Cell Bio Part 3 Lecture 1, 2 & 3- Cancer Bio (Complete)

Front 1

Why understand cancer genetics?

Back 1

Diagnostics, prognostics, stratification, therapeutic targeting

Front 2

Strategy to prevent recurrent cancer

Back 2

Targeted cancer treatment based on individual gene expression patterns

Front 3

Malignant cell transformation

Back 3

State change from normal cell to a cancer cell; Malignant cancer cells invade neighboring tissues, enter blood vessels and metastasize to different sites; caused by several mutations, not just one.

Front 4

Benign hyperplastic cells

Back 4

Tumor cells grow only locally and cannot spread by invasion or metastasis

Front 5

Normal cell division vs. Cancer cell division

Back 5

Normal: cell damage without repair--> apoptosis; Cancer: mutation--> passes on to daughter cells, 2nd mutation--> passes on to daughter cells, 3rd mutation---> uncontrolled growth

Front 6

Common features of cancer cells (12)

Back 6

(1) Sustained angiogenesis (2) tissue invasion & metastasis (3) Evading apoptosis (4) Self-sufficiency in growth signal (5) insensitivity to anti-growth signals (6) limitless replicative potential (7) DNA damage stress (8) Oxidative stress (9) Mitotic stress (10) Proteotoxic stress (11) Metabolic stress (12) Evading immune surveillance....basically cancer cells live a stressful life

Front 7

Causes of cancer (8)

Back 7

(1) Viruses & bacteria- example: Hepatitis B, cervical cancer (Gardasil vaccine) (2) Chemical exposure (3) Radiation exposure (4) Hereditary (5) Diet (6) Hormones (7) Oncogene & Tumor suppressor mutation (8) Random accumulation of mutations due to DNA replication & oxidative stress--this is why we can't prevent all cases because we can't stop mutations from happening

Front 8

Somatic mutations

Back 8

Occur in nongermline tissues; are nonheritable

Front 9

Germline mutations

Back 9

Present in egg or sperm; are heritable- all cells affected in offspring; cause cancer family syndrome

Front 10

Cancer cells have mutations in:

Back 10

primarily: oncogenes, tumor suppressor genes, DNA repair genes;
also: cell death genes, cell signaling genes, cell checkpoint genes, cell senescence genes, cell differentiation genes, metastasis/invasion genes

Front 11

Oncogene

Back 11

gene mutated in cancer, whose increased expression or activity drives cell transformation; these get turned on in cancer

Front 12

Tumor suppressor

Back 12

gene mutated in cancer, whose decreased expression or activity allows cell transformation; are inactive in cancer

Front 13

Stages where mutations can occur

Back 13

growth factors, receptors (Her2, EGFR), signaling enzymes (Ras, Raf), transcription factors (Myc, NF-kB)

Front 14

Gene amplification

Back 14

leads to overexpression of gene which leads to more signaling than you should actually be getting, leads to insensitivity

Front 15

Translocation of genes

Back 15

example: in leukemia, Bcr-Abl genes, leads to higher expression of abl

Front 16

Genes that act like brake pedals

Back 16

Tumor suppresor genes; can inhibit at each stage: receptor--->signaling enzymes-->transcription factors; also if the recycling of receptors is inhibited, this inhibits receptor

Front 17

Tumorigenesis

Back 17

Caused by the loss of BOTH copies of tumor suppressor (called loss of heterozygosity event)

Front 18

p53

Back 18

A tumor suppressor gene that triggers cell suicide and regulates apoptosis; usually mutated in cancer cells which causes inappropriate cell survival; looking for a way to change mutant back to non-mutant

Front 19

Oncogene Cooperation

Back 19

Interaction between oncogene mutations causes the emergence of malignant transformation; cancer doesn't happen with just one mutation of oncogene or of one tumor suppressor; 3-5 mutations cause cancer; the cooperation drives malignant transformation; Just Ras mutation or just Myc mutation doesn't cause cancer, but mutation in both causes cancer

Front 20

Cancer genome landscapes

Back 20

Show how many mutations are in each gene; certain genes have many mutations (p53)

Front 21

Predicted rates of colon cancer based on 1, 2 or 4 mutations

Back 21

If only one mutation caused cancer, there would be a linear relationship between age and risk of cancer. The more mutations needed to cause cancer, the more curved the graph becomes. Comparing to actual data shows that 3-5 mutations cause cancer

Front 22

Cancer cells have complex architecture

Back 22

They rely on changes in effectors which underlies malignant transformation:
A +B -----> invasion, growth, angiogenesis, survival ---> transformation;
NOT:
A ----> Invasion, angiogenesis ---> transformation;
B -----> survival, growth -----> transformation;

Front 23

Two functions of Myc; Cooperation of Myc with Bcl-2

Back 23

(1) Myc-Max ----> Proliferation
(2) Myc-Max -----> Death; inhibited by Bcl-2 & IGF1;

In normal cells, Myc causes cell death

Front 24

Cooperation of mutant Ras/Raf with p53

Back 24

-Promotes cell proliferation
-Ras/Raf + p53 ----> p21 -----| cyclin cdk; (p21 inhibits growth arrest)
-Ras/Raf alone ------------> cyclin cdk on

Front 25

Cooperation response genes

Back 25

Essential mediators of malignant transformation synergistically (more than additive) regulated in response to the combination of loss-of-function mutant p53 and constitutively active Ras. Changes in apoptosis, transcription, signaling, metabolism, & adhesion.

