CANCER

Ajeng Diantini

Fakultas Farmasi UNPAD

Cancer: collection of many different diseases,caused by an accumulation of genetic alterations.

Risk of developing cancer and response of treatment:

- Environment

- Heredity

- Behaviour

Effective options for cancer patients

- Treatment strategies

- Supportive care

- Novel therapies (based on advances in our fundamental understanding of the basic pathophysiology of cancer)

CANCER CHARACTERISTIC AND TERMINOLOGY

Greek: cancer derives a word: crab, karkinoma

Tumor : a swelling (exp, that caused by inflammation)

Now, generally reserved for describing a new growth , neoplasm.

Not all tumors or neoplasms are cancer.

Cancer refers to a malignant tumor and is not used to refer to benign tumor, such as lipomas or to hypertrophy of an organ.

Benign neoplasm also can cause life-threatening symptoms if they enlarge in critical locations, for exp. Meningioma at the base of the skull may cause symptoms by compressing adjacent normal brain tissue.

Characteristic of cancer cells

Greatly prolonged life spans compared to normal cells

Immortal

Fail to develop the specialized functions of their normal counterparts.

Developing their own network of bloodvessels

Has a tendency to break off from the original tumor, float in bloodstream and colonize other tissue.

Tumor :

- a swelling caused by the abnormal growth of cells.

- If tumor invades adjacent normal tissue or spreads through lymph vessels or the blood vessels to other normal tissue, this tumor is considered malignant.

- Benign tumor: are encapsulated by fiber, insulating body from their toxic effects.

Tumor Classification and Nomenclature Benign tumor are generally named according to the tissue

from which they arise, and include the suffix oma.

e.g. Benign tumor of fat cells is a lipoma

Benign tumor cancer (malignant tumor)

Malignant tumor :

- More rapid growth rates

- Specific microscopic alterations (loss of differentiation and absence of normal tissue organization

- Lack of capsule and grow to invade nearby bloodvessels, lymphatics, and surrounding structures

- Spread to other distance locations (metastasis).

Differentiation of cancer: aggresiveness

1. Aggressive (more malignant) : cancer that metastasized quickly, even the total number is small.

Aggressive tumors contain cells that are :

- generally less mature

- less physically defined

- lack some of a cells standard constituents.

less well-developed or well differentiated.

- doubling time of 60 days or less.

2. Moderate : doubles in 61 150 days.

3. Indolent : doubles in 300 days.

PROGRESSION OF DYSPLASIA TO NEOPLASM

In general, cancers are named according to the cell type from which they originate.

Cancers arising in epithelial tissue are called

carcinomas, if they arise from or form ductal or glandular structures are named adenocarcinoma.

Cancer arising from connective tissue usually have

the suffix sarcoma.

Skeletal muscles rhabdomyosarcomas lymphatic tissue lymphomas blood forming cells leukemias

Cancer Classification

Carcinomas form in the epithelial cells that cover the surface of the skin, mouth, nose, throat, lung airways, genitourinary, gastrointestinalis, or that line glands such as the breast or thyroid.

Diseases: Lung, breast, prostate, skin, stomach and colon cancers are solid tumors.

Sarcomas are those that form in the bones; soft connective and

supportive tissues surrounding organs and tissues, such as cartilage, muscles, tendons, fat and the outer lining of the lung, abdomen, heart, central nervous system, and blood vessel.

Sarcomas are solid tumors; the most rare of malignant tumors and the most deadly.

Leukemia form in the blood and bone marrow. Abnormal WBC

produced there travel through the bloodstream creating problems in the spleen and other tissue. Leukemias are not solid tumors, and characterized by an overproduction of abnormal WBC.

Lymphoma are cancers of the lymph glands that concentrated in

the neck, groin, armpits, spleen, the center of the chest and around intestines. The 2 most prevalent : Hodgkins and Non Hodgkins.

