1. CANCER BIOLOGY PHL 417

2. SOLID TUMOURS Anal carcinoma Billary tract carcinoma
Brain tumours (Gliomas)
Breast cancer
Cervical Carcinoma
Colorectal Carcinoma
Endometrial carcinoma
Esophageal carcinoma
Gastric carcinoma
Germ cell carcinomas
Head and neck carcinomaoma
Hepatocellular carcinoma
Lung cancer (SCLC and NSCLC)
Malignant melanoma
Neuroblastoma
Ovarian carcinoma
Pancreatic carcinoma
Prostatic carcinoma
Renal cell carcinoma
Retinoblastoma
Throid carcinoma
Wilms’ tumour (Nephroblastoma)

3. HEMATOLOGIC TUMOURS Acute lymphoblastic leukemia (ALL)
Acute myeloid leukemia (AML)
Chronic lymphocytic leukemia (CLL)
Chronic myeloid leukemia (CML)
Hairy cell leukemia (HCL)
Hodgkin’s lymphoma (HL)
Non-Hodgkin’s lymphoma (NHL)

4. CANCER
CANCER is the uncontrolled growth of cells due to damage to DNA (mutations).
Cell division (proliferation) is a physiological process that occurs in almost all tissues and under many circumstances. Normally homeostasis, the balance between proliferation and programmed cell death (apoptosis) is maintained by tightly regulating both processes to ensure the integrity of organs and tissues.
Mutations in DNA that lead to cancer disrupt these orderly processes by disrupting the programming regulating the processes. In fact, a series of several mutations to certain classes of genes is usually required before a normal cell will transform into a cancer cell. Only mutations in those certain types of genes which play vital roles in cell division, cell death, and DNA repair will cause a cell to lose control of its proliferation.

5. Characteristics of Cancer Cells
1- They are resistant to apoptosis ("programmed" cell death).
2- They have an uncontrolled ability to divide (or, they are immortal),
and they often divide at an increased rate.
3- These cells are self-sufficient with respect to growth factors.
4- They are insensitive to antigrowth factors.
5- They have the ability to invade neighboring tissues, usually through
the secretion of metalloproteinases that can digest extracellular
matrix material. They can form new tumors (metastases) at distant
sites.
6- They secrete chemical signals that stimulate the growth of new
blood vessels (angiogenesis).

6. NORMAL CELL cytoplasm nucleus Growth factor Growth factor receptor
Signal transduction
Activation of transcription
nucleus

7. NEOPLASTIC CELLS Increased In growth factor receptors Increased
Increased in signal transduction
Increase in activation of transcription

8. Causes of Neoplasia Environmental causes: (Carcinogens) Chemicals
Viruses
Radiation
Hereditary causes- Genetic defects.
Combination – common.
All cancer is genetic, not all cancer is hereditary

10. Chemical Carcinogenesis
Initiation
DNA damage eg.
DENA (diethylnitrosamine)
Benzpyrene
Promotion
Histologic change
Ccl4
Turpentine (co-carcinogens)
DENA + Ccl4 (Liver Cancer)
Malignant transformation:
Visible tumor formation

11. INITIATION
Initiation is an irreversible genetic alteration which result from the interaction of the ultimate carcinogen with the DNA in the target cell.
(1) Is an irreversible process
(2) Caused only by carcinogenic compounds
(3) Occurs after carcinogen exposure
(4) Initiator alone does not result in tumor formation

12. PROMOTION
Promotion refers to a phenomenon of gene activation in which the latent altered phenotype of the initiated cells becomes expressed through selection and clonal expansion.
1- Is a reversible process
2- Acts only after exposure to an initiator
3- Requires repeated administration
4- Promotor is not carcinogenic in itself
5- promotr alone does not result in tumor formation

13. INITIATION AND PROMOTION

14. Molecular Basis of Carcinogenesis
Four classes of regulatory genes.
1- Tumour Promotors: Proto-oncogenes
2- Tumour Inhibitors:Tumour-suppressor genes
3- Genes regulating Apoptosis
4- DNA repair genes.

15. Non-lethal Genetic damage lies at the center of carcinogenesis
Loss/damage to suppressor genes
Overexpression of promotor genes
Loss/damage to Apoptosis genes
Loss/damage of DNA repair genes.

16. PROTO-ONCOGENES
are genes which promote cell growth and mitosis (cell division).
TUMOUR SUPPRESSOR GENES: discourage cell growth, or temporarily halts cell division from occurring in order to carry out DNA repair. Typically, a series of several mutations to these genes are required before a normal cell transforms into a cancer cell.

