1. Cancer: A Genetic Disease
Mutations in genes that control cell growth and division are responsible for cancer.
(cell proliferation and differentiation)
Carcinogens  DNA mutations

2. Cancer
Cancers arise when critical genes are mutated, causing unregulated proliferation of cells.
These rapidly dividing cells pile up on top of each other to form a tumor.
When cells detach from the tumor and invade surrounding tissues, the tumor is malignant and may form secondary tumors at other locations in a process called metastasis.
A tumor whose cells do not invade surrounding tissues is benign.

3. Tumor – is a condition where there is abnormal cellular growth thus
forming a lesion or in most cases, a lump in some part of your body.
Benign tumor – grows in confined area
Malignant tumor – capable of invading surrounding tissues
Cancer – degenerative disease with a cellular condition where there is uncontrolled growing mass of cells capable of invading neighboring tissues and spreading via body fluids to other parts of the body.

4. Named for site of origin
Carcinomas – epithelial cells; cover external & internal body
surfaces (90%)
Sarcomas – supporting tissue; bone, cartilage, fat, connective
tissue, pancreas, Liver.
Lymphoma & leukemias – blood & lymphatic tissue
(leukemia reserved for cancers that reside in bloodstream
not as solid tissue)

5. Comparison of Normal and Tumor Growth in the Epithelium of the Skin

6. Comparison of Normal and Tumor Growth in the Epithelium of the Skin
Location/distribution

7. Normal cells vs. Cancer cells
Normal cell proliferation
Cancer cell proliferation
Anchorage dependent
Anchorage independent
Density-dependent inhibition
Can grow on top of one another
Limited number of cell divisions
Immortal
Telomere shortening
Telomere maintenance
Proliferation dependent upon extracellular signals
Constant signal to divide
Checkpoints activated at appropriate times
Loss of checkpoint
Apoptosis functional
Apoptosis inhibited
independent

8. Basic Properties of a Cancer Cell
In culture, normal cells can be transformed by chemicals or viruses.
Different types of cancer cells share a number of similarities:
Aberrant chromosome numbers (aneuploidy)
High metabolic requirements
Unregulated growth
Synthesis of unusual cell surface proteins

9. Stages in the Process of Invasion and Metastasis
Basal lamina
Invasion
Metastasis
Matrix

10. Cell Cycle Checkpoints
Transitions between different phases of the cell cycle (G1, S, G2, and M) are regulated at checkpoints.
A checkpoint is a mechanism that halts progression through the cycle until a critical process is completed.

11. Cancer and Genes
Oncogenes are genes that, when mutated, actively promote cell proliferation.
Tumor suppressor genes are genes that, when mutated, fail to repress cell division.

12. SEVERAL MUTATED OR ALTERED GENES IN CANCER
Cancer cells contain several (6-8) mutated genes.
Several categories of genes
1. Oncogenes
An oncogene is a gene that when mutated or altered contributes to converting a normal cell into a cancer cell.
The term oncogene is derived from the Greek word "oncos," meaning tumor.
The cellular oncogenes in their normal form are called proto-oncogenes and do not cause cancer. They code for a variety of normal enzymes, growth factors and receptors that relay signals to a cell's nucleus, stimulating growth.
The activation to oncogene may result in overproduction of growth factors; flooding of the cell with replication signals; and/or unrestrained cell growth.

13. The activation of a proto-oncogene to oncogene can occur in several ways:
mistakes during DNA replication, ie. point mutation, chromosomal rearrangement, gene amplification
from damage to DNA cause by exposure to chemicals or radiation
from viral infection and insertion into the DNA resulting in more active production of oncogene
from other causes not yet known

14. To other points about oncogenes:
- Oncogenes act as dominants; if the cell has one normal gene at a locus and one mutated gene, the abnormal product takes control.
- No single oncogene can, by itself, cause cancer. It can increase the rate of mitosis of the cell. Dividing cells are at increased risk of acquiring mutations.
- Oncogenes may be transmitted from generation to generation when a proto-oncogene mutates in the germ line. This results in a dominantly inherited tumor predisposition. For example, multiple endocrine neoplasia type 11 (MEN 2) is the outcome of a germline transmission of an activated RET oncogene.

15. 2. Tumor Suppressor genes
- Suppress tumor formation.
- Their protein products act to inhibit cell growth and the division cycle.
Mutations in tumor suppressor genes cause the cell to ignore one or more of the components of the network of inhibitory signals, resulting in a higher rate of uncontrolled cell proliferation.
Tumor suppressors behave as recessives. Both normal alleles must mutate before cancerous growth begins.

16. Examples of Tumor Suppressor genes
53 kD protein that prevents a cell from completing the cell cycle if its DNA is not properly replicated in S phase. It responds to cell damage.
- It binds to transcription factor (E2F) and prevents E21F from binding to the promoters of the proto-oncogenes c-myc and c-fos, needed for mitosis
- The p53 protein may triggers programmed cell death (apoptosis) if the damage to the cell is too great to be repaired.
- Defects in the p53 gene are found in most cancers.

