General information on cancer

• Disease of multicellular organisms

• Characterized by the accumulation of mutations and
uncontrolled cell division
• ~1.5 million Americans are diagnosed with cancer
each year
• Over 500,000 will die from the disease
• In about 10% of cancers, a higher predisposition to
develop the disease is an inherited trait
• Most cancers, about 90%, do not involve heritable
genetic changes
1
 Carcinogens
• About 80% of all human cancers are related to
exposure to carcinogens – agents that increase the
likelihood of developing cancer
• Most carcinogens, such as UV light and certain
chemicals in cigarette smoke, are mutagens that
promote genetic changes in somatic cells
• DNA alterations can lead to effects on gene
expression that ultimately affect cell division, and
thereby lead to cancer

2
 Cancer
• Cancers originate from a single cell
• Cell and its offspring mutate so cells grow
abnormally
• Tumor – an overgrowth of cells with no useful
purpose
• Tumor may begin as benign or pre-cancerous
Do not invade or spread
• May become malignant

3
 Cancer continued
• Malignant stage
Lost normal growth regulation
Invasive – can invade healthy tissue
Metastatic – can migrate to other parts of the body
• Left untreated, malignant cells will cause the
death of the organism

4
5
 Oncogenes
• Cell division regulated by growth factors
– Bind to cell surface and initiate cascade, activating
specific genes, leading to cell division
• Mutations in genes for cell growth signaling proteins
can change them into oncogenes – producing
abnormally high level of activity
• An oncogene may promote cancer by keeping the
cell division signaling pathway in a permanent “on”
position
– In some cancers the amount of gene product is too high
– in others the gene produces a functionally hyperactive
protein
6
7
 Example: ras

• Intracellular signaling
protein that hydrolyses
GTP
• When GTP is bound, ras
promotes cell division
• Oncogenic mutations
may decrease ability of
ras to hydrolyze GTP or
exchange GDP/GTP faster
• Both keep signaling
pathway constantly on

Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of 8
McGraw-Hill Education.
 Proto-oncogene
• Normal gene that, if mutated, can become
an oncogene
• Four common genetic changes
1. Missense mutations
2. Gene amplifications
3. Chromosomal translocations
4. Retroviral insertions

9
 Missense mutations
Chemical mutagens have been shown to cause
missense mutations (mutation in DNA that codes
for a wrong amino acid), leading to cancer

10
 Gene amplifications
Increase in copy number results in too much protein
Many human cancers are associated with
amplification of particular proto-oncogenes

11
 Chromosomal translocations
Chromosomes break and rearrange
Very specific rearrangements associated with certain
types of tumors.
Can create chimeric genes

12
13
 Retroviral insertions
Viral DNA inserts into a
chromosome, putting a viral
promoter next to a proto-
oncogene
• If proto-oncogene
becomes
overexpressed, it will
promote cancer
Some viruses cause
cancer because they
carry an oncogene
in the viral genome
Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of 14
McGraw-Hill Education.
 Some cancers caused by viruses
• A few viruses are known to cause cancer in
plants, animals, and humans
• Some viruses may cause cancer by modifying
host DNA
• Others carry oncogenes in the viral genome

15
 Tumor-suppressor genes
• Normal role to prevent cancerous growth
• Typical functions:
1. Maintain genome integrity by monitoring and/or
repairing DNA damage
• Checkpoint proteins check the integrity of the genome
and prevent a cell from progressing past a certain point
in the cell cycle
2. Inhibitors of cell division
• Necessary to properly halt cell division otherwise division
becomes abnormally accelerated

16
17
 Checkpoint proteins
• Proteins called cyclins and cyclin-dependent
protein kinases (cdks) are responsible for
advancing a cell through the four phases of
the cell cycle
• Formation of activated cyclin/cdk complexes
can be stopped by checkpoint proteins
• p53 – about 50% of all human cancers are
associated with defects in this gene
18
 p53
• G1 checkpoint protein
• DNA damage induces expression to prevent cell from
progressing from G1 to S phase
• If DNA is repaired, cell may proceed

19
 p53 continued
• If the DNA damage is too severe, the p53
protein will also activate other genes that
promote programmed cell death or apoptosis
• Caspases function as proteases that digest
selected cellular proteins causing the cell to
break down
• It is beneficial for a multicellular organism to kill
an occasional cell with cancer causing potential

20
 Rb protein
• Rb protein inhibits the
transcription factor E2F, which
activates genes for G1 to S
phase cell cycle progression
• Binding of functional Rb
protein inhibits E2F and
prevents cell division
• If both copies of Rb are
defective, E2F protein is
always active, resulting in
uncontrolled cell division

Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of 21
McGraw-Hill Education.
Loss of tumor-suppressor gene function

• Three common ways

• Mutation within a tumor-suppressor gene to
inactivate its function
• Chromosome loss may contribute if the
missing chromosome carries one or more
tumor-suppressor genes
• Abnormal methylation of CpG islands near
promoter regions of the tumor-suppressor
gene 22
 Cancer is a series of changes
• Cancer usually requires multiple genetic
changes to the same cell
• Begin with a benign genetic alteration that,
over time and with additional mutations, leads
to malignancy
• Malignancy can continue to accumulate
genetic changes that make it even more
difficult to treat
23
 Cancer progression
• Mutation occurs in a cell
• Mutations accumulate in cells and their numbers
increase – hyperplasia
• As more mutations accumulate, the cells develop
more abnormal morphologies – dysplasia
• The cells begin to invade other tissues - malignancy
• Metastasis of these cells to other parts of the body
can kill the patient

24