Cell Bio- Cell Transformation

Front 1

What is cell transformation:

Back 1

Process of forming (metanorphosis) tumor cell from normal cell

Front 2

Transformed cells: (5)

Back 2

1. Decreased dependance of stimulatory cytokines
2. Loss of anchorage dependance (Can grow in liquid medium)
3. Loss of contact inhibition (--> capability of growing to high density)
4. Immortality
5. Capability of growing in host organism

Front 3

What represents the basic characteristic of transformed (tumor) cells:

Back 3

Abnormal proliferation in space and time

Front 4

What kind of character do proliferation of transformed cells mostly have?

Back 4

Clonal character

Front 5

Are cell transformations a multistage process?

Back 5

YES! (Need more then one mutation to be transformed)

Front 6

Characteristics of transformed cells which point at possible mechanisms of cell transformation (development of cancer): (6)

Back 6

1. Clonal growth
2. Multistage transformation
3. Immortality
4. Inability to differentiate
5. Resistance to apoptosis
6. Genetic instability

Front 7

Theory of immune surveillance:

Back 7

Role of genetic changes: Activation of oncogenes, inactivation of anti- oncogenes

Front 8

Genetic changes activating oncogenes & inactivating anti- oncogenes: (4)

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1. Point mutations
2. Deletions
3. Chromosomal translocations
4. Gene amplifications

Front 9

Induced transformations:

Back 9

Induces mutations (mutagens)

Front 10

Spontaneous transformations:

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Spontaneous mutations

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Three main groups of environmental factors which induce genetic changes leading to transformation:

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1. Chemical carcinogens
2. UV radiation and ionizing radiation
3. Viruses

Front 12

Chemical carcinogens:

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Substances causing cell transformations on the basis of interactions with DNA, they cause mutations (mostly point mutations):
- Aromatic hydrocarbons (--> carcinogenic epoxides): Benzpyrene
- Nitrosamines (<-- nitrates, nitrites)
- Acridine dyes: Acridine orange

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UV radiation and ionizing radiation (physical carcinogens):

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1. UV radiation:
Excitation of atoms--> rare tautomeric forms of nucleic bases, forming thymine dimers

2. Ionizing radiation:
(X radiation, gamma radiation): Ionization of molecules--> reactive radicals (chromosomal translocations)

Front 14

Viruses:

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1. Oncogenic RNA viruses: retroviruses (classical oncogenes)

2. Oncogenic DNA viruses: Papovaviruses, herpesviruses, adenoviruses, hepadnaviruses, oncogenes of DNA viruses

Front 15

Oncogenes:

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Genes which, by means of their protein products onco- proteins (e.g. v- Src), transforms cells

Front 16

Protooncogenes:

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Normal cellular genes from which transforming oncogenes are derived (e.g. c-src)

Front 17

Viral oncogenes:

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Protooncogenes which by means of incorporation into genome of retroviruses gain capability of transforming cells (e.g. v-src)

Front 18

Cellular oncogenes:

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They develop in cell from protooncogenes by their change, or as a result of change of their expression (e.g. trkA)

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Conversion of protooncogene into oncogene:

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1. Change of the gene resulting from deletion or point mutation: Outcome is a protein with increased activity but produced at normal amounts

2. Change of gene expression on the basis of chromosomal translocation or gene amplification: Outcome is increased production of normal protein

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Functional groups of oncogenes: (7)

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1. Growth factors: Autocrine stimulation
v--sis: c-sis (B chain of PDGF)

2. Receptor tyrosine kinases:
v- erbB: c- erbB (EGF receptor)
trkA: gene for NGF receptor

3. Nonreceptor tyrosine kinases:
v- src: gene for NGF receptor

4. G proteins:
v- Hras: cHras (Ras protein: Ras--> Raf- MAPKK- MAPK)

5. Serine threonine kinases:
v- raf: c-raf (Raf-1 kinase)

6. Transcription factors:
v-fos: c-fos (transcription factor Fos)
v-myb: c-myb (transcription factor Myb)
v-myc: c-myc (transcription factor Myc)

7. Factors controlling apoptosis:
bcl- 2: bcl-2 (antiapoptotic protein of Bcl-2 family)

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Anti- oncogenes:

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Genes which, by means of their protein products, block cell transformation (tumor suppressor genes)

Front 22

Function of anti- oncogenes vs. oncogenses:

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1. Loss of normal function of protein products of anti- oncogenes leads to cell transformation (development of cancer). Anti- oncogene products are mainly involved in mechanisms which leads to inhibition of proliferation.

2. Functioning of protein products of oncogenes (oncoproteins) leads to cell transformation (development of cancer). Protooncogene products are mainly involved in signaling pathways which leads to the stimulation of proliferation.

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Well known anti- oncogenes:

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Rb-1 gen: Rb-1 protein
p53 gen: protein p53

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Possibility of cancer therapy
Classical approaches:

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1. Local therapy: Surgery, local irradiation (gamma radiation)

2. Systemic approach to the therapy (combination with surgery and irradiation): Chemotherapy

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Chemotherapy: (2)

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1. Cytotoxic agents: Cyclophosphamide, cisplatin, methotrexate, doxorubicin (interaction with DNA)

2. Cytostatic agents: Vinca alkaloids (vinblastine, vincristine)

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Employment of cytokines in therapy: (Cancer therapy)

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1. Inhibition of cell proliferation and induction of apoptosis: Interferons, TNF

2. Supportive effects of cytokines: IL-2, GM- CSF

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Employment of monoclonal antibodies in therapy (Cancer therapy):

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1. Inhibition of cell proliferation

2. Selective targeting (targeted drugs)

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Gene therapy (Cancer therapy):

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1. Antisence oligonucleotides: Against relevant oncogenes
2. Tranfection: Working anti- oncogenes