DNA cross-

linking agents (nitrogen mustard)

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linking agents (nitrogen mustard)

• Anemia

• Predisposition to cancer

Acquired Pre–neoplastic Disorders

• Cell replication is involved in cancerous transformation

• Fertile soil for the origin of malignant neoplasm:- regenerative proliferation: hepatoma- hyperplasia: endometrium

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- hyperplasia: endometrium- dysplasia: cervical- metaplasia: bronchogenic Ca

the risk to develop neoplasm isgreater than average

• Certain non-neoplastic disorder pre-neoplastic

- chronic atrophic gastritis

- solar keratosis

Acquired Pre–neoplastic Disorders

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- solar keratosis

- leukoplakia

The great majority of instances no malignant neoplasm emerges the term persists because it calls attention to the increased risk

The question then …….

Is there any risk with all benign neoplasms?

• although some risk may be inherent, most benign neoplasm neoplasms do not become cancerous.

• Some malignant tumors were developed from benign tumors: leiomyoma leiomyosarcoma, pleomorphic adenoma Ca

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Was the tumor an indolent form of cancer from the outset, or was there a malignant focus in the benign tumor?

• Generalization is impossible because each type of benign neoplasm is associated with a particular level of risk ranging from almost zero to frequently present

PATOGENESIS KANKER

• Faktor geografik dan lingkungan

• Umur

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• Umur

• Predisposisi genetik

• Predisposisi non-herediter

Bacteria?

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CARCINOGENESIS

The Molecular basis of Cancer

• Jantung permasalahan karsinogenesis: kerusakan genetik non-letal

• Tumor terbentuk dengan eksansi klonal sel

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• Tumor terbentuk dengan eksansi klonal sel prekursor tunggal akibat dari kerusakan genetik

• Karsinogenesis adalah suatu proses multistep pada tingkat genetik dan fenotipik sekaligus

CARCINOGENESIS

The Molecular basis of Cancer

• 4 kelas gena regulator normal (target utama kerusakan genetik): (1) growth promoting protooncogenes, (2) antioncogenes (growth inhibiting suppressor genes), (3) apoptotic genes (mengatur programmed cell death), dan

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genes (mengatur programmed cell death), dan (4) gena reparasi DNA

• Gena reparasi DNA mempengaruhi proliferasi sel dan survival secara tidak langsung dengan kemampuan reparasi kerusakan non letal gena lain, termasuk gena-gena replikasi sel.

Perubahan fenotipik• Sifat pertumbuhan

- lepas dari kontrol- kegagalan maturasi- transplantable- immortal

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- immortal• Perubahan morfologik• Kariotipik• Antigenik• Deviasi metabolik• Membran sel

AKTIVASI ONOGENA

Mekanisma perubahan protoonkogena menjadi onkogena

• Perubahan struktur gena prodk gena abnormal (onkoprotein) - Mutasi titik

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- Insersi dan delesi• Perubahan regulasi: expresi gena meningkatkan

produksi berlebihan protein perangsang pertumbuhan (growth-promoting protein)- translokasi kromosom- amplifikasi gena

Mutasi titik• ras oncogene the best example

• A very large number of human tumors carry ras point-mutations

• Mutation affect a domain critical to the GAP-induced hydrolysis of GTP mutant ras proteins have a reduced ability to hydrolyze GTP

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ability to hydrolyze GTP

• Frequency:

- 90%: pancreatic adenocarcinoma

- 50%: colon and thyroid cancer

- 30%: lung adenocarcinoma & myeloid leukemia

- 0%: most ovarian and breast tumors

Chromosomaltranslocations

Burkitt’s lymphoma

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Chronic Myelogenous Leukemia

GeneAmplification

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• Amplification of N-myc gene in neuroblastoma: double minutes / HSR (Homogenous-staining region)

CANCER SUPPRESSOR GENES

• Misnomer

• Physiologic function: regulate cell growth

apply brakes to cell proliferation

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apply brakes to cell proliferation

• Discovered by studying rare disease such as retinoblastoma

• Knudson “two-hit” hypothysis of oncogenesis

Sub-cellular location of protein product of tumor suppressor genes

2 broad categories regarding the functions:Molecules that regulate nuclear transcription and cell

cycle• Cell surface: TGF-receptor, E-cadherin• Under plasma mebrane: NF-1

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• Under plasma mebrane: NF-1• Cytoskeleton: NF-2• Cytosol: APCMolecules that regulate signal tranduction• Nucleus: Rb, p53, WT-1, p16(INK4a), BRCA-1,

