3. Neoplasia III- Enabling Characteristics And Emerging Hallmarks Of Neoplastic Cells

Question 1

Incorporating concepts of neoplasia, articulate how some common solid tumors exhibit one or more of the six hallmarks of cancer (objective)

Answer 1

Answer later

Question 2

Describe how two enabling characteristics support carcinogenesis: genomic instability and mutation; tumor-promoting inflammation (objective)

Answer 2

Answer later

Question 3

Describe two emerging hallmarks of neoplastic cells: reprogramming of cellular energy metabolism pathways; evasion of immune destruction (objective)

Answer 3

Answer later

Question 4

Sustaining proliferative signaling: cancer hallmark (example)

Answer 4

Breast cancer
ERBB2 gene amplification leads to overexpression of HER2 receptor (tyrosine kinase receptor) resulting in increased cellular proliferation

Question 5

Evading growth suppressors: cancer hallmark (example)

Answer 5

Pancreatic cancer

MENIN gene mutation results in release of growth control due to diminished tumor suppressor function

Question 6

Resisting cell death: cancer hallmark (example)

Answer 6

Colon cancer

Mutations in TP53 (tumor suppressor gene) also results in deregulation of apoptotic mechanisms in response to DNA damage

Question 7

Inducing angiogenesis: cancer hallmark (example)

Answer 7

Renal cancer
Mutations in VHL gene result in upregulation of expression of genes such as VEGF and PDGF, whose products are involved in agniogenesis

Question 8

Enabling replicative immortality: cancer hallmark (example)

Answer 8

Uterine cancer
Alterations in the promoter of the gene encoding telomerase reverse transcriptase (TERT) lead to protection of telomeres and increased cellular longevity

Question 9

Activating invasion and metastasis: cancer hallmark (example)

Answer 9

Breast cancer

CDH1 gene mutation leads to loss of E-cadherin (intercellular adhesion molecule) which enhances invasiveness

Question 10

Enabling Characteristics of Cancer

Answer 10

Phenomena which facilitate normal cells acquiring any one or more of 6 hallmarks of cancer

1. Genomic instability and mutation
2. Tumor-promoting inflammation

Question 11

Genome instability and mutation

Answer 11

1. Single or cumulative genomic alterations enhance the acquisition of one or more of the hallmarks of cancer
2. Susceptibility to mutations occurs when defects occur in:
   - DNA damage sensors and repair activators (TP53)
   - DNA repair apparatus like mismatch repair proteins
   - Systems which inactivate or intercept mutagenic molecules before DNA damage can occur

Question 12

Tumor-promoting inflammation

Answer 12

Inflammatory state facilitates acquisition of hallmarks due to increased bioactive molecules:

1. Growth factors: enhance proliferative signaling
2. Survival factors: help avoid apoptosis
3. Proangiogenic factors: stimulate angiogenesis
4. Extracellular matrix modifying factors: may stimulate angiogenesis, invasion, metastasis
5. Inductive signals: help activate epithelial-mesenchymal transition program

Question 13

Emerging Hallmarks of Cancer

Answer 13

Phenomena which are increasingly being recognized as playing important role in cancer development:

1. Deregulating cellular energetics
2. Avoiding immune destruction

Question 14

Deregulating Cellular Energetics

Answer 14

Reprogramming of normal cellular energy metabolism by tumor cells via:

1. Converting from oxidative phosphorylation to aerobic glycolysis
   - Lower energy yield is compensated for by upregulating glucose uptake receptors (GLUT-1)
   - Concept employed in PET-CT scans (staging protocol, light up cancer labeling)
2. Glycolytic fueling associated with activated oncogenes and mutated tumor suppressor genes

Question 15

Avoiding immune destruction

Answer 15

1. Immunogenic tumor cells may secrete immunosuppressive factors like TGF-B
2. Tumor cells may recruit suppressive inflammatory cells such as regulatory T cells

Question 16

Sustaining proliferative signaling (drug goals)

Answer 16

EGFR inhibitors

Question 17

Evading growth suppressors (drug goals)

Answer 17

Cyclin-dependent kinase inhibitors

Question 18

Avoiding immune destruction (drug goals)

Answer 18

Immune activating anti-CTLA4 MAb

Question 19

Enabling replicative immortality (drug goals)

Answer 19

Telomerase inhibitors

Question 20

Tumor-promoting inflammation (drug goals)

Answer 20

Selective anti-inflammatory drugs

Question 21

Activating invasion and metastasis (drug goals)

Answer 21

Inhibitors of HGF/c-Met

Question 22

Inducing Angiogenesis (drug goals)

Answer 22

Inhibitors of VEGF signaling

Question 23

Genome instability and mutation (drug goals)

Answer 23

PARP inhibitors

Question 24

Resisting cell death (drug goals)

Answer 24

Pro-apoptotic BH3 mimetics

Question 25

Deregulating cellular energetics (drug goals)

Answer 25

Aerobic glycolysis inhibitors