Transcript Day 13: Cancer Powerpoint

Cancer
Learning Objectives
By the end of this class you should
understand:

The steps required for a cell to become cancerous

The link between genes, mutation and cancer

The models of retinoblastoma, breast cancer, and colon cancer

Translocation events that create a risk for cancer

Treatments for cancer including new ones currently under study
What is Cancer?


Cancer is the result
of a single cell that is
undesirably and
constantly
reproducing
Any cell in the body
can become
cancerous

But some are more
likely candidates than
others!
Cell Replication

There are molecular
mechanisms
(checkpoints) that
prevent a cell from
constantly undergoing
mitosis

Occur at G1/S and G2/M

Cells also cannot
replicate without an
external signal
Cancer Checklist

To become cancerous, a
cell must:

Have its control genes fail
via mutation (fresh or
inherited)

Have its go-ahead signal
stuck in the “on” position

Develop expression of
telomerase if it was not
already a stem cell
This is a long list!

Typically, to
facilitate the
checklist being
met, cancer cells
also have a
failure of mutation
repair

This begins to
prompt many,
many mutations
Types of Cancer

A cell that has begun to
undergo mitosis until it
has exhausted all its
blood supply forms a
tumor


A lump, sometimes hard,
sometimes just an
outgrowth of flesh
If no further mutation
takes place, it is
typically benign (not
harmful)
Dangerous Cancer

For cancer to
become malignant,
two additional steps
must be met:

Angiogenesis
(ability to create
new blood vessels
to feed the tumor)

Metastasis (ability
to spread through
tissues and blood)
Cancer Genes

Cancer genes fall into
two major categories:

Tumor-suppressor
genes normally block
mitosis and must be
knocked out for
cancer to occur

Proto-oncogenes
normally pass on
signals to grow, and
must be stuck in the
“on” mode
Tumor-Suppressor Genes




p53 is the classic tumorsuppressor gene
Produces a protein that
blocks mitosis when
DNA is damaged
Protein also induces
apoptosis (cell suicide) if
genome is irretrievable
p53 knockouts are
nearly universal in
cancer
Tumor-Suppressor Gene



RB1 is another
tumor-suppressor
gene found in
many cells
Produces a protein
called pRB that
blocks cell cycle
RB1 failure is
linked to
retinoblastoma and
other cancers
Proto-Oncogenes



ras is the classic
proto-oncogene
Codes for a protein
that passes a growth
factor signal to the
nucleus
If mutates in amino
acid 12 or 61, fails to
switch off and cell is
permanently
stimulated
ras Mutations
Cancer Categories


There are hundreds of kinds of cancer, but
some are clearly more common than others
Epithelial cancers are most common for two
reasons:
–
Epithelial tissue is exposed to the outside more
–
Epithelial stem cells are very common (e.g.
skin)
Model Cancers

Model cancers are
especially well-studied for
their genetics
–

Often studied due to
being relatively common
Models discussed here:
–
Retinoblastoma
–
Breast Cancer
–
Colon Cancer
–
Leukemia (CML)
Retinoblastoma

Familial retinoblastoma is
caused by having a bad
RB1 gene
–
Typically individuals are
heterozygous
–
If the “good” allele is
deactivated by any
mutation, this loss of
heterozygosity results
in cancer in affected
organ
Breast Cancer

Breast cancer is very
common, so a major
study searched for
commonly mutated
genes in all breast
cancer cells
–
BReast CAncer
genes BRCA1 and
BRCA2 were isolated
–
These were
patended by Myriad,
patent recently
overturned
BRCA1 and BRCA2


The BRCA genes are for DNA repair
BRCA1 activates when a break in DNA is
discovered
–

Inactivated BRCA1 protein cannot bind to
Rap80 and fix the DNA
Loss of heterozygosity occurs in up to 85% of
women with one mutant allele, resulting in most
of the heritable breast cancer cases
–
Still only about 20% of all breast cancer cases
Colon Cancer

Two major pathways for
colon cancer:
–
Familial adenomatous
polyposis
(chromosomal
instability) or FAP
–
Hereditary
nonpolyposis colon
cancer (failure to
repair DNA) or
HNPCC
FAP Colon Cancer


In FAP, polyps forms
much more than
usual, increasing
mitosis and risk of
cancer
Identifying FAP
genes helped
overall
understanding of
cancer
Sequential Gene Failure
HNP Colon Cancer


HNPCC is caused by
failed DNA repair
enzymes that work
during mitosis
Even without polyps,
mutation rate in colon
is increased and
cancer risk increases
Leukemia


Chronic Myelogenous Leukemia
is often caused by a particular
translocation
–
Chromosomes 9q and 22q
–
The “Philadelphia
Chromosome”
The exact point of translocation
creates a hybrid gene
–
Combination of C-ABL and
BCR genes
Philadelphia Chromosome
Hybrid Gene


The C-ABL gene and the
BCR gene produce a
single protein that
contains properties of
both
–
C-ABL is for signal
transduction
–
BCR activates and
deactivates proteins
The hybrid protein
signals white blood cells
to constantly multiply
Cancer Treatments


Two standard treatments
today are radiation therapy
and chemotherapy
Both work by poisoning cells
during mitosis
–
Since cancer cells are
constantly undergoing
mitosis they are affected
the most
–
This is why you also lose
your hair
Targeted Therapy


A new model of cancer
treatment is to
determine what protein
in the cancer is
constantly signaling
mitosis and block it
The C-ABL/BCR hybrid
can be deactivated by a
special messenger
molecule
Targeted Therapy

Works better in earlier
stages
– Many late-stage cancer
cells have so many
mutations they will not
respond to targeted
therapy

Provides promising lessdestructive ways to cure
cancer in the future
Have a good weekend!
Have you picked your genetic disorder yet?