BRCA-2

CANCER SUPPRESSOR GENES

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The central role of the pRB in regulating the cell cycle

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Selected tumor-suppressor gene involved in human neoplasm

TGF-β receptor

• Function: Growth inhibition

• Tumors associated with somatic mutation:

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• Tumors associated with somatic mutation:Carcinoma of colon

• Tumors associated with inherited mutation:Unknown

E-cadherin

• Function:

Cell adhesion

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Ca. gaster & breast

• Tumors associated with inherited mutation:

Familial gastric cancer

• Function:

Inhibition of ras signal transduction

Schwannoma

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Schwannoma

Neurofibromatosis type 1 and sarcomas

• Function:

Unknown

Schwannoma and meningioma

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Schwannoma and meningioma

Neurofibromatosis type 2,

acoustic schwannoma & meningioma

• Function:

Inhibition of signal transduction

Ca. of stomach, colon, pancreas;

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Ca. of stomach, colon, pancreas; melanoma

Familial Adenomatous Polyposis coli;

colon cancer

Rb• Function:

Regulation of cell cycle

Retinoblastoma, osteosarcoma,

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Retinoblastoma, osteosarcoma,

Ca breast, colon, lung

Retinoblastoma, osteosarcoma

• Function:Regulation of cell cycle & apoptosis

in responseto DNA damage

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• Tumors associated with somatic mutation:Ca. gaster & breast

• Tumors associated with inherited mutation:Li-Fraumeni syndromeMultiple carcinoma and sarcoma

WT-1• Function:

Nuclear transcription

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Wilms tumor

p16(INK-4a)• Function:

Regulation of cell cycle by inhibiting CDK

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Pancreatic, esophageal cancer

Melanoma

BRCA-1

• Function:

DNA repair

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Unknown

Ca of female breast and ovary

BRCA-2

• Function:

DNA repair

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Unknown

Ca of male and female breast

The role of p53 in maintaining the integrity of the genome

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Apoptosis(programmed cell death)

Internally programmed and coordinated death / loss of single cells spread among healthy cells,

in a form of cell death designed to eliminate unwanted

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in a form of cell death designed to eliminate unwanted cells,

through the serial event activities,

by a set of responsible gene product.

Genes that Regulate Apoptosis

bcl-2 family:

Antagonists

bcl-2 and bcl-xL

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bcl-2 and bcl-xL

Agonists

bax, bcl-xS, bad, bid

Regulation of cell death

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Biological Mechanism

1. Signaling pathways apoptosis initiation

2. Control and integration balance between negative regulatory molecule

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(inhibit) and positive (stimulate)

3. Common-execution phase actual death program accomplished largely by caspase family protease

4. Removal of death cells by phagocytosis

APOPTOSIS

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Promotion of Carcinogenesis

• Promoters: phorbol esters, hormone, phenols, drugs

• Not mutagenic how do they contribute to tumorigenesis study of TPA

• TPA: - phorbol esters

- powerful activator for protein kinase C, an

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- powerful activator for protein kinase C, an

enzyme that phophrylates several substrates

involved in signal transduction pathways

Initiation&

Promotion

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Initiation & promotion

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Radiation Carcinogenesis

• Transform all kind of cells in vitro and induce neoplasms in vivo, in human & experimental animal

• UV light skin cancer

• Ionizing radiation of medical, occupational, and bomb of

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• Ionizing radiation of medical, occupational, and bomb of origins produce a variety of malignant neoplasms

• The effect of UV light is somewhat differ from those of ionizing radiation

Hierarchy of Vulnerability1. Leukemia

2. Thyroid

3. Breast, lung, salivary gland (intermediate)

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(intermediate)

4. Skin, bone, gastrointestinal tract (relatively resistant)

Sifat dasar transformasi sel

1. Pemenuhan kebutuhan sendiri signal pertumbuhan

2. Insensitif terhadap signal inhibisi

3. Kemampuan mengelak dari aapoptosis

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3. Kemampuan mengelak dari aapoptosis

4. Kehilangan kemampuan reparasi DNA

5. Potensi replikasi tak terbatas

6. Kemampuan angiogenesis terus menerus

7. Kemampuan invasi dan metastasis

8. Melepaskan diri dari imunitas dan rejeksi

Department of Pathology Gadjah Mada University School of ... Dasar Neoplasia Blok Biomedis... ·...

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