Multi-Step Tumorigenesis

(1)

 Umur  berkaitan dengan terkenanya

kanker

(2)

 Insiden kanker paru meningkat dengan

meningkatnya penggunaan rokok

 Insiden kanker paru vs kematian

 a ⁴ – a ⁷

 Memiliki tipe kecenderungan yang sama

(3)

 Tumorigenesis  multistep process

 Urutan proses perkembangan kanker sampai terbentuk  berbeda

 Beberapa langkah terjadi dengan frekuensi tinggi

 Umur bertambah  insiden kanker meningkat



Resiko terjadinya tumor pada mesothelioma pada pekerja yang terdedah asbes (kiri)

percobaan pada mencit –

pembentukan tumor kulit

akibat asbes

(4)

 Saluran pencernaan

 Sel epitel  flux konstan :

 20-50 juta sel di duodenum : mati &

regenerasi

 Kolon 10 kali lipat

CIN, cervical intraepithelial neoplasia; CIS. carcinoma in situ; DCIS, ductal carcinoma in situ: LCIS. lobular carcinoma m situ: PIN, prostatic inlraepithelial neoplasia

(5)

Evidence for adenoma-to-carcinoma progression

microsatellite instability (MSI)

(6)

 Pertumbuhan kanker  akumulasi

perubahan genetik dan epigenetik

(7)

 Dimulai dari mutasi pada kromosom 5

 Perkembangan mutasi melibatkan resistensi sel

Alternative paths during cancer progression

(8)

 Metaplasia awal  aneuploid, tetraploid,

LOH

(9)

 tumor sporadic  menyebar pada kelompok2 sel yang mungkin berbeda tempat Field cancerization

 Perkembangan kanker mengikuti teori evolusi Darwin

 Seleksi

 Clonal expansion

(10)

Figure 11.14a The Biology of Cancer (© Garland Science 2007)

 Dalam jaringan kanker tidak semua sel memiliki kemampuan tumorigenik

Figure 11.15 The Biology of Cancer (© Garland Science 2007)

 Pada tumor otak

 CD133  brain

tumor stem

cell antigen

(11)

 Mutasi pada sekelompok populasi sel dapat diteruskan ke sekelompok populasi sel, tetapi tidak ke kelompok lain  karena adanya keterbatasan potensi

proliferasi sel

Asymmetric cell division

Symmetric cell division

 Pada tumor terdapat

diversifikasi klon sel

karena adanya tingkat

mutasi yang tinggi 

berbeda pada pasien

berbeda

(12)

islands infiltrate the cervical stroma (red circles).

 Columnar cell differentiation within such a nest of basaloid cells (green circle).

 neoplastic squamoid cells (yellow, blue)

reveals great phenotypic diversity within small sectors of these tumor xenografts;

cells

CSC from glioblastoma tumors differentiate in vitro into at least two distinct lineages of neuroectodermal cells, one exhibiting neuron-specific β-tubulin (red) and the other the astrocyte GFAP (glial fibrillary acidic protein) marker (green).

 Tumorigenesis diawali minimal akibat 2 gen

onkogen mutan yang berkolaborasi

(13)

 One or two oncogenic lesions do not suffice to generate full-blown tumors

(14)

Inisiasi Double mutation  tumorigenesis

five distinct cellular regulatory circuits needed to be altered experimentally before human cells can grow as tumor cells in immunocompromised mice :

(1) the mitogenic signaling pathway controlled by Ras (2) the cell cycle checkpoint controlled by pRb (3) the alarm pathway controlled by p53

(4) the telomere maintenance pathway controlled by hTERT (5) the signaling pathways controlled by protein phosphatase 2A

(15)

The bumblebee bat of Thailand

The blue whale has a body weight of about 1.3 × 10⁸ g, reaches sexual maturity in 5–10 years, and has a life span of about 80 years ~ human

Etruscan shrews reach reproductive age by 3–4 weeks

• The bat and the whale together with the approximately 40-fold difference in life span suggests a difference of more than 10⁹ in the number of cell divisions that the two organisms experience in a lifetime

• Metabolic rate of the small mammals may be as much as 10³ times higher than the whale’s, and since much of the mutational burden of the cell genome derives from by-products of oxidative metabolism  the blue whale may experience only a 10⁶- fold higher risk of cancer than the bat

passage through each cell cycle creates the danger of genome alterations, this suggests that the risks of cancer can vary enormously from one species to the next

Initiator : DMBA (7,12- dimethilbenzanthrace ne) karsinogen Promotor : nonkarsinogeneik – TPA (12-O-

tetradecanoylphorbol -13-acetate)

(16)

 Senyawa toksik dan mitogenik dapat berperan sebagai promotor tumor

 Rokok mengandung berbagai karsinogen mutagenik, misalnya 3-metilkolanthrene

 Ethanol : mutagenik lemah

 Estrogen, progesteron  mitogenik 

▪ Makin banyak siklus menstruasi dialami  resiko breast cancer meningkat

Dapat saling bekerja sama dalam menyebabka n kanker pada mulut, throat

(17)

Inflamasi kronik pada empedu menyebabkan kanker)

Perkembangan adenoma & karsinoma kolon dengan adanya Infeksi Helicobacter pada kolon