BI203 & 281: CELL BIOLOGY

Lecture 25: Cancer

December 8, 2016
Compulsory Reading to Date:
Chapters 1, 2, 14, 4 thru 11
Chapter 12 (skip chloroplasts), Chapter 3 (pp. 90-95)
Chapter 13, 15-18 (only items covered on slides)
Chapter 19 (only material covered on slides)

BI203 & 281: CELL BIOLOGY

Lecture 25: Cancer
December 8, 2016
Most general definition: Disease caused by uncontrolled cell proliferation

QUESTION: Why are we talking about cancer???

Cancer is extremely common responsible for about 25% of deaths in
the USA (~600,000)
Cancer is a disease of many tissues prostate, breast, lung, blood, etc.
Cancer is a disease resulting from breakdown of normal cell
regulatory processes many of which weve been discussing
Weve learned a lot of basic cell biology
by studying cancer and vice versa

Cancer is a genetic disease

Cancer arises from the accumulation of genetic
changes (mutations).
Most cancers have a minimum of 6-9 different
mutated genes.
Not a hereditary disease we do not pass on cancer
to offspring.
We can inherit dispositions (susceptibility) to cancer.
Many genes that are mutated in cancer are involved
in regulating the cell cycle.

The Development and Causes of Cancer

Most cancers are in three main groups:

Carcinomasmalignancies of epithelial
cells (about 90% of human cancers).
Sarcomassolid tumors of connective
tissue such as muscle, bone, cartilage,
and fibrous tissue (rare in humans).
Leukemias and lymphomas arise from
the blood-forming cells and immune
system cells, respectively.

Table 19.1 Most Frequent Cancers in the United States

Figure 19.2 Tumor clonality

A fundamental feature of cancer

is tumor clonality tumors
develop from single cells that
begin to proliferate
abnormally.
The single-cell origin has been
demonstrated by analysis of
X chromosome inactivation
patterns.

Figure 19.3 Increased rate of cancer with age

The development of cancer is

a multistep process: cells
gradually become
malignant through a
progressive series of
alterations.
One indication of this is that
most cancers develop late
in life.

Figure 19.4 Stages of tumor development

Tumor initiation: mutation leads to

abnormal proliferation of a single cell,
which grows into a population of clonal
tumor cells.

Tumor progression: additional mutations

occur within cells of the tumor
population.

Cancer
Cancer development
cells exhibit one
& progression
(or more) fundamental
is a multistep
properties
process
Development
of colon
carcinomascells)
Abnormal Example:
proliferation
(e.g., colon
carcinoma
Lumen
of colon

Benign tumor

Epithelial cells

Malignant tumor

Metastatic tumor

Fig 19.6

See Video 19.1

Cancer cells exhibit one (or more) fundamental properties

Abnormal proliferation (e.g., colon carcinoma cells)

Failure of normal differentiation (e.g., hematological cancers)

Hematopoietic cells are maintained by the proliferation

& differentiation of hematopoietic stem cells

Fig 18.18

Figure 19.10 Defective differentiation and leukemia

All types of blood cells are derived from stem

cells in the bone marrow. Once they are
fully differentiated, cell division ceases.
Leukemic cells dont undergo terminal
differentiation; they are arrested at early
stages and retain the capacity for
proliferation.

Cancer cells exhibit one (or more) fundamental properties

Abnormal proliferation (e.g., colon carcinoma cells)

Failure of normal differentiation (e.g., hematological cancers)

Failure to undergo programmed cell death (e.g., hematological

cancers)

Hematopoietic cells are maintained by the proliferation

Lifetime of mature hematopoietic cells = a day a few months
& differentiation of hematopoietic stem cells

Fig 18.18

Cancer cells exhibit one (or more) fundamental properties

Abnormal proliferation (e.g., colon carcinoma cells)

Failure of normal differentiation (e.g., hematological cancers)

Failure to undergo programmed cell death (e.g., hematological

cancers)
QUESTION: What causes normal cells to take on these properties?
In other words..What causes cancer?

General causes of Cancer:

(1) Mutations in critical regulatory genes

- Mutations that occur during life, for example via:

- chemical carcinogens (e.g., cigarette smoke)
- causes 90% of all lung cancers and 1/3 of all cancer deaths
- radiation (e.g., UV irradiation from the sun)

(2) Chemicals that increase cell proliferation as tumor promoters

- e.g. estrogen links to breast & endometrial cancers
(3) Tumor viruses 10-20% of human cancers

QUESTION: What causes normal cells to take on these properties?

