ONCOGENESIS

Primariadewi.Rustamadji
Maria Francisca Ham
Department of Anatomical Pathology
FMUI
2023
 Tumor or neoplasia
is abnormal tissue, excessive growth,
uncoordinated with normal tissue and continue
growing eventhough the initial stimulus already
gone
(cells/tissue grow autonomously )

Study of tumors is called : ONCOLOGY

ONCOLOGY (ONCOGENESIS)

Normal Cells

Cellular stage changes

Permanent genetic changes

Uncontrolled cell division

Tumor
 Normal Growth Regulation
Mechanisms
1. Proto-oncogenes — Oncogenes

2. Tumor supressor genes — anti oncogenes

3. Apoptosis regulating genes

4. DNA repair genes

 CANCER GENES

• Genes that are recurrently affected by genetic

aberrations in cancers divided into 4 major types :

• 1. ONCOGENES
• 2. TUMOR SUPRESSOR GENES
• 3. APOPTOSIS REGULATING GENES
• 4. Tumor cell-host cells interaction regulating genes

Robbins&Kumar
Basic Pathology, 2023
CELL CYCLE

Stimulated by
growth factor
; PDGF,EGF

Inhibited
by pRb,p53
CELL CYCLE

Stimulated by
growth factor
; PDGF,EGF

Inhibited
by pRb,p53
Robbins&Kumar
Basic Pathology, 2023
Classification of cells based on cell/tissue
origin (histogenesis)
1. Totipotent cell
2. Pluripotent embryonal cell
3. Differentiated cell

NEOPLASMA come from totipotent cell

1. Totipotent cell

Cells which can differentiate into every

type of cells in the body
(i.e : zygote developed into fetus)
This cell frequently found in the gonad,
the GERMINAL CELL
2. Pluripotent embryonal cell
Pluripotent embryonal cell
can differentiate into various type of cells
and as a tumor can form various organ
structure of the body.
(i.e.: Nephroblastoma,
differentiated into renal tubules, muscle
tissue, cartilage or rudimentary bone)
 Based on the tumor behaviour

Benign Tumor Malignant Tumor

Epithelial- Oma
Adenoma (gland) Epithelial - Mesenchymal -
Papilloma Carcinoma Sarcoma
(Surfac/glande)

Mesenchymal- Oma
Mixed tumor Epithelial & Mesenchymal
Fat tissue : LIPOMA
Carsinosarcoma
i.e :Pleomorphic
Fibrous tissue: FIBROMA
adenoma (mixed tumor
of salivary gland) Bone : Osteoma
Cartilage : Chondroma
 MULTISTEP ONCOGENESIS
THEORY

Carcinogenesis : a multistep process resulting

from accumulation of multiple genetic alteration
transformation normal cell malignant
n initiation

n promotion

n persistency
Transformation
Initation
Genetic transformation by carcinogen
(inisiator) i.e: carcinogen
Promotion
Further changes because of presence of
promotor which causing clonal proliferation
in tranformed cells
Persistency (permanent)
Occur if clonal proliferation of tumor cell does
not require initiator and promotor---tumor cells
grow autonomously
MULTISTEP CARCINOGENESIS
Robbins&Kumar
Basic Pathology, 2023
8 HALLMARK OF CANCER
CELLS
Robbins&Kumar
Basic Pathology, 2023
 BREAST CANCER
CARCINOGENESIS

https://europepmc.org/articles/PMC4079839/bin/nihms595187f1.jpg
Lester SC. The Breast. In: Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease. 9 Ed. Philadelpia: Elsevier
Saunders; 2015. 1043–72 p.
 INVASIVE CARCINOMA OF BREAST

• Classified based on morphology and molecular profile

• Differentiate prognosis and therapy.

• Etiology of breast cancer  multifactorial

• hormone, diet,and genetic (esp BRCA1 and BRCA2).
INVASIVE BREAST CARCINOMA
OF NO SPECIAL TYPE (NST)

TUMOR MASS
Cervical cancer oncogenesis
MILD DYSPLASIA (LSIL / CIN 1)
MODERATE DYSPLASIA(HSIL/CIN 2)
&
KOILOSITOSIS
HSIL (CIN III) & KOILOSIT
 KERATINIZING SCC OF THE
CERVIX

Ca
 GENETIC ONCOGENESIS
MECHANISMS

• 1. Telomerase expression
• 2. Inactive Tumor suppressor genes
• 3. Protooncogene ----> oncogenes
• 4. Apoptosis regulating genes
1. TELOMERASE EXPRESSION
 2. Tumor suppressor genes