Front 26

What do DNA tumor viruses do?

Back 26

They alter cellular gene function; example: HPV, Epstein-Barr, chronic infection

Front 27

What do transforming retroviruses do? What did Bishop & Varmus find?

Back 27

They acquire and transmit cellular DNA.

B & V showed that gene sequences in transforming retroviruses were homologous to sequences in cellular DNA;

Example: Rous Sarcoma virus (Src); myelocytomatosis virus (myc);

Front 28

p53: tumor suppressor or oncogene?

Back 28

Oncogene evidence: (1) adding anti p53 to mouse 3T3 cells causes growth arrest (2) in rat embryonic fibroblasts, p53 cDNA immortilizes cell and p53 cDNA + Ha-Ras causes transformation into tumor. Experiment lacks loss of function control.

Tumor suppressor evidence: Mutant (& inactive) p53 found in tumor cells, the 2nd allele is either lost through loss of the chromosome, or inactived by deletion. This seems to confer a selective growth advantage to cells

Answer: wild type p53 is a tumor suppressor, mutant is an oncogene. Why was there oncogene evidence? the cDNA was for a mutated p53

Front 29

p53 and cancer

Back 29

1- p53 mutations can be found in 50% of human cancers, but their penetrance is highly heterogeneous, as reflected by the diverse remaining transactivation activity that ranges from O to 100%. 2- Various DNA viruses, such as SV40, HPV or adenoviruses, encode proteins that target p53 protein. 3- In inflammatory breast cancer and neuroblastoma, p53 is predominantly found in the cytoplasm. 4- mdm2 accumulation is found in numerous cancers, such as sarcoma or breast carcinomas. 5- PTEN, a p53 regulated gene, is mutated in various types of cancer including glioblastoma. 6- Although no mutation of AKT has been found in human cancer, constitutive activation of its kinase activity has been observed via deregulation of the upstream pathway. 7- Mutations in various pathways upstream of p53 (ATM, p19ARF or Hcdk2 gene) can be observed in various types of cancer

Front 30

What does Rb do?

Back 30

Inhibits cell cycle

Front 31

Telomerase

Back 31

The reactivation of telomerase is the key to unlock human cell transformation--immortality, because it maintains chromosome length. Without it, telomeres are shortened after each cell division so after a certain number of divisions, the cell dies.

Front 32

Gleevec

Back 32

A molecular targeted therapy that inhibits BCR-Abl. It's highly selective for tumors with this translocation and has a strong selective pressure for insensitivity. Gleevec binds to BCR-Abl ATP binding site preventing it from phosphorylating

Front 33

Herceptin

Back 33

A molecular targeted therapy. It's an antibody antagonizing Her2 receptor activation in breast cancer; inhibits growth of Her2+ tumors

Front 34

Iressa

Back 34

A molecular targeted therapy. It's an EGFR antagonist, turns out it only works against very specific mutant EGFR forms

Front 35

Extrinsic factors that can be essential for cancer growth (2)

Back 35

(1) Blood supply (angiogenesis & neovascularization)
(2) Hormone signaling (androgen or estrogen dependence)

Front 36

Angiogenesis

Back 36

Tumors secrete factors that drive formation of new blood vessels. Blocking developement of new blood vessels inhibits tumor development and spreading.

Front 37

Tomoxifen

Back 37

Drug that targets estrogen hormone dependence by blocking ligand binding

Front 38

Flutamide

Back 38

Drug that targets testosterone hormone dependence of prostate cancer by blocking cofactor interaction

Front 39

Metastasis

Back 39

Dissemination or spread of cancer cells to distance locations within the body; a hallmark of malignant disease

Front 40

Seed & Soil hypothesis

Back 40

Hypothesis that some organs are congenial for tumor cells; cancer cells metastasize in target organs due to certain genetic factors

Front 41

Dominant circulation hypothesis

Back 41

Hypothesis that cancer spreads based on circulation; cancer cells target first highly vascularized organ encountered. Lungs are a major target- one of the first highly vascularized organ encountered, but why not the heart?

Front 42

Evolution models of where cancer cells spread

Back 42

Selection of rare clones in specific organs by random acquisition of pro-metastatic mutations

Front 43

Pre-determination models of where cancer cells spread

Back 43

Poor-prognosis genes expressed in primary tumors support primary tumor and distant metastasis

Front 44

Measuring acquisition of Metastatic capability with gene expression programs

Back 44

Use microarrays to measure differences in gene expression. Upregulated combinations of genes that were upregulated in metastasis and saw this caused more metastasis.

Front 45

Cancer stem cell/tumor initiating cell

Back 45

Cells within tumor population that are transplantable and produce heterogeneous progeny. They are the drivers of metastasis and tumor recurrence.

Front 46

What type of disease is cancer?

Back 46

A cellular disorder. There are transforming viruses that carry oncogenes which are cellular in origin.