2. Neoplasia II- Six Hallmarks Of Cancer

Question 1

Describe the 6 hallmarks of neoplasia (objective)

Answer 1

Answer later

Question 2

List common examples of the above 6 steps and describe the mechanisms of these hallmarks (objective)

Answer 2

Answer later

Question 3

Describe tumor microenvironment (objective)

Answer 3

Answer later

Question 4

6 Hallmarks of Neoplasia (list)

Answer 4

1. Sustaining proliferative signaling
2. Evading growth suppressors
3. Resisting cell death
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Activating invasion and metastasis

Question 5

Hallmark 1: Sustaining Proliferative Signaling

Answer 5

Malignant cells can proliferate without external stimuli

Usually oncogene activation

Question 6

Oncogenes Created by Mutations in Proto-Oncogenes

Answer 6

Proto-Oncogene (normal gene) gets mutated or amplified to oncogene, then through gene expression to onco-protein

Question 7

Role of Oncogenes

Answer 7

1. Created by mutations in proto-oncogenes
2. Oncogenes: genes that promote autonomous cell growth in cancer cells
3. Proto-oncogenes: un-mutated
4. Onco-proteins: proteins encoded by oncogenes

Question 8

Examples of Oncogene

Answer 8

EGF receptor (ERBB1)
RAS
RAF
MYC
CCND1 (Cyclin D1)

Slide 13 Diagram

Question 9

Oncogenes in Colon Cancer

Answer 9

40-50% colon cancers: activating KRAS mutations
Sometimes: activating BRAF mutations

Metastatic colon cancers tested in clinical molecular lab for KRAS and BRAF mutations

Question 10

Oncogenes in Colon Cancer (treatment)

Answer 10

Cetuximab (Erbitux)

• EGFR inhibitor
• Monoclonal antibody against EGFR (chimeric mouse/human antibody)
• Treatment of KRAS wild-type metastatic colon cancer
• Treatment of metastatic lung adenocarcinoma and head and neck cancers

Question 11

Oncogenes in Breast Cancer

Answer 11

15-20% have ERBB2 (HER) gene amplification

• ERBB2 gene encodes Her2 receptor (EGFR family member)
• gene amplification results in over-expressed Her2 receptor

Question 12

Oncogenes in Breast Cancer (treatment)

Answer 12

Trastuzumab (Herceptin)

• monoclonal antibody that binds to Her2 receptor
• for Her2 amplified breast cancers
• drug binds to extracellular domain of Her2 which leads to cell cycle arrest

Question 13

Hallmark 2: Evading Growth Suppressors

Answer 13

1. Tumor suppressor genes in normal cells: apply brakes to proliferation
2. Mutated genes in cancer cells: fail to inhibit growth, uncontrolled proliferation
3. Most tumor suppressor genes encode: TF’s, cell cycle inhibitors, signal transduction molecules, cell surface receptors, regulators for responses to DNA damage

Question 14

P53 (normal, guardian of the genome)

Answer 14

DNA damage-p53 activation-cell cycle arrest in G1-induction of DNA repair

If successful repair, then normal cells
If repair fails, then apoptosis

Question 15

P53 (abnormal, mutated or lost)

Answer 15

DNA damage-no p53 activation-no cell cycle arrest-DNA damage unrepaired-genetically damaged cells grow-malignant tumor

Question 16

Most Human Cancer Have ???

Answer 16

Biallelic “loss of function” mutation of TP53

Question 17

RB (governor of cell proliferation)

Answer 17

1. Key negative regulator of G1/S cell cycle transit

2. Direct/indirect inactivation in most human cancers

Question 18

Hypo-phosphorylated RB

Answer 18

Binds and inhibits E2F transcription factor, which blocks transcription for an antiproliferative effect

Question 19

Hyper-phosphorylated RB

Answer 19

Releases E2F transcription factor which leads to transcriptional activation for a proliferative effect

Question 20

Examples of Tumor Suppressor Genes and Cancer

Answer 20

APC (stomach, colon, pancreas cancers), WNT signaling
PTEN (diverse cancers), PI3K/AKT pathway
RB (retinoblastoma, breast, colon, lung)
CDH1 (gastric, lobular breast), cell adhesion
TP53 (most human cancers)

Question 21

Hallmark 3: Resisting Cell Death

Answer 21

Apoptosis

Cancer cells can evade apoptosis

Question 22

Apoptosis

Answer 22

• Cell death induced by tightly regulated cellular program
• Cells destined to die activate intrinsic enzymes that degrade DNA/proteins
• Cell break into fragments called apoptotic bodies that contain cytoplasm and nucleus
• Fragments phagocytosed by macrophages

Question 23

Cancer Cells Can Evade Apoptosis

Answer 23

• Mutations in TP53
• Mutations in other regulatory apoptosis genes
• Overexpression of anti-apoptotic signaling molecules like Bcl-2

Question 24

Hallmark 4: Enabling Replicative Immortality

Answer 24

1. All cancers contain cancer stem cells (which have unlimited replicative potential, are immortal)
2. Most normal human cells can divide 60-70 times (then senescence or apoptosis)

Question 25

Telomeres

Answer 25

• Specific DNA sequences at end of chromosomes
• shorten with each cell division
• when telomeric DNA is eroded, DNA damage is sensed and p53 is upregulated, leading to apoptosis

Question 26

Telomerase

Answer 26

• Expressed in cancer stem cells and embryonic stem cells
• Maintains telomeres
• Extends telomeric DNA to counter erosion
• Protects ends of chromosomes
• Makes cancer cells resistant to either senescence or apoptosis

Question 27

Hallmark 5: Inducing Angiogenesis

Answer 27

1. Tumors bigger than 1-2mm outgrow blood supply (need nutrients, oxygen, and to evacuate metabolic waste and carbon dioxide)
2. Angiogenesis: forming new blood vessels
3. Regulators of angiogenesis: VEGF, inhibited by bevacizumab (Avastin)

Question 28

Hallmark 6: Activating Invasion and Metastasis

Answer 28

Later