Myelomas are rare tumors that arise in the antibody-producing

plasma cells or hemopoietic (blood cells-producing) cells in various tissues in the bone marrow.

Cancer cells

Normal cells cancer cells (transformation)

Autonomy : cancer cells independence from normal cellular controls and is part of the transformational process.

Dont have contact inhibition

Will grow without attach to substrate

Anchorage-independent

Immortal (normal: 10-50 times divide in petridish)

HeLa cells (cervical cancer specimen in 1951)

Defect normal process of differentiation

Anaplasia: is the absence of differentiation (without form) loss of organization n a marked increase in nuclear size (on going proliferation), variable of size and shape (pleomorphic).

CANCEROUS CELLS SHOW UNINHIBITED GROWTH

NORMAL AND ANAPLASTIC SKELETAL MUSCLE

CELLS

SEQUENTIAL ACQUISITION OF GENETIC

CHANGES

Six Hallmarks of cancer

Self-sufficiency in growth signals

Insensitivity to antigrowth signals

Evading apoptosis

Limitless replicative potential

Sustained angiogenesis

Tissue invasion and metastasis

MODEL FOR ACTION OF Ras GENES

ANGIOGENESIS

Cancer need their own blood supply to deliver oxygen and nutrients.

Normal angiogenesis:

- wound healing

- female uterus during the proliverative phase of

the menstrual cycle.

- angiogenic factors: factors that stimulate new

blood vessel growth (VEGF)

TUMOR-INDUCED ANGIOGENESIS

TELOMERES AND IMMORTALITY

Telomeres : protective ends, or caps on each chromosome that are placed and maintained by a specialized enzyme called telomerase.

cells proliferate abnormally, their telomere caps become smaller and smaller with each of cell division telomere critically small chromosomes unstable cells die.

Cancer cells can activate telomerase to maintain and restore their telomere, so become possible to divide over and over again.

Telomere dan telomerase

Ciri pd kanker adl instabilitas genetik, yg terjadi melalui bbg cara:

Mismatch repair

Segregasi kromosom yg tidak tepat

Rearrangement kromosom

Kehilangan telomere

Telomere: kompleks DNA dan protein yang menutup dan melindungi ujung kromosom.

Telomerase: enzim protein-RNA yang memperpanjang telomere setiap kali setelah pembelahan sel

Pd org dewasa, hanya sedikit sel yg memiliki aktivitas telomerase, shg telomere secara bertahap akan memendek sejalan dg bertambahnya umur sel. Erosi ujung kromosom akan membatasi jml pembelahan sel.

Pd kanker: aktivasi abnormal telomerase.

CONTROL OF REPLICATION: TELOMERES

ONCOGENES AND TUMOR-SUPPRESSOR GENES:

ACCELERATORS AND BRAKES

Oncogenes: are mutant genes that in their normal nonmutant state direct synthesis of proteins that positively regulate (accelerate) proliferation.

Tumor-supressor genes encode proteins that in their normal state negatively regulate proliferation (anti-oncogenes).

Proto-oncogenes: normal, non mutant state of oncogene.

e.g : growth factor ( e.g:epidermal growth factor), a growth factor receptor (e.g:epidermal growth factor receptor).

other positive regulator of proliferation are in signal transduction pathway that transmits the signal from the growth factor receptor to the cell nucleus. Normally, ras is a proto-0ncogene

Aktivasi onkogen: mutasi, translokasi, amplifikasi

Inaktivasi tumor supressor gen

Disfungsi gen DNA repair

Sel normal yg telah berdiferensiasi lengkap akan berhenti berproliferasi atau berproliferasi lambat

Sel ganas akan berhenti berdiferensiasi dan akan berproliferasi aktif tanpa batas.

Sel ganas tidak mampu menjalani apoptosis, yg merupakan program diferensiasi banyak jenis sel.

ONKOGEN

Proto onkogen onkogen Aktivasi proto-onkogen dapat terjadi melalui: - Perubahan struktural dalam gen - Translokasi kromosom - Amplifikasi gen - mutasi Proto-onkogen diekspresi pd sel normal utk perkembangan

dan pertumbuhan sel normal, aktivitasnya dikontrol ketat,jd tdk menyebabkan keganasan.

Proses transduksi sinyal melibatkan proses forforilasi dan

defosforilasi protein dalam sitoplasma ke dalam nukleus. Onkogen menyandi : - Faktor pertumbuhan - Hormon dan reseptornya - Berbagai faktor transkripsi

Mutasi somatik

Produk protein dari proto-onkogen dan onkogen diklasifikasikan berdasarkan lokasi subseluler atau aktivitas biokimianya:

1. Faktor pertumbuhan

2. Reseptor faktor pertumbuhan dg aktivitas tirosin kinase

3. Protein tirosin kinase sitoplasmik

4. Protein pengikat guanin yg melekat pada membran sel

5. Protein kinase spesifik serin-threonin terlarut yg tdp dlm sitoplasma

6. Protein nukleus

Peran Onkogen dalam tumorigenesis

sel

Molekul

sinyal/hormon

Molk

sinyal+reseptor pd

sel sasaran

Reseptor aktif

Modifikasi jalur sinyal:

Ekspresi gen Siklus sel metabolisme Struktur

sitoskeleton adhesi migrasi

Dlm keadaan normal aktivasi dan inaktivasi jalur ini diatur melalui fosforilasi dan defosforilasi.

Mutasi onkogenik mengubah kemampuan sandi gen shg tjd perubahan protein yg disandi (onkoprotein) dan kehilangan kemampuan mengatur fosforilasi/defosforilasi

WOUND HEALING VS INVASIVE TUMOR

GROWTH

Pathogenesis of metastasis

Central premis of Halstead theory (1852-1922):the primary fact about cancer is the tumor, not the patient as living organism

Tumor removal should cure the patients

It did not change the biological outcome of the disease

It emphasizes the tumor and ignore the patient

Cancer in simplest terms:

An accelerating process of

inappropriate,

uncontrolled cell growth

Cancel cells under microscope:

abnormally shaped, inconsistently

formed, disorganized, contain

mishapen internal structures

Horror for the individual Natural phenomenon: it represents

the bodys response to a continuous attack on its balancing and regulatory

mechanism

Infection by:

bacteria

viruses

fungi

Cancer:

Immune

system

supressed

Cancer death

Weakening

by cancer

process

Toxic effects of

conventional

cancer treatment

Cancer Process can become life threatening

PENYEBAB KANKER

Faktor

lingkungan:

virus, bakteri,

bhn kimia,

radiasi pengion,

UV

merusak DNA

kanker

kanker disebabkan oleh perubahan DNA

DNA mrpk sasaran utama bhn karsinogenik

SASARAN GENETIK KARSINOGENESIS

Bahan kimia:asbes,

benzen, benzidin dll

Radiasi: pengion

Faktor endogen:

Stress oksidatif

Virus onkogenik:

Hep B, EBV, HTLV-1

Sasaran utama:

DNA/gen regulator

siklus/pertumbuhan

Transformasi sel

KARSINOGENESIS

Bukti bahwa karsinogenesis merupakan proses bertahap:

Insidens kanker meningkat sesuai dengan peningkatan usia

Diperlukan waktu cukup panjang antara paparan pertama thd bahan karsinogen (rokok, asbes) dg timbulnya kanker.

insidens kanker meningkat berpuluh tahun sejak dijatuhkannya bom atom di jepang.

Dari aspek genetik dan molekular:

Kanker disebabkan akumulasi kelainan atau mutasi beberapa gen yang berinteraksi satu dengan yg lain yg pd akhirnya menyebabkan transformasi sel.

Bbrp gen tsb diwariskan , shg kanker dapat diturunkan.