Studies ofIn
tumor
were key to
our early
understanding of cancer
otherviruses
words..What
causes
cancer?

First key observations were from

studies of rous sarcoma virus (RSV):

Fig 19.15

RSV induced cell transformation,

but the closely related virus ALV did NOT

QUESTION:
What was responsible for RSVs
capacity to induce transformation?

The RSV genome contained an

additional gene that induced cell
transformation
Studies of tumor viruses were key to our early understanding of cancer

Src

The RSV genome contained an

additional gene that induced cell
transformation
Fig 19.14
Over two dozen retroviral genes responsible for
transformation by different tumor viruses were identified

Oncogenes

TIME OUT FOR NOMENCLATURE:

Oncogenes: A gene that has the potential to cause cancer.
In tumor cells, they are often mutated or expressed at high levels.

Proto-oncogenes: A normal gene that can become an oncogene due

to mutations or increased expression.
Examples include Ras, Wnt, Myc and ERK.
Tumor suppressors: or anti-oncogene, is a gene that protects a cell
from one step on the path to cancer.
Examples include Rb, p53, BRCA1 and BRCA2.

Table 19.3 Representative Retroviral Oncogenes

More than 40 oncogenic

retroviruses have been
isolated.
All have at least one
oncogene that is not
required for replication
but is responsible for
cell transformation.
Many oncogenes encode
components of signaling
pathways that stimulate
cell proliferation.

QUESTION: What causes normal cells to take on these properties?

In other words..What causes cancer?

General causes of Cancer:

(1) Mutations in critical regulatory genes (e.g., proto-oncogenes)

- Mutations that occur during life, for example via:

- chemical carcinogens (e.g., cigarette smoke)
- causes 90% of all lung cancers and 1/3 of all cancer deaths
- radiation (e.g., UV irradiation from the sun)

(2) Chemicals that increase cell proliferation

- E.g., estrogen
& breast & endometrial
cancers
The
first identified
gene
= Ras
(3) Tumor viruses 10-20% of human cancers

REMINDER:

Ras activates the ERK MAP kinase pathway

The first identified gene = Ras

Fig 16.28

ERK phosphorylates a variety of

proteins involved in cell proliferation

The first identified gene = Ras

A glycine-to-valine point mutation converted
the normal ras gene (proto-oncogene) into an oncogene

Fig 19.20

NOTE: ~100 human proto-oncogenes have now been

identified in human cancers

Including several other players in the ERK MAP kinase pathway

Increased by oncogenic mutations

NOTE: ~100 human proto-oncogenes have now been

identified in human cancers
Decreased by oncogenic
Gly-to-Val mutation
mutations

Fig 16.27

NOTE: ~100 human proto-oncogenes have now been

identified in human cancers
Including several other players in the ERK MAP kinase pathway

Fig 16.28

ERK phosphorylates a variety of

proteins involved in cell proliferation

NOTE: ~100 human proto-oncogenes have now been

identified in human cancers
Oncogenic mutations in PI 3-kinase pathway proteins promote abnormal cell survival

Fig 16.32

NOTE: ~100 human proto-oncogenes have now been

identified in human cancers
Oncogenic mutations in Bcl-2 also promote abnormal
cell survival

Bad
Bad

Bcl-2
Antiapoptotic
members

Bim
Bim

Bid
Bid

Bax
Bax
Bak
Bak
Multidomain
proapoptotic
members

Puma
Puma

Noxa
Noxa

Bmf
Bmf

Mitochondria

cc

Tumor Suppressor Genes

Tumor suppressor genes normally

inhibit cell proliferation and tumor
development.
In many tumors, these genes are lost or
inactivated, contributing to abnormal
proliferation of tumor cells.

Table 19.5 Representative Tumor Suppressor Genes

Mutations that INACTIVATE p53

are commonly found in several forms of cancer
p53 both inhibits cell proliferation & induces apoptosis

Fig 19.36

p53 = tumor suppressor

Tumor Suppressor Genes

BRCA1 and BRCA2 genes
(responsible for some
inherited breast and
ovarian cancers) are
stability genes that
maintain the integrity of
the genome.
Mutations and inactivation
of stability genes leads to
high mutation frequency in
oncogenes or tumor
suppressor genes.

