Cancer Hallmarks