2. Neoplasia II- Six Hallmarks Of Cancer Flashcards
Describe the 6 hallmarks of neoplasia (objective)
Answer later
List common examples of the above 6 steps and describe the mechanisms of these hallmarks (objective)
Answer later
Describe tumor microenvironment (objective)
Answer later
6 Hallmarks of Neoplasia (list)
- Sustaining proliferative signaling
- Evading growth suppressors
- Resisting cell death
- Enabling replicative immortality
- Inducing angiogenesis
- Activating invasion and metastasis
Hallmark 1: Sustaining Proliferative Signaling
Malignant cells can proliferate without external stimuli
Usually oncogene activation
Oncogenes Created by Mutations in Proto-Oncogenes
Proto-Oncogene (normal gene) gets mutated or amplified to oncogene, then through gene expression to onco-protein
Role of Oncogenes
- Created by mutations in proto-oncogenes
- Oncogenes: genes that promote autonomous cell growth in cancer cells
- Proto-oncogenes: un-mutated
- Onco-proteins: proteins encoded by oncogenes
Examples of Oncogene
EGF receptor (ERBB1) RAS RAF MYC CCND1 (Cyclin D1)
Slide 13 Diagram
Oncogenes in Colon Cancer
40-50% colon cancers: activating KRAS mutations
Sometimes: activating BRAF mutations
Metastatic colon cancers tested in clinical molecular lab for KRAS and BRAF mutations
Oncogenes in Colon Cancer (treatment)
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
Oncogenes in Breast Cancer
15-20% have ERBB2 (HER) gene amplification
- ERBB2 gene encodes Her2 receptor (EGFR family member)
- gene amplification results in over-expressed Her2 receptor
Oncogenes in Breast Cancer (treatment)
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
Hallmark 2: Evading Growth Suppressors
- Tumor suppressor genes in normal cells: apply brakes to proliferation
- Mutated genes in cancer cells: fail to inhibit growth, uncontrolled proliferation
- Most tumor suppressor genes encode: TF’s, cell cycle inhibitors, signal transduction molecules, cell surface receptors, regulators for responses to DNA damage
P53 (normal, guardian of the genome)
DNA damage-p53 activation-cell cycle arrest in G1-induction of DNA repair
If successful repair, then normal cells
If repair fails, then apoptosis
P53 (abnormal, mutated or lost)
DNA damage-no p53 activation-no cell cycle arrest-DNA damage unrepaired-genetically damaged cells grow-malignant tumor
Most Human Cancer Have ???
Biallelic “loss of function” mutation of TP53
RB (governor of cell proliferation)
- Key negative regulator of G1/S cell cycle transit
2. Direct/indirect inactivation in most human cancers
Hypo-phosphorylated RB
Binds and inhibits E2F transcription factor, which blocks transcription for an antiproliferative effect
Hyper-phosphorylated RB
Releases E2F transcription factor which leads to transcriptional activation for a proliferative effect
Examples of Tumor Suppressor Genes and Cancer
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)
Hallmark 3: Resisting Cell Death
Apoptosis
Cancer cells can evade apoptosis
Apoptosis
- 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
Cancer Cells Can Evade Apoptosis
- Mutations in TP53
- Mutations in other regulatory apoptosis genes
- Overexpression of anti-apoptotic signaling molecules like Bcl-2
Hallmark 4: Enabling Replicative Immortality
- All cancers contain cancer stem cells (which have unlimited replicative potential, are immortal)
- Most normal human cells can divide 60-70 times (then senescence or apoptosis)
Telomeres
- 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
Telomerase
- 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
Hallmark 5: Inducing Angiogenesis
- Tumors bigger than 1-2mm outgrow blood supply (need nutrients, oxygen, and to evacuate metabolic waste and carbon dioxide)
- Angiogenesis: forming new blood vessels
- Regulators of angiogenesis: VEGF, inhibited by bevacizumab (Avastin)
Hallmark 6: Activating Invasion and Metastasis
Later