2. Can you answer these
questions?
What is the leading cause of death in
Western Countries?
How many people will experience a
diagnosis of cancer in his/her lifetime?
(1 in ?)
Approximately how many people die
of cancer in the U.S. each year?
3. What research has taught
us… Cancer is a genetic disease at the
somatic cell level
Characterized by the presence of gene
products derived from mutated or
abnormally expressed genes
Leads to uncontrolled growth and
spread of cancer cells
4. CANCER IS A GENETIC
DISEASE AT THE LEVEL
OF SOMATIC CELLS
5. What is Cancer?
Cancer predominantly occurs in
somatic cells
Only ~1% are associated with germ-
line mutations
Rarely arises from a single mutation
6. Two fundamental properties:
1. abnormal cell growth and division
(proliferation)
2. defects in normal restraints that
keep cells from spreading and
invading other parts of the body
(metastasis)
13. Cancer Stem Cells
Tumors are a mix of cells
Only some proliferate – cancer stem
cells
◦ Self-renewal
More commonly found in leukemias
and solid tumors
29. Cell-Cycle and Signal
Transduction
Focus on G0
Phase
◦ Cancer cells can
not enter G0
◦ Rate of
proliferation is not
greater
◦ Not able to
become quiescent
30. Cell Cycle and Signal
Transduction
Signal Transduction
31. Cell Cycle Control and
Checkpoints
Three important checkpoints:
G1/S
G2/M
M
35. Proto-oncogenes
Encode transcription factors that
stimulate expression of other genes,
signal transduction molecules that
stimulate cell division, and cell-cycle
regulators that move the cell through
the cell cycle
36. Proto-oncogenes
In normal cells, proto-oncogenes
become quiescent and they the
repress proto-oncogenes
In cancer cells, one or more proto-
oncogenes are altered
◦ Constantly “on”
◦ Mutated
◦ Aberrantly expressed
39. Tumor-Suppressor Genes
Products normally regulate cell-cycle
checkpoints or initiate apoptosis
When inactivated, and other changes
keep the cell growing and dividing, the
cell may become tumorigenic
41. The ras Proto-Oncogenes
Some the most frequently
mutated genes in human
tumors
◦ Mutated in more than 30%
of human tumors
◦ Encode signal transduction
molecules and regulate cell
growth and division
◦ Get frozen in “on” position
44. The p53 Tumor-Suppressor
Gene
Most frequently mutated gene in
human cancers
◦ In over 50% of cancers
◦ Encodes a nuclear protein that acts as a
transcription factor, repressing or
stimulating transcription of more than 50
different genes
46. Li Fraumeni Syndrome
One mutant copy of the p53 gene
Can lead to many different cancers
◦ Breast, leukemia, brain
47. The RB1 Tumor-Suppressor
Gene
Loss or mutation of the RB1
(retinoblastoma 1) tumor suppressor
gene contributes to the development
of many cancers
Originally identified as a result of
studies on retinoblastoma
G1/S checkpoint control
51. Metastasis
Includes the ability to:
◦ disengage from the
original tumor site
◦ enter the blood or
lymphatic system
◦ invade surrounding
tissues
◦ develop into secondary
tumors
52. Tumor cells:
Dissociate from other cells and digest
components of the extracellular matrix
and basal lamina
53. Proteolytic Enzymes
E-cadherin glycoproteins – in low
levels in epithelial tumors
Metalloproteinases – in high levels in
highly malignant tumors, not
susceptible to TIMPs
56. Predisposition of Some
Cancers
Only a small percent of cancers are
familial or hereditary
Loss of heterozygosity: The
phenomenon where a second, wild-
type allele is mutated in a tumor
◦ Further mutations are needed for a tumor
rot be malignant
57. Familial Adenomatous Polyposis
(FAP)
1% of colon cancers
Inherit 1 copy of the APC
(adenomatous polyposis) gene on
chromosome 5
Normally a tumor-suppressor gene for
cell-to-cell contact and growth
inhibition
Leads to polyp (adenoma) formation
Second gene often becomes mutated
in later cancer stages
59. APC and ras proto-
oncogenes
Combined APC and ras mutations
Develop intermediate adenomas
Defects in cell differentiation
Not growth inhibited
Transformation occurs
60. DCC
Third step in malignancy of polyps
requires loss of both DCC (Deleted in
Colon Cancer) genes
Involved in cell adhesion and
differentiation
Late stage adenomas
Usually loss of functional p53 genes
62. Viruses and Cancer
~15% of human cancers are
associated with viruses
DNA viruses, double-stranded DNA
Most DNA viruses contain genes
encoding products that stimulate cell
growth
Often inactivate tumor-suppressor
genes
63. Viruses and Cancer
Retroviruses
RNA to DNA with reverse
transcriptase
Cause cancer by:
◦ Complete integration into host genome
(provirus)
◦ Host DNA integrated into viral genome,
DNA now under control of viral promotors
◦ Expression of viral genes
66. Carcinogens
Any substance can become
carcinogenic
Ex. about 30% of human cancer
deaths are linked to cigarette smoking
67. Carcinogens
Red meat and
animal fats –
imitate hormones
or creation of
carcinogens
through cooking
Alcohol – liver
inflammation and
liver cancer
68. Carcinogens
Some of the most common
carcinogens are natural
Ex. aflatoxin – a component of mold
that grows on peanuts and corn
Nitrosamines
Pesticides
Antibiotics
69. Carcinogens
It is estimated that the human body
suffers about 10,000 damaging DNA
lesions per day to the oxygen free
radicals
Repair enzymes handle most damage