17. Pathogenesis MALIGNANT NEOPLSM Acquired environmental factors
chemicals ,radiation ,viruses
Pathogenesis
Genetic factors
Changes in genome
of somatic cells
Activation of growth
promoting oncogenes
Inactivation of tumour
supressor genes
Expression all altered gene products
and loss of regular gene products
MALIGNANT NEOPLSM

18. Molecular Basis of Neoplasia
Proto-oncogene
Heredity
Radiation
V-Onc
Other
Chemical
Oncogene

19. Tumor suppressor genes
A tumor suppressor gene is a gene that reduces the probability that a cell in a multicellular organism will turn into a tumor cell. A mutation or deletion of such a gene will increase the probability of the formation of a tumor.
Unlike oncogenes, tumor suppressor genes generally follow the 'two-hit hypothesis,' which implies that both alleles that code for a particular gene must be affected before an effect is manifested. This is due to the fact that if only one allele for the gene is damaged, the second can still produce the correct protein. However, there are cases where mutations in only one allele will cause an effect. A notable example is the gene that codes for p53.

20. Tumor suppressor genes, or more precisely, the proteins for which they code, either have a dampening or repressive effect on the regulation of the cell cycle or promote apoptosis, and sometimes do both.
Examples of tumour suppressor Genes Includes:
P53, Rb, BRCA-1 and BRCA-2
The first tumor suppressor protein discovered was the pRB protein in human retinoblastoma; however, recent evidence has also implicated pRb as a tumor survival factor. Another important tumor suppressor is the p53 tumor suppressor protein produced by the TP53 gene.
Families in which there is a high breast cancer frequency have mutations affecting the tumor suppressor gene BRCA-1 and BRCA-2.

21. Role of p53 gene 1- p53 senses DNA damage. 2- Induces G1 arrest.
3- Induces DNA repair process.
4- induces apoptosis in cells with un-repairable DNA.
5- “P53 is a guardian of the genome.
Its homozygous loss leads to accumulation of damaged DNA may result in malignancy”
Homozygous loss of p53 is seen in virtually every type of cancer.
Over half of human malignant cells show loss of p53 gene by special tests.

23. proto-Oncogenes
* A proto-oncogen is a normal gene that can become an
oncogene, either after mutation or increased expression.
* Proto-oncogenes code for proteins that help to regulate
cell growth and differentiation.
*Proto-oncogenes are often involved in signal transduction
and execution of mitogenic signals, usually through their
protein products.
* Upon activation, a proto-oncogene (or its product) becomes a tumor inducing agent, an oncogene.

24. C-MYC
C-MYC is a major transcription factor that encodes nuclear DNA binding proteins that regulate cell growth, transformation, angiogenesis, cell-cycle control and apoptosis .
This could explain the aggressiveness and poor prognosis associated with tumours over expressing C-MYC proteins.

25. HER-1
HER1 gene, codes for epidermal growth factor receptor (EGFR), which has extracellular ligand binding domain and cytoplasmic domain with high tyrosine kinase activity.
It plays an important role in cell proliferation, migration and protection against apoptosis.
Poor prognosis of breast tumors over expressing HER1 has been reported.
It is well documented that HER1 protein is targeted by inhibiting its extracellular legend binding domain using monoclonal antibodies and/or its tyrosine kinase activity in cytoplasmic domain by tyrosine kinase inhibitors (TKIs).

26. HER2/neu.
HER2/neu gene, codes for the human epidermal growth factor receptor 2 (HER2), which has extracellular ligand binding domain and cytoplasmic domain with high tyrosine kinase activity. It plays an important role in cell proliferation, migration and protection against apoptosis.
HER2 is overexpressed by many adenocarcinomas, particularly breast adenocarcinomas. Trastuzumab is a monoclonal antibody and must only be administered to female HER-2-positive patients, i.e., in whom the tumours overexpress the HER-2 protein or amplify the HER-2 gene.

27. Protein kinases and related proteins
* Receptor tyrosine kinases:
that become constitutively (permanently) active like the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR alpha/beta), and vascular endothelial growth factor receptor (VEGFR1,2,3), colony-stimulating factor 1 receptor (CSF1R).
* Cytoplasmic tyrosine kinases:
like the Src-family, Syk-ZAP-70 family and BTK family of tyrosine kinases. For example, Bcr-Abl fusion protein tyrosine kinase, an abnormal enzyme produced by chronic myeloid leukemia cells that harbor the Philadelphia chromosome.
* Regulatory GTPases:
for example, the Ras protein which is coded by RAS gene.

28. Cell cycle

29. Cell Cycle
The term cell cycle refers to the sequence of events that take place within a cell as it tools up for division.
Scientists have determined that cell cycle can be divided into:
Gap 0 (G0): There are times when a cell will leave the cycle and quit dividing. This may be a temporary resting period or more permanent. An example of the latter is a cell that has reached an end stage of development and will no longer divide (e.g. neuron).
Gap 1 (G1): Cells increase in size in Gap 1, produce enzymes needed for DNA synthesis

30. Cell Cycle
S Phase: To produce two similar daughter cells, the complete DNA instructions in the cell must be duplicated. DNA replication occurs during this S (synthesis) phase.
Gap 2 (G2): It is the gap between DNA synthesis and mitosis, the cell will continue to grow and produce new proteins & RNA.
Mitosis or M Phase: Cell growth and protein production stop at this stage in the cell cycle. All of the cell's energy is focused on the complex and orderly division into two similar daughter cells.