1. M.B.Ch.B, MSC, MRCPCH, DCH (UK)
Dr. Mohammed Hussein
M.B.Ch.B, MSC, MRCPCH, DCH (UK)

2. Objectives By the end of these lectures, student should:
Understand the process of apoptosis and its role in the prevention of cancer development
Understand the mechanism of oncogenesis
Have an idea about the molecular carcinogenesis
Understand the DNA repair processes in the prevention of carcinogenesis
Know some of the molecular markers used in cancer biology

3. Cancer Killed Cancer Normal Cell No Cancer  Oncogene
 Apoptosis
 Oncogene
Killed Cancer
 Tumor suppressor
gene
Normal Cell
 Oncogene
 Tumor suppressor
gene
No Cancer

4.  Tumor suppressor gene
 Oncogene
Cancer
 Tumor suppressor gene
 Apoptosis

7. Oncogenes Fibroblast growth factors (FGFs)
Platelet-derived growth factor (PDGF)
Epidermal growth factor receptors (EGFRs)
Rearranged during transfection (RET)
The ras gene
Nonreceptor tyrosine kinase proteins
proto-oncogene myc

8. Surface receptor
Signal transduction
Nuclear transcription

9. Tumor Suppressor Genes
Transforming growth factor-b receptor
The protein product of the DCC gene
The NF-1 gene product
The APC gene product
The Rb gene
The p53 gene (gate-keeper)

10. Apoptosis

11. Apoptosis
Is defined as the programmed destruction of the cell

12. Apoptosis is characterized by
Decrease in cell volume
Mitochondrial destabilization
Chromatin condensation with nuclear fragmentation
Cellular dispersion into fragmented apoptotic bodies without the release of cellular material

13. Terminal events in the process of apoptosis

14. Terminal events in the process of apoptosis

15. Caspases
Contain both ‘‘C’’ (cysteine) and ‘‘aspase’’ (aspartic acid) protease activity, and once activated, they begin the apoptotic cascade
Caspases normally exist in the cytoplasm as inactive zymogens until stimulated through any of the major pathways triggering apoptosis.

16. Degradation of intracellular proteins
Mitochondria cytochrome c
Degradation of intracellular proteins
Caspase
Activate DNAases
DNA fragmentation

17. Mechanism of Oncogenesis

18. Mechanism of Oncogenesis
Numerous mechanisms exist to create the genetic changes that result in uncontrolled cell growth.
Point mutations
Chromosomal translocations

19. Point mutations
Point mutations are changes in the individual nucleotides in the gene encoding either proto-oncogenes or tumor-suppressor genes that can result in cancer.

20. Chromosomal translocations
Malignancy
t(8;14)
Burkitt lymphoma
t(14;18)
Follicular lymphoma
t(11;14)
Mantle cell lymphoma
t(9;22)
Philadelphia chromosome
Chronic myelogenous leukemia
t(15;17)
Acute myelogenous leukemia

21. Molecular Carcinogenesis

22. Molecular Carcinogenesis
As cells proceed through the multiple rounds of division during the growth and maintenance of the organism, mistakes in the replication of the genome are inevitable.
Fortunately, these mistakes can be repaired by DNA repair mechanisms
However if the cell is subjected to insults, such as chemicals, radiant energy, or viruses, the normal DNA repair mechanisms may become overwhelmed, leading to the chemical changes that result in mutations.

23. Carcinogenesis Chemical carcinogenesis Radiation carcinogenesis
Viral carcinogenesis

24. Chemical carcinogenesis
Both natural and synthetic compounds are capable of damaging cells either directly, after being acted on by the cell, or in synergy with other chemicals.

25. Substance
Cancer
Aniline dyes
Bladder cancer
Asbestos
Mesotheliomas
Radon
Lung cancer
Arsenic
Skin cancer
Chromium and nickel
Vinyl chloride
Angiosarcoma of the liver
Diethylstilbestrol (DES)
Vaginal cancer
Nitrosamines (food preservatives)
Stomach cancer

26. Radiation carcinogenesis
DNA and other macromolecules are capable of being damaged by different wavelengths of electromagnetic radiation including both
UV from the sun is responsible for causing mutations in DNA
Ionizing radiation: High-energy radiation (x-rays and gamma rays) causes direct damage to DNA

27. Viral carcinogenesis
Viruses have evolved numerous strategies for promoting the aberrant growth of their host cell types.
Human papilloma virus (HPV)
Epstein-Barr virus (EBV)
Hepatitis B virus (HBV)
RNA retroviruses

28. Human papilloma virus (HPV)
Some facilitates the degradation of cellular p53
Others perturb the normal function of the protein Rb.

29. Epstein-Barr virus (EBV)
Promotes the expression of bcl-2, leading to protection from the normal apoptotic pathways that trigger cell death.

30. Hepatitis B virus (HBV)
This virus does not encode any known oncoproteins, its association with human liver cancer has been clearly demonstrated as most likely multifactorial

31. DNA Repair and Carcinogenesis

32. The cell has evolved several mechanisms for the repair of DNA damaged by the multitudes of insults encountered in the environment. Multiple proteins exist to correct such errors in two major DNA repair pathways:
Nucleotide excision repair
Mismatch repair

34. Molecular Progression of Cancer

35. Many genetic alterations are required for the about 109 tumor cells required to form 1 g of tissue mass , which corresponds to the smallest clinically detectable mass.
Every human cancer reveals the activation of several oncogenes and the loss of two or more tumor-suppressor genes

36. The adenoma-carcinoma sequence of colon carcinogenesis
Normal epithelium
Loss of APC (tumor suppressor gene)
Hyperproliferative epithelium
Early adenoma
Activation of Ras (most common oncogene)
Intermediate adenoma
Loss of tumor suppressor gene
Late adenoma
Loss of P53 (the gate keeper)
Carcinoma
Other alterations
Metastasis

37. Molecular Markers in Cancer Biology

38. There are numerous proteins that are overexpressed in cancer cells.
Some are actually capable of being detected in the serum of patients with specific cancers.
Many of these proteins lack either the specificity or sensitivity needed for their use as screening tests.
Their true utility is in monitoring the progression of the disease once confirmed or in monitoring therapy or recurrence