NOTE: ~100 human oncogenes have now been

identified in human cancers

Different Mechanisms of Oncogene Activation

(1) Point mutation: increase activity of protein

The first identified proto-oncogene = Ras

A glycine-to-valine point mutation converted
the normal ras gene (proto-oncogene) into an oncogene

Fig 19.20

NOTE: ~100 human oncogenes have now been

identified in human cancers

Different Mechanisms of Oncogene Activation

(1) Point mutation: increase activity of protein

(2) DNA rearrangement: increase activity and / or

expression of protein

(2) Rearrangement
DNA rearrangement:
increase
activity
and
/ or
A DNA
Converts the RTK
PDGF Receptor
into an
Oncogene
expression of protein

DNA Region 1:

DNA Region 2:

A DNA Rearrangement Converts the RTK PDGF Receptor into an Oncogene

Fig 19.24

A DNA Rearrangement Converts the RTK PDGF Receptor into an Oncogene

DNA Region 1:

PDGF Receptor gene

Tel dimerization domain

DNA Region 2:
Tel gene

KEY: Tel is a protein that forms dimers with ITSELF

Bcl-2 (B cell lymphoma-2) was identified due to a DNA rearrangement

A DNA Rearrangement Converts
PDGF Receptor into an Oncogene
in B-cellthe
lymphomas

Fig 19.24

Bcl-2 (B cell lymphoma-2) was identified due to a DNA rearrangement

in B-cell lymphomas

REMINDER: Bcl-2 inhibits apoptosis by blocking Bax & Bak activiation

Bad
Bad

Bcl-2
Antiapoptotic
members

Bim
Bim

Bid
Bid

Bax
Bax
Bak
Bak
Multidomain
proapoptotic
members

Puma
Puma

Noxa
Noxa

Bmf
Bmf

Mitochondria

cc

Bcl-2 (B cell lymphoma-2) was identified due to a DNA rearrangement

in B-cell lymphomas
KEY: B cells are specialized for producing antibodies (aka, IgGs)

Fig 17.17

Bcl-2 (B cell lymphoma-2) was identified due to a DNA rearrangement

in B-cell lymphomas
KEY: B cells are specialized for producing antibodies (aka, IgGs)

IgG promoter

DNA Region 1:

IgG gene

DNA Region 2:
Bcl-2 gene

Bcl-2 (B cell lymphoma-2) was identified due to a DNA rearrangement

in B-cell lymphomas
KEY: B cells are specialized for producing antibodies (aka, IgGs)

IgG promoter

DNA Region 1:

IgG gene

Causes increased expression of Bcl-2

DNA Region 2:
Bcl-2 gene

Bcl-2 (B cell lymphoma-2) was identified due to a DNA rearrangement

in B-cell lymphomas
KEY: B cells are specialized for producing antibodies (aka, IgGs)

Fig 17.17

NOTE: ~100 human oncogenes have now been

identified in human cancers

Different Mechanisms of Oncogene Activation

(1) Point mutation: increase activity of protein

(2) DNA rearrangement: increase activity and / or

expression of protein

(3) DNA amplification: increase expression of protein

(3) DNA amplification:

increase expression of protein
Fig 7.40
Example: ErbB-2 in breast & ovarian cancer

NOTE: ~100 human oncogenes have now been

identified in human cancers

Different Mechanisms of Oncogene Activation

(1) Point mutation: increase activity of protein

(2) DNA rearrangement: increase activity and / or

expression of protein

(3) DNA amplification: increase expression of protein

BI203 & 281: CELL BIOLOGY

Lecture 25: Cancer
December 8, 2016

How can we treat cancer?

Primary mechanisms of chemotherapy drugs is to induce apoptosis

The major obstacle is drug targeting / specificity

Can we develop drug treatments that induce apoptosis SPECIFICALLY in cancer cells?

Many - most current treatments induce apoptosis specifically in proliferating cells

QUESTION: Are there normal cells in our body that normally proliferate?
QUESTION: What are the side effects of chemotherapy? Why those side effects?

Figure 19.40 Survival rates of patients with colon carcinoma

Many cancers can be cured by

localized treatment, before they
metastasize.
Early stages of colon cancer
(adenomas) are usually curable
by minor surgical procedures.

Molecular Approaches to Cancer Treatment

Molecular biology can be used to identify
individuals with inherited susceptibilities to
cancer development.
Mutations in tumor suppressor genes,
oncogenes (ret and cdk4), stability genes
(BRCA1 and BRCA2), and others, can be
detected with genetic testing.
Some patients at high risk may choose
prophylactic surgery to prevent cancer
from developing.
Monitoring of high-risk individuals can allow
early detection and treatment.

Extended Office Hours:

After classes end on December 12, I will continue
to have office hours on the regular days
(Thursday 11-12:30pm and Friday 2-3:30pm).
I will also have open office hours on Monday
December 19 and Tuesday December 20 from 912 and 1-4pm, so please drop by with any
questions.