17. Viruses Associated With Human Cancers
Family
Virus
Cancer
Papillomaviridae
Human papillomaviruses
Genital tumors
Squamous cell carcinomas
Oropharyngeal carcinomas
Herpesviridae
Epstein-Barr virus
Nasopharyngeal carcinoma
African Burkitt’s lymphoma
B cell lymphoma
Hepadnaviridae
Hepatitis B virus
Hepatocellular carcinoma
Retroviridae
Human T lymphotrophic viruses
Human immunodeficiency viruses
Adult T cell leukemias
AIDS-associated tumors (due to impaired T cell responses
Flaviviridae
Hepatitis C virus

18. General Features of Viral Carcinogenesis
Most are DNA viruses (exceptions: some retroviruses and flaviviruses)
Influence the cell cycle by
Encoding proteins that direct cell cycle progression
Integrating near cellular genes that control cell cycle progression
The Central Principle of Viral Carcinogenesis
Viruses can cause cancers in humans and animals
Tumor viruses frequently establish persistent infections
Host susceptibility factors are important determinants
Viruses are seldom carcinogenic on their own
Virus infections are far more common than viral cancers
Prolonged periods (years) are usually required for viral carcinogenesis
Viral strains may be different in their capacity to cause cancers
Cancer viruses modulate cell cycle progression
Animal models can reveal mechanisms of viral carcinogenesis
One virus species can be associated with multiple tumor types

19. Tumor-Inducing Retroviruses and Viral Oncogenes
Retroviruses have an RNA genome.
The Rous sarcoma virus, the first tumor-inducing virus, contains four genes
gag encodes the capsid protein of the virus
pol encodes the reverse transcriptase
env encodes a viral envelope protein
v-src encodes a protein kinase that inserts into the plasma membranes of infected cells. The v-src gene is an oncogene that is responsible for the virus’s ability to induce abnormal cell growth.

20. Proteins Encoded by Viral Oncogenes
© John Wiley & Sons, Inc.
Proteins Encoded by Viral Oncogenes
Growth factors similar to those encoded by cellular genes
Proteins similar to growth-factor and hormone receptors
Transcription factors homologous to cellular proteins
Any protein

21. Interactions of Tumor Viruses With Their Hosts
Persistent infections
All known human tumor viruses establish persistent infections
Genetic differences in individuals results in differential susceptibilities
Host immune response
Persistent viruses must evade the host immune response
Different viruses have evolved different evasion mechanisms
Mechanisms of action by human cancer viruses
Viral gene is able to subvert cell cycle control
Viruses alter the expression of normal cell cycle progression genes
Either results in cellular transformation into an oncogenic state

22. Interactions of Tumor Viruses With Their Hosts
Cell susceptibility to virus
Tumor viruses possess cell specificity and do not infect other cells
EBV infects B cells
HTLV infects T cells
Retention of viral nucleic acid in a cell
Viral genes are always present in the transformed cells

23. Retroviruses Structure and composition
Diploid single-stranded RNA viruses (5-8 kb)
Helical ribonucleoprotein
Enveloped
Genetics
Only diploid viruses
About 10 genes, 16 proteins
reverse transcriptase
protease
envelope
gag
tax
rex

24. Retroviruses Epidemiology Typical infectious viruses (exogenous)
Sexual transmission
IV drug abusers
Other, unknown transmission mechanisms
Classification
Leukemia viruses
Alpharetrovirus
Gammaretrovirus
Nontransforming retroviruses
Deltaretrovirus
Lentivirus

25. Mechanisms of Retroviral Carcinogenesis
Infection leads to uncoating in the cytoplasm
Reverse transcriptase makes a double-stranded DNA copy
An RNA-dependent DNA polymerase
A DNA-dependent DNA polymerase
A DNA-dependent RNA polymerase
The ds-DNA translocates into the nucleus where it randomly integrates in host cell chromosome
This version of the viral genome is termed the provirus
Two replication strategies
Induce cell division - leads to copies of the viral genome in each daughter cell
Productive infection - spread of virus to other cells

26. DNA Tumor Viruses Virus Viral Oncoproteins Cellular Targets
Polyomavirus SV40
Large T antigen
Small t antigen
p53 and pRb tumor suppressor genes
PP2A
Human papillomavirus E6 E7
p53, DLG, MAGI-1, MUPP1
pRb
Bovine papillomavirus E5
PDGFβ receptor
Adenovirus
E1A
E1B-55k
p53
Adenovirus 9
E4ORF1
DLG, MAGI-1, MUPP1
Epstein-Barr virus
LMP1
vIL10
BCL2 homolog
TRAFs
IL-10 receptor (soluble viral cytokine)
Rescues cell from apoptosis

27. DNA Tumor Viruses Papillomaviruses Features Many human types
Non-enveloped icosahedral (55 nm)
Circular ds-DNA (8 kb)
Nuclear replication
Stimulate cellular DNA synthesis
Highly restricted host range and tissue range
Many human types
Only a few are known to cause cancers
Cervical cancer is the most important
Vaccine is now available
Cause warts (abnormal cellular proliferation)