Cancer

From the syllabus

A. Define cancer. B. List some types of cancer. C. List characteristics of cancer cells including:

A. lack of contact inhibition, B. vascularity,C. plasma membraneD. cytoskeleton and cytoplasm changesE. abnormal disorganized growth.

D. List some mechanisms and causes of cancer. E. Identify and define the genes involved F. proto-oncogenes, oncogenes. G. tumor suppresser genes H. DNA repair genes. Define apoptosis. I. Briefly discuss the multistep theory and genetic predisposition. J. Identify treatment and side effects K. historical perspectives such as drug discovery L. screening and early detection M. surgery N. concept of how chemotherapy works using fluorouracil, taxol O. radiation

• Don’t forget to include stuff from chapter 6 next semester.

From the syllabus

A. Define cancer. B. List some types of cancer. C. List characteristics of cancer cells including:

A. lack of contact inhibition, B. vascularity,C. plasma membraneD. cytoskeleton and cytoplasm changesE. abnormal disorganized growth.

D. List some mechanisms and causes of cancer. E. Identify and define the genes involved F. proto-oncogenes, oncogenes. G. tumor suppresser genes H. DNA repair genes. Define apoptosis. I. Briefly discuss the multistep theory and genetic predisposition. J. Identify treatment and side effects K. historical perspectives such as drug discovery L. screening and early detection M. surgery N. concept of how chemotherapy works using fluorouracil, taxol O. radiation

CANCEREvolution in action

Survival of the fittest and natural selection are directly observable.

A disease of the genomeGenomic instability

A disease of the cell cycleCheckpoint failures

A disease of the agedMutations occur throughout life.

Benign vs. MalignBenign isn’t necessarily “good” – a benign brain tumor can still pinch nerves and arteries. Benign

cancers are simply not spreading.Malignant cancers are those in which cells are shedding off the primary tumor, and going throughout

the body.

OVERVIEW

The pathway to carcinogenesis consists of 4-7 rate-limiting events. It can also be as little as only 2!1. Activation of a pro-growth factor2. Activation of a survival factor or suppression of a “death” factor

Tumor development proceeds by a process analogous to Darwinian evolution.

The multiple lines of cellular defense may explain why cancer is not more frequent during an average human lifetime.

If you live long enough, you will develop cancer.

Reference:Cell, Vol. 100, 57–70, January, 2000

Cell, Vol. 100, 57–70, January, 2000

General Charactistics of Cancer

All cancers must acquire several of the same six hallmark capabilities

Means and order of acquisition vary significantly.

The catalyst of acquiring these is Genomic Instability.

CANCER: A DISEASE OF THE GENOME

Genomic StabilityGiven the standard mutation rate in dividing cells, coincident

with the fidelity of DNA replication, the time it would take to achieve a sufficiently mutated state for cancer would far surpass the human lifespan.A normal error frequency of 1 base-pair change in roughly 109 base

pairs for each cell generation (1 in a billion).A single gene that encodes an average-sized protein (~103 base pairs)

suffers a mutation once in about 106 cell generations. This number is roughly consistent with the evolutionary estimate -

one mutation appears in an average gene in the germ line every 200,000 years.

How is Fidelity Normally Maintained?

• Protein level: Wobble Effect.• Genetic level: Distinct DNA repair mechanisms.– DNA polymerase exonuclease activity– post-replicative recognition, excision, and repair of

mismatches

• Other strategy Affecting stability:• 5% exons• Extensive introns

NORMAL CELL

Cancer Cell

Apoptosis

No!

DamagedRepair

Mechanism

InabilityTo SenseDamage

Inability to Arrest

DNA Damage

Growth ArrestCan DamageBe Repaired?

Damage to Apoptotic Pathway

Mitosis Rapid accumulationof genetic damage

Perpetuation ofErrors to

Daughter Cells

GENOMIC INSTABILITY

Mitosis

Yes!

DNA Damage

Aneuploidy• Euploidy: Having a chromosome number that is an exact multiple

of the monoploid number.• Aneuploidy: Having a chromosome number that is not an exact

multiple of the usually haploid number.• Develops from defects in the process of chromosome segregation.• Most benign tumors are diploid.• All malignant tumors are aneuploid; this is one of the identifying

characteristics of malignant tumor cells.• Is required for cell immortalization; it is a critical rate-limiting step

of tumorigenesis – therefore, it develops early in the progression.

• Caused by the same factors which cause genomic instability.

Environmental Causes of Genomic Instability and Aneuploidy

• Oncogenic Viruses• Chemical carcinogens• Ionizing radiation

Loss of checkpoints +

circumvention of apoptosis =

genomic instability

Once genomic instability is in effect, cancer cells then follow a quicker path towards the accumulation of necessary mutations required to reach full-blown carcinogenesis.

ACQUIRED CHARACTERISTICS OF TUMOR CELLS

1. Self-Sufficiency in Growth Signals2. Insensitivity to Antigrowth Signals3. Evading Apoptosis4. Limitless Replicative Potential

(Immortalization)5. Sustained Angiogenesis6. Tissue Invasion and Metastasis

ACQUIRED CHARACTERISTICS OF TUMOR CELLS

Self-Sufficiency in Growth Signals

Normally, cells need to be TOLD to grow. If they aren’t given the signal to start the cell cycle (recall the cell cycle…), they will rest (remember G0 / quiescence?)

Cancer cells don’t listen to the environment – they do what they want. And they want to grow!They will bear a mutation in a gene normally involved in cell growth – the mutation causes the gene to be turned on ALL THE TIME.

ACQUIRED CHARACTERISTICS OF TUMOR CELLS

Insensitivity to Antigrowth Signals

Normal cells can be told to die. (recall apoptosis).

Cancer Cells ignore the environment again – this time not killing themselves when being told to.

Keep in mind, the cancer cell might still have all the machinery in place to kill itself – it just doesn’t use it.

ACQUIRED CHARACTERISTICS OF TUMOR CELLS

Evading Apoptosis

Normal Cells, once they start killing themselves, have to follow complex “genetic programs” to carry out this self-destruction.

Cancer cells that can “listen” to the order to self-destruct might have a mutation in a gene that carries out the order. You can’t kill yourself if your gun is broken.

ACQUIRED CHARACTERISTICS OF TUMOR CELLS

Limitless Replicative Potential (Immortalization)

Normal cells stop growing after a certain number of divisions. Why? The linear chromosomes shrink a little after each generation. Finally, they stop growing (this is senescence).

Cancer cells all (yes, ALL) have a way to maintain the ends of their chromosomes. In this way, cancer cells can divide “forever”. Most of them use the enzyme telomerase to keep their telomeres healthy.

ACQUIRED CHARACTERISTICS OF TUMOR CELLS

Sustained Angiogenesis

Normal cells need to be in contact with the body’s blood supply – this is how cells get the oxygen to carry out cellular respiration.

As tumors get larger, they need more oxygen – so they send out signals to the body to grow new blood vessels!

ACQUIRED CHARACTERISTICS OF TUMOR CELLS

Tissue Invasion and Metastasis

Normal cells can’t grow beyond their immediate environment. Why? The environment tells them to kill themselves if they “get out of line”.

Cancer cells, which ignore these signals, can grow in places they normally can’t.

Draw “metastasis” on the board. Show the major capillary beds, and show this is why these areas are the most common places for metastatic tumors.

CAMs

antigrowth signals

Epithelial Cancers

antigrowth signals

Growth Inhibitory Signal via binding

Extracellular Matrix

Integrins

Apoptotic signals

Apoptotic Signals via detachment

DR-4/5

TRAIL

DcR

TRAIL

Decoy Receptor

Can still bind ligand, but unable to transduce signal

DD

5. Sustained Angiogenesis

• All cells, normal and cancer alike, must reside within 100 mm of a capillary blood vessel.

• A tumor which fails to activate angiogenesis can only grow to ~2mm in diameter

Cell 2000 Jan 7;100(1):57-70

Molecular Defects in Cancer:Two Paradigms

Tumor SuppressorsLoss of function• p53• p16• p53• p16• Rb• pTEN• p27• etc. etc.

OncogenesGain of function• c-myc• Ras• Cyclin D• CDK4• Bcl-2• Survivin• Oncogenic Viral Proteins

Each protein is resopnsible in evading one or more of the core six characteristics necessary for tumorigenesis

Fighting Cancer

Chemotherapy• The idea behind chemotherapy is simple: kill cells that are

proliferating. • Chemotherpeutic agents induce apoptosis (specific to the cycling

cells) and necrosis (nonspecific and therefore less effective)

• The Failure of Chemotherapy– unfortunately, many cancers have damaged apoptotic response

pathways, leading to ineffective treatment– 50% of cancers have a mutation in p53, which is crucial for apoptotic

response.– Many normal cells proliferate at the same rate (if not faster) than

tumor cells– Many tumor cells don’t necessarily grow faster as they simply just don’t

die.

Myc

Growth Apoptosis

Lesion 1 Lesion 2

current chemotherapeuticapproaches

Novelapproaches

Strategy: Exploit cancer’s inactivated apoptotic pathways