HALLMARK OF CANCER

NUR MAHMUDAH
nurmahmudah12@gmail.com
 EPIDEMIOLOGI KANKER

• Cancer is a 2nd leading cause of death worldwide

after vascular disease accounting for 7.6 M
deaths (~13% of all deaths)
------Indonesia : cancer is no 7 leading disease
incidence 100/ 100.000 5.7% of death cause
(Riskesdas, 2007) ------
• 70% of all cancer deaths occurred in low-and
middle-income countries
• Deaths from cancer worldwide are projected to
continue rising, with an estimated 13.1 million
deaths in 2030
EPIDEMIOLOGI KANKER

http://globocan.iarc.fr/
• Kanker---karkinos(Yunani) = crab
• Appearance of tumor: the main portion as the
body and the various extension looks like the
legs
 Nomenclature

• Benign
– “Polyp”
• Malignant
– Epithelial
• ‘Carcinoma’
– Mesenchyme
• ‘Sarcoma’
– Hematopoietic
• Leukemia, lymphoma, myeloma
 Etiology
• Nature
– Inherited cancer syndromes
• p53, BRCA1 and 2, MMR
– Immune deficiency syndromes
• Inherited/Congenital or acquired
• Nurture
– Radiation (cosmic, fallout, radon)
– Chemotherapy (MDS)
– Viruses and bacteria
• EBV, HTLV-I/II, H. pylori
– Repeated injuryeflux, hepatitis)
 KARSINOGENESIS

http://sph.bu.edu/otlt/MPH-Modules/PH/PH709_Cancer/PH709_Cancer_print.html
Loss of cell cycle control at the Restriction
Point
Two types of genes are mutated in cancer:
G0

proto-oncogenes
Activity: stimulate cell cycle progression
M
Mutation in cancer: gain of function
proto-oncogene = wt; oncogene = mutant
G2 G1
Examples: cyclin D1, Mdm2, myc, ras

S
tumor suppressors
Activity: Inhibit cell cycle progression
Mutation in cancer: loss of function
Examples: Rb, p53, p16, ARF, PTEN
Cell Cycle Checkpoints
The Guardian Mechanisms of
the Genome

THEY ARE DISRUPTED

IN CANCER!

Figure 8.4 The Biology of Cancer (© Garland Science 2007)

FUNGSI TUMOR SUPRESSOR GENE
MYC ONCOPROTEIN
• Myc belongs to a family
of bHLH transcription
factors, act as
heterodimers
• Myc-Max complexes act
to promote transcription
• Mad-Max complexes act
to repress transcription
• As cell differentiate, Mad
levels increase
progressively and Myc is
displaced by Mad
Kanker muncul setelah bertahun-tahun
terpapar karsinogen
Normal cell growth
Abnormal cell growth
• Hyperplasia: growth of cells that exhibit almost normal
histology
• Dysplasia : growth of cells that exhibit abnormal histology
• In situ cancer : localized abnormal growth of abnormal
histology
• Invasive cancer : distant spread of abnormal growth of
abnormal histology
• Inisiator: substansi yang menyebabkan
perubahan pada level DNA (mutagen)
• Promotor : substansi yang mungkin
menginduksi proliferasi sel (bukan mutagen)
INISIASI

PROMOSI

PROGRESI
• Inisiasi bersifat reversibel,tidak semua sel yang
terinisiasi berkembang menjadi tumor.
• Promosi menyebabkan terjadinya ekspansi klonal
dari sel yang mengalami perubahan akibat inisiasi
• Promoter tumor:
Proliferasi sel tanpa diferensiasi terminal
Sel preneoplastik dan pembentukan lesi benigna
• Tumor memiliki kemampuan untuk tumbuh dan
menginvasi jaringan lokal.
 Tumor Progression & Heterogeneity
• Tumor progression: means increase aggressiveness & and
is acquired occurring in an increasing fashion

• Development of new subset of cells that are different in

aspects such as invasivness,ability to Mets, hormonal
response-Heterogeneous group

• Results from multiple mutations occurring independently in

different cellssubclone of cells that is different
 The path to cancer
• Clonal proliferation
• Starts from a single cell
• Expansion in steps
• Pre-malignant states
– Polyp
• Serial accumulation of mutations
– Clonal evolution
– Resistance
 Hallmarks of Cancer
1. Sustaining proliferative signaling
2. Evading growth supressors
3. Resisting cell death
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Activating invasion and metastasis
7. Genome instability
8. Tumor promoting inflammation
9. Deregulating cellular energetic
10. Avoiding immune destruction
Hanahan & Weinberg, 2011
Sustaining proliferative signal
 Alternatif Mempertahankan Sinyal
Proliferasi
• Sel kanker mengirimkan sinyal menstimulus sel-
sel normal di sekitarnya untuk mendukung
terbentuknya tumor-associated stroma (stoma
terkait tumor), kemudian sel normal dan stroma
tersebut menyediakan berbagai faktor
pertumbuhan untuk sel kanker.
• Selain itu sel kanker juga mampu menata ulang
reseptor proliferasi, dengan meningkatkan jumlah
reseptor proliferasi di permukaan membran sel
kanker, sehingga sel kanker makin hiperesponsif
terhadap ligan faktor pertumbuhan.
 Evading Growth Supressor
• Sel kanker menginaktivasi TSG, sehingga tidak ada
yang menekan proliferasi sel.
• Menghilangnya kontak inhibisi
• Mekanisme kontak inhibisi diperankan oleh 2 macam tumor
suppressor genes, yaitu oleh gen NF2 dan LKB1.
• Pada keadaan normal, NF2 mengekspresikan protein merlin
yang akan berikatan dengan molekul-molekul cell-surface
adhesion (seperti: E-cadherin) dan reseptor transmembran
tyrosine kinase (seperti: reseptor EGF receptor), sehingga
protein merlin dapat menghambat sinyal mitogenik.
• Pada keadaan kanker, terjadi inaktivasi gen NF2, sehingga
kontak inhibisi menghilang.
• Protein lkb1 berperan mengatur struktur epitel dan
membantu mempertahankan integritas jaringan, dengan
menghambat efek dari onkogen myc, namun, ketika ekspresi
LKB1 ditekan, terjadi ketidakstabilan integritas epitel, dan
epitel menjadi rentan terhadap perubahan yang diinduksi
myc
 Resisting Cell Death
• Some tumors have high level of protein that
bind to death inducing signals complex &that
prevent the activation of caspase 8
• BCL2 activation in Burkitt lymphoma in the
translocation of chromosome t(14:18) helps
in protecting lymphocytes from apoptosis
 Resisting Cell Death
1. menghilangkan fungsi TP53 (yang berperan
meningkatkan ekspresi protein famili BH-3 Noxa dan
Puma yang proapoptosis) sebagai tumor supressor
gene,
2. meningkatkan ekspresi gen regulator antiapoptosis
(seperti: Bcl-2 dan Bcl-XL)
3. menurunkan ekspresi faktor proapoptosis lainnya
(seperti: Bax, Bim, dan Puma).
4. Sel kanker yang nekrotik memicu sel inflamasi datang.
Sel ini mengeluarkan IL-1α yang menstimulasi sel
tetangga yang masih hidup untuk berproliferasi, yang
potensial untuk progresi jaringan kanker.
 Enabling Replicative Immortality
• Most normal human cells have a capacity of 60-70
doubling, after the cell will enter non replicative
senescence & result in shortening of telomeres at the end
of chromosome.
• loss of telomeres beyond a certain point will lead to
massive chrosomal abnormalities & death
• In order to develop tumor, need to maintain cells i.e. avoid
cell senescence
• This is done by enzyme TOLEMERASE which maintain
chromosome length
• 85-95% of cancer have up regulation of enzyme telomerase
 Inducing Angiogenesis
• Tumors cannot enlarge beyond 1-2 mm thickness unless
they are vascularized, hypoxia will induce apoptosis by
activation of TP53 .
• Angiogenesis is required for tumor growth & metastasis.
• Tumor-associated angiogenic factors may be produced
by the tumor or by inflammatory cells
• TP53 inhibit angiogenesis by stimulation of anti-
angiogenesis molecules
• VEGF is under the control of RAS oncogene .
• Proteases are involved in regulating angiogenic &
antiangiogenic factors .
Activating Invasion And Metastasis

• A series of biological steps

•Once tumor cell breach the basal
membrane and reach stromal
compartment access to blood &
lymphatic vessel intravasation
•Cancer cells in blood nutrient & oxygen
source
• Hilangnya E-cadherin pad sel
kanker.
• E-cadherin merupakan suatu
molekul adhesi sel ke sel.
• E-cadherin membentuk ikatan
antar sel yang berdekatan
melalui adherens junction,
sehingga terbentuk lapisan sel
epitel yang rapi dan
mempertahankan sel pada
keadaan quiescence.
• Ekspresi N-cadherin pada sek
kanker ditingkatkan, sehingga sel
mampu bermigrasi.
• Ekspresi N-cadherin berkebalikan
dengan ekspresi E-caherin pada
keadaan kanker.
• β-catenin serves to link the cytoplasmic of E-cadherin
• Loss of E-cadherin  liberates β-catenin migrate to
nucleusassociate transcription factors expression
of genes orchestrating the EMT program
 Genomic Instability
• mutasi DNA yang multipel (banyak) sel normal
sehingga menjadi sel kanker, seperti: mutasi proto-
onkogen dan tumor supressor gene (TSG)
• BRCA1&BRCA2 mutation in 80% of familial breast ca,
• BRCA1&BRCA2 mutation in males & females
increase risk of breast, prostate, ovaries, pancrease,
bile duct, & melanocytes
• Females with BRCA1 mutation are at higher risk of
developing ovarian ca & males are at higher risk of
prostate ca
 Evading Immune Destruction
• Sel kanker mampu melumpuhkan komponen
sitem imun yang bekerja untuk
mengeliminasinya.
• Mensekresi TGF β atau faktor imunosupresan
lainnya untuk melumpuhkan CTLs dan sel NK
dengan (Yang et al., 2010; Shields et al., 2010).
• Rekrutmen sel imun yang bersifat imunosupresif,
seperti : sel T reg (T regulatory) dan myeloid-
derived suppressor cells (MDSCs). Keduanya
dapat menyupresi kerja CTL (Mougiakakos et al.,
2010; Ostrand-Rosenberg and Sinha, 2009).
 Tumor Promoting Inflammation
• Tumor diinfiltrasi oleh sel imun inate maupun
adaptif.
• Keadaan ini semakin menguntungkan karena
mampu mensuplai molekul bioaktif (GF untuk
proliferasi, survival factors untuk mencegah
kematian sel, extracellulare matrix-modifiying
enzyme untuk memfasilitasi angiogenesis,
invasi, dan metastase, inductive signals untuk
aktivasi EMT)
 Deregulating Cellular Energetic
• Warburg effect membatasi pembuatan energi dari glikolisis
tetapi anerobik glikolisis
• Pembuatan energi melalui anaerobik untuk sel yang hipoksik
TERAPI KANKER