6 Hallmarks of Cancer Flashcards
The 6 hallmarks of cancer
1) sustaining proliferative signaling
2) evading growth suppressors
3) resisting cell death
4) enabling replicative immortality
5) indicing angiogenesis
6) activating invasion and metastasis
6 hallmarks of cancer pic
Hallmark 1: sustaining proliferative signaling
malignant cells can proliferate without external stimuli
usually as a consequence of oncogene activation
Proto-oncogenes
Normal genes that turn into oncogenes through mutation
Role of oncogenes
oncogenes created by mutations in proto-oncogenes
oncogenes promite autonomous cell crowth in cancer cells
proto-oncogenes
unmutated counterparts of oncogenes
Onco-proteins
proteins encoded by oncogenes
Examples of oncogene
EGF receptor (ERBB1)
RAS
RAF
MYC
CCND1 (Cyclin D1)
Examples of oncogenes chart
Oncogenes in colon cancer
Activating KRAS mutation occurs in 40-50% of colon cancers
Activating BRAF mutations occur in a smaller subset of colon cancers
metastatic oclon cancers tested in clinical molecular lab for KRAS and BRAF mutations
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% of breast CAs have amplification of ERBB2 (HER) gene
ERBB2 encodes Her2 receptor, a member of EGFR family
gene amplification results in over expression of Her 2 receptor
Trastuzumab (herceptin)
Monoclinan antibody that binds to Her 2 receptor
used to treat pts with Her2 amplified breast CAs
Trastuzumab binds to extracellular domain of Her2 -> cell cycle arrest
Hallmark 2: Evading growth suppressors
Tumor supressor genes in normal cells apply breaks to cell proliferation
Mutated tumor supressor genes in cancer cells fail to inhibit growth -> uncontrolled proliferation
Most tumor supressor genes encode
transcription factors, cell cycle inhibitors, signal transduction molecules, cell surface receptors, regulators of cellular responses to DNA damage
Normal p53 (guardian of the genome)
DNA damage -> p53 activation -> cell cycle arrest in G1
indiction of DNA repair
if successful DNA repair -> normal cells
if repair fails -> apoptosis
Abnormal p53 (mutated or lost)
DNA damage -> no p53 activation -> no cell cycle arrest
DNA damage unrepaired -> genetically damaged cells grow
malignant tumor
Most human cancers have
biallelic loss of function mutation of p53
Rb
Governer of the cell
Rb
RB is a key negative regulator of G1/S cell cycle transit
RB is directly inactivated in most human cancers
hypophosphorylated RB binds and inhibits E2F TF and blocks transcription -> antiproliferative effect
Hyperphosphorylated RB releases E2F transcription factor -> transcroptional activation -> proliferative effect
Examples of tumor supressor genes
Hallmark 3: resisting cell death
Apoptosis (programmed cell death)
is a pathway of cell death indices by tightly regulated cellular program
cells destined to ddie activate intrinsic enxymes that degrade DNA and proteins
Cells break up into fragments called apoptotic bodies that contain portions of cytoplams and nucleus
fragments are phagocytosed by macrophages
Cancer cells can evade apoptosis
mutations in TP53
mutations in other genes that regulate apoptosis
overexpression of anto-apoptotic signaling molecules like Bcl-2
Hallmark 4: Enabling Replicative Immortality
All cancers contain cancer stem cells
cancer stem cells have unlimited replicative potential- are immortal
most human cells can divide 60-70 times
then senescence or apoptosis
TELOMERES
