Cancer

From the syllabus Define cancer. List some types of cancer. List characteristics of cancer cells including: lack of contact inhibition, vascularity, plasma membrane cytoskeleton and cytoplasm changes abnormal disorganized growth. List some mechanisms and causes of cancer. Identify and define the genes involved proto-oncogenes, oncogenes. tumor suppresser genes DNA repair genes. Define apoptosis. Briefly discuss the multistep theory and genetic predisposition. Identify treatment and side effects historical perspectives such as drug discovery screening and early detection surgery concept of how chemotherapy works using fluorouracil, taxol radiation

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

From the syllabus Define cancer. List some types of cancer. List characteristics of cancer cells including: lack of contact inhibition, vascularity, plasma membrane cytoskeleton and cytoplasm changes abnormal disorganized growth. List some mechanisms and causes of cancer. Identify and define the genes involved proto-oncogenes, oncogenes. tumor suppresser genes DNA repair genes. Define apoptosis. Briefly discuss the multistep theory and genetic predisposition. Identify treatment and side effects historical perspectives such as drug discovery screening and early detection surgery concept of how chemotherapy works using fluorouracil, taxol radiation

Cancer Evolution in action A disease of the genome Survival of the fittest and natural selection are directly observable. A disease of the genome Genomic instability A disease of the cell cycle Checkpoint failures A disease of the aged Mutations occur throughout life. Benign vs. Malign Benign 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 factor 2. 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

General Charactistics of Cancer 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 Stability Given 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

Genomic Instability DNA Damage Normal Cell No! Yes! Cancer Cell Apoptosis No! Growth Arrest Can Damage Be Repaired? Mitosis Yes! Cancer Cell DNA Damage Damaged Repair Mechanism Inability To Sense Damage Inability to Arrest Damage to Apoptotic Pathway Mitosis Rapid accumulation of genetic damage Perpetuation of Errors to Daughter Cells

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 Self-Sufficiency in Growth Signals Insensitivity to Antigrowth Signals Evading Apoptosis Limitless Replicative Potential (Immortalization) Sustained Angiogenesis 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 Integrins Growth Inhibitory Signal via binding Extracellular Matrix CAMs Integrins Epithelial Cancers antigrowth signals antigrowth signals

Apoptotic Signals via detachment

Can still bind ligand, but unable to transduce signal Decoy Receptor TRAIL TRAIL Can still bind ligand, but unable to transduce signal DD DR-4/5 DcR

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 Suppressors Loss of function p53 p16 Rb pTEN p27 etc. etc. Oncogenes Gain 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.

current chemotherapeutic Strategy: Exploit cancer’s inactivated apoptotic pathways current chemotherapeutic approaches Novel approaches Lesion 1 Lesion 2 Myc Growth Apoptosis