Transcript cancer slides-1 - University of Windsor

Cigarette Consumption and Lung Cancer
Figure 11.2 The Biology of Cancer (© Garland Science 2007)
Tissue organization and
protection of the stem cell
genome
Figure 12.1 The Biology of Cancer (© Garland Science 2007)
Stem cells and the organization of
GIT
4-6 actual stem cells (red)
Emigration of transit-amplifying cell from the crypt
can be traced by thymidine labeling.
Figure 12.2a The Biology of Cancer (© Garland Science 2007)
Figure 12.3a The Biology of Cancer (© Garland Science 2007)
Hematopoietic
differentiation
Figure 12.4 The Biology of Cancer (© Garland Science 2007)
Conserved DNA strand and the
stem cell genome
Figure 12.5a The Biology of Cancer (© Garland Science 2007)
Proofreading by DNA polymerase and Cancer incidence: Death due to malignancy
in mice containing Mutation in DNA pol d (D400A)>
Heterozygous and homozygous in a wid type p53 background
Figure 12.7 The Biology of Cancer (© Garland Science 2007)
Oxidation of bases in DNA
Figure 12.12a The Biology of Cancer (© Garland Science 2007)
Metabolic rate and DNA oxidation: Thymidine glycol is an excretory product of DNA
oxidation measured in urine.
Figure 12.13 The Biology of Cancer (© Garland Science 2007)
Product of UV radiation
Figure 12.14a The Biology of Cancer (© Garland Science 2007)
Action of cytochromes on pro-carcinogen: Natural Detoxification on benzoapyrene leads
to the production of carcinogen
Polycyclic aromatic hydrocarbons (PAHs) from tobacco smoke, broiled food and
polution.
Figure 12.15b The Biology of Cancer (© Garland Science 2007)
DNA adduct produced by
BPDE
Figure 12.16 The Biology of Cancer (© Garland Science 2007)
Aflatoxin (fungal toxin) and Liver carcinogenesis: Incidence of hepatocellular carcinoma
(HCC) is 8 times higher in the very humid southestern Qidong penisula
Figure 12.18a The Biology of Cancer (© Garland Science 2007)
Figure 12.18b The Biology of Cancer (© Garland Science 2007)
Table 12.1 The Biology of Cancer (© Garland Science 2007)
Xeroderma pigmentosum patient:
Caused by Mutation in nucleotide
excision repair genes.
These patients are very sensitive to UV
light and have 1000 fold higher rate of
incidence of melanoms, squamous and
basal cell carcinoma.
Figure 12.25 The Biology of Cancer (© Garland Science 2007)
Multi-step tumorigenesis in variety of organ sites
Figure 11.7 The Biology of Cancer (© Garland Science 2007)
Evidence of adenoma to carcinoma progression
Figure 11.8b The Biology of Cancer (© Garland Science 2007)
The ErB signaling network:
Figure 5.1 The Biology of Cancer (© Garland Science 2007)
Table 5.1 The Biology of Cancer (© Garland Science 2007)
Table 5.3 The Biology of Cancer (© Garland Science 2007)
Figure 5.24 The Biology of Cancer (© Garland Science 2007)
How a cancer develops? 1. Uncontrolled cell division
a. mutation leading to activation or overproduction of oncogenes (cell division
promoting signaling molecules. And/or
b. By mutation leading to inactivation or underproduction of cell cycle blocking genes or
anti-oncogemnes or tumor suppressor genes.
2. Blockage of cell death mechanisms caused by DNA abnormalities, leading to
the growth of cells with mutated genes, thus encouraging more mutations. This is
achieved by mutation in p53 genes, over production of Bcl2 genes etc.
3. Acquiring immortality: all mammalian cells can divide to a limited number of
population doublings, after which they become senescent. Recent work suggests
that a check on the number of cell division is achieved by telomere length at the
end of chromosomes that keeps getting shorter in each replication cycle. In many
cancers there is production of an enzyme called telomerase (a reverse
transcriptase). This enzyme keeps the telomere length constant and cells become
virtually immortal.
4. Induction of blood capillary formation or angiogenesis.
5. Detachment from the tissue, invasion of other tissues.
6. Mutations leading to escape from immune system, immuno-supression,
expression of decoy receptors etc.
Chromosomal aberrations in a cervical cancer cells (bottom) compared to the
normal (top)
Ch. 8: three abnormalities, a. number, b. deletion of genetic material and c.
mismatch joining of two fragments.
Ch. 13: Copy loss, Ch. 12, 17, and 18; copy number.
APC gene mutation: Adenoma polyposis coli: found mutated or truncated in all polyps
and advance colon cancers.
Oncogenic mutations of a Ras gene, followed by loss of p53 and DCC are present
in successive stages of colon carcinoma.
Figure 11.10 The Biology of Cancer (© Garland Science 2007)
1. Chromosome 17 in almost all the brain tumors. Later on the gene on this
chromosome was identified to be p53 gene.
2. In the later advanced stage of the brain tumors, loss of chromosome 9 was observed.
The region of chromosome 9 that was deleted contained a cluster of genes encoding
interferons, the proteins involved in triggering immune response. Thus these mutations
may help the cancer cells escape the immune system. This region may also include the
multiple tumor supressors -1 and 2 (MTS-1, MTS-2). The protein products of these
genes in involved in regulating cell division.
3. In most aggressive form of tumors, there was loss of one copy of chr. 10 (we do not
know the role of any important gene on this chromosome in advancement of tumor) and
there was multiplication of
Figure 11.17 The Biology of Cancer (© Garland Science 2007)
K-ras mutation and tumor initiation
Figure 11.22a The Biology of Cancer (© Garland Science 2007)
Toxic and mitogenic agents can act as human tumor promoters: e.g. TPA or phorbol 12
myristate 13 acetate (phorbol ester)
Figure 11.27 The Biology of Cancer (© Garland Science 2007)
Infammation contributes to carcinogenesis in gastrointestinal tract
Human ulcerative
colitis
Figure 11.34a The Biology of Cancer (© Garland Science 2007)
Chronic Inflammation leading to cancer
Carcinoma of epithellial
lining of gallbladder
associated with gallstones.
Inflammation due to Hepatitis B or c virus infection leads to
100 fold incresased risk of cancer
Figure 11.35a The Biology of Cancer (© Garland Science 2007)
In vivo model of chronic liver inflammation and hepatocellular carcinoma: Loss of
MDR gene leads to chronic inflammation
Figure 11.37a The Biology of Cancer (© Garland Science 2007)
Figure 11.37b The Biology of Cancer (© Garland Science 2007)
Action of Cox-2 enzyme and their inhibition by aspirin
Figure 11.38b The Biology of Cancer (© Garland Science 2007)
Figure 11.40e The Biology of Cancer (© Garland Science 2007)
Figure 11.41 The Biology of Cancer (© Garland Science 2007)
Table 11.3 The Biology of Cancer (© Garland Science 2007)
Therapeutic strategies:
There are more than a million new cases of cancers diagnosed in 1994 in united
states. The major cancers were, Lung carcinoma, 172,000, Colorectal cancer
149,000, breast cancer 183,000, prostate cancer 200,000, various lymphomas and
leukemia >90,000, cervical, uterine and ovarian >70,000, Bladder and Kidney
80,000 and melanoma 32000.
The first challenge is to diagnose the cancer in early stage:
Physical examination and some physiological symptoms are used in
combination to tissue pathology: mostly can reveal only late stage stagecancers.
Some tumors diagnosed by scanning and the processes mentioned above are
cured by surgical procedures.
New developments are needed for early diagnosis:
Gene Microarrays
Protein microarrays e.g. prostrate cancer diagnosis
The treatments:
Prevention: Avoid mutagens eg radiations (radio active, and UV), smoking and
tobacco, carcinogen in food, vaccination against viral diseases, dietary intake of
fruits, vegetable, fiber containing diets etc.
Surgery
Chemo therapy
Radiotherapy
Both the chemo and radio therapies induce apoptosis in fast dividing cells. Most of the
drugs are DNA damaging agents which induce apoptosis by DNA damage.
Obviously, the treatment kills other normal dividing cells, and the collateral damage is
significant.
Other drugs like taxol disrupt the tubulin polymerization and inhibit growth and induce
cell death in dividing cells.
Since the discovery of different pathways of apoptosis, a new hope is there to induce
the cell death program targeted specifically to cell cells.
Followings are the cutting edge research and developments in the therapeutic
development of cancers:
Targeted delivery of chemotherapeutic agents via liposomes containing specific anticancer antibodies.
Delivery of photo-sensitive chemotherapeutic agents conjugated to specific targets.
Localized laser targeted radiotherapy
Many of the tumors have p53 mutations, and they do not respond to
DNA damage-inducing agent. Researchers are trying to restore p53
function by gene therapy or by chemical modulator.
Some companies are developing antagonists to epidermal growth
factor to neutralize its effect and control tumor growth in brain.
A smart approach is being developed by a chemist Dr. Taylor at
Washington University St. Louis. He plans to make specific probes for
mutated genes in cancer and conjugate it to a drug release system.
PNA: Peptide nucleic acid synthesized complimentary to mutated
mRNA (or over-expressed mRNA). Then this specific PNA is tagged on
to a drug delivery vesicle, which is catalytically released only when
PNA binds to the target. This way killing the cancer cells specifically
can be achieved.