Homework #3 is due 11/15 Bonus #2 is posted No class on 11/20

Mitosis is tightly regulated: checkpoints

A cell becomes cancerous when there are incorrect positive AND negative signals.

GO! STOP! cancer similar to Fig 15.36

Causes of mutations: Replication errors –Exacerbated by poor DNA repair –Limited by telomere length Other biological agents –Viruses –Transposons Environmental factors –Ultraviolet light –Mutagenic chemicals smoking, industrial waste, natural toxins

Treating cancer: Avoid it –Avoid mutagens –DNA repair gets less efficient as we age

Environment plays a large role in the chance of contracting cancer.

T-cells recognize and eliminate abnormal cells; such as cells with many mutations Our immune system protects us from cancer

P53 is activated by DNA damage

p53 can induce apoptosis via two pathways: Nuclear and/or Mitochondrial

Treating cancer: Avoid it –Avoid mutagens –DNA repair gets less efficient as we age Surgery –Must remove all cancer cells –Non-invasive

Treating cancer: Avoid it –Avoid mutagens –DNA repair gets less efficient as we age Surgery –Must remove all cancer cells –Non-invasive Radiation –Directed at tumor; causes DNA damage -> cellular self-destruction –Mutagenic, side effects

Treating cancer: Avoid it –Avoid mutagens –DNA repair gets less efficient as we age Surgery –Must remove all cancer cells –Non-invasive Radiation –Directed at tumor –Mutagenic, side effects Chemotherapy –Toxins directed at rapidly dividing cells –Mutagenic, many side effects

Chemotherapy a rapidly dividing cell Toxin XX

Normal Multi-Drug Resistance protein MDR toxin/hormone/etc

Some cancers over-express MDR Toxin MDR toxin I’m a cancer cell with over-expressing MDR. I laugh at your toxins.

The Epigenetic Progenitor Origin of Human Cancer (2007) A P Feinberg, R Ohlsson, S Henikoff Nature Reviews Genetics 7: Mutations continue after cancer develops

O O OOO O O OO OO Cancer cell with mutation causing MDR over-production Evolution: changes in DNA as information transmitted

O O OOO O O OO OO O O OOO O O OO OO Apply chemo- therapy X XX XXXX X XX Kills most cells. Except if some have mutation that allow them to be resistant. Evolution: changes in DNA as information transmitted Cancer cell with mutation causing MDR over-production

O O OOO O O OO OO O O OOO O O OO OO O X XX XXXX X XX Kills most cells. Except if some have mutation that allow them to be resistant. Continues to replicate Evolution: changes in DNA as information transmitted Apply chemo- therapy Cancer cell with mutation causing MDR over-production

O O OOO O O OO OO O O OOO O O OO OO O O OOO O O OO OO O X XX XXXX X XX Kills most cells. Except if some have mutation that allow them to be resistant. Continues to replicate Tumor with cells expressing MDR Evolution: changes in DNA as information transmitted Apply chemo- therapy Cancer cell with mutation causing MDR over-production

Some cancers over-express MDR Toxin MDR toxin I’m a cancer cell with over-expressing MDR. I laugh at your toxins.

Cells need the proximity of blood vessels to survive One of the latest chemotherapy treatments involves cutting off the blood supply to the tumor. (anti-angiogenesis)

Tumors must have sufficient blood flow to continue cell division induce blood vessel growth (angiogenesis)

Tumors Evolve: Only tumor cells near blood vessels or that can attract blood vessels survive.

Targeting toxins to cancer cells… A vesicle with mutant genes that cause blood vessels to die is directed to newly growing blood vessels by interacting with Integrins. Integrins are present on newly growing blood vessels, but not on established blood vessels.

Detecting Cancer or Types of Cancer Fig

A Microarray is a chip with DNA sequences (genes) bound to the surface at known locations. It can be used to track or monitor expression of many genes.

Tracking changes in gene expression using a Microarray

Making cDNA from RNA

Tracking changes in gene expression using a Microarray

Use of microarray to estimate genes likely present in malignant cancers

Patients cancer free for 5+ years Patients cancer spread in 5 years Use of microarray to estimate genes likely present in malignant cancers similar to Fig different genes

Young (>55) Breast cancer patients More accurate profiling of tumors results in more accurate choices of treatments. Patients with benign tumors can avoid chemotherapy (adjuvant).

Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari, K M Lonergan, R T Ng, C MacAulay, W L Lam, and S Lam BMC Genomics, 8:297

Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297 CS=current smoker, FS=former smoker, NS=never smoked Table 1: Subject Demographics

Overlapping and unique genes expression Fig 1B Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297

Table 3: Reversible gene expression upon smoking cessation related to mucus secretion (genes in bold have not been previously associated with smoking)

CABYRENTPD8TFF3 Fig 4A Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297 Some changes in gene expression induced by smoking are reversible

MUC5ACGSK3B Fig 4B Effect of active smoking on the human bronchial epithelium transcriptome (2007) R Chari et el. BMC Genomics, 8:297 Smoking can induce irreversible changes in gene expression

Treating cancer: Avoid it –Avoid mutagens –DNA repair gets less efficient as we age Surgery –Must remove all cancer cells –Non-invasive Radiation –Directed at tumor –Mutagenic, side effects Chemotherapy –Toxins directed at rapidly dividing cells –Mutagenic, many side effects

Homework #3 is due 11/15 Bonus #2 is posted No class on 11/20