® Growth-inhibiting gene and stimulate cells differentiation

® Recessive gene
®
® Mutation occur in both alleles
mutated gene inactive protein loss inhibiting
® power
® i.e. p53 gene
® ۰ wild-type
۰ mutant-type
 MECHANISMS

gatekeeper
Supress cell proliferation directly
TSG i.e. RB, p53

Caretaker
Regulate genome integrity by repairing
DNA damage
i.e . BRCA 1,2
p53. Positive/ strong
3. ONCOGENES :
Genes determine tumor neoplastic
characteristics
According oncoprotein function:
1. nuclear-binding oncoprotein involves in
cellular proliferation regulation
2. tyrosine kinase activity
3. growth factor
4. growth factor receptor
5. cyclic nucleotide-related activity
 Abnormality of Tumor oncogenes
expression
Protein produced may be:
a. normal quantity, different molecule
— different biological effect
i.e.: mutant ras, hyperactive

b. normal molecule, excessive quantity

i.e : erb B1, erb B2, C myc
Immunohistochemical staining of c-erb-B2 strongly positive(3 +)
HER-2/NEU WITH HIGH AMPLIFICATIONS
BY FISH
4. Apoptosis regulation
Carcinogenesis
• Transformation process of normal cells
becoming tumor cell due to permanent genetic
alterations

• long-time process
•require long-time for division from one
transformed cell becoming one group of cells
Malignant tumor dissemination

• Invasion local spread

- in situ phase
- invasion phase
There is tissue susceptibility to invasion

• Metastasis distant spread

steps : - extracellular matrix invasion
- vascular spread
- tumor cell growth in new site
 INVASION COMPONENTS

• Matrix degrading enzymes: MMP

• Cell adhesion ; - integrin

- e-cadherin

• Cell motility ; - Hepatocyte Growth Factor

- Insulin Like Growth Factor
 METASTASIS
5 major stages :
• 1. Invasion and infiltration to surrounding
normal tissue with lymphatic and small
vascular penetration

• 2. Release of neoplastic cells, one by one cell

or small group into circulation

• 3. Survive inside circulation

• 4. Stuck of tumor cells to the capillary
wall of distant organ unrelated to the
origin organ

• 5. Penetration to the
vascular/lymphatic wall and tumor cells
can grow in new site
STEPS OF INVASION
METASTASIS

CARCINOMA destruct near

tissue

destruct far tissue

METASTASIS CANCER
Carcinogen : cancer-causing agent

- Chemical carcinogen i.e:

Polycyclic hydrocarbon
§ Nitrosamina
§ Asbestos

- Physical carcinogen i.e:

UV -- skin cancer

- Biologic carcinogen i.e:

Virus (HPV, EBV, HBV)
Ko karsinogen :
• Hormonal factor

• Immunologic factor
Tumor mass growth
influenced by :
1. Kinethic of tumor cell growth
time : one cell transformation to tu mass formation
2. Tumor angiogenesis
Blood vessels bring nutrition for tumor cells
3. Tumor progression and heterogenity
۰ tumor cells : spontaneous mutation
۰ possibility of clonal and subclonal
with slight different characteristics
Grading & staging of malignant tu

Ø Bacground r untreated malignant tumor

Ø increased progressively

Ø AIM :
1. bring planned-therapy
2. bring prognosis clue
3. information exchanges between cancer centers
 Grading
• Determine degree of malignancy and aggresivity

• Histological grading
• (mitosis count, nuclear pleomorphism,
• degree of normal tissue similarity)

• In very anaplastic tu : histologic features and biological

• behavior relationship not perfect

• Scored I – IV

• Pathological staging : assessment of the tumor invasion

• depth in microscopic examination
Staging
• Clinical assessment
•Prmary tumor size and spread to lymph node, distant
• site ( metastasis )

•TNM classification:
•T= Tumor (primary tumor size)
•N= Node (lymph node containing tumor)
M= Metastasis (presence/abscence of metastasis)

•T(0–4), N(0–3), M( 0-2)

• Tumor location and morphology based on
International Clasifications Diseases-0ncology (ICD-O)
coding from WHO
Surgery
Wide excision : surgical margin free of tumor cells?
Radical surgery : remove regional lymph node
Palliative : to reduce pain, restore organ function which is affected
Radiation
Isolated : radiosensitive tumor –deep-seated umor
Post operative : to destroy tumor cell residue which is not taken by
surgery
Palliative : malignant/wide tumor, to ease the excision
Chemotheraphy
Isolated : certain tumor
After surgery

Immunotherapy : interferon, interleukin-2

Targeted therapy : Her-2, CD 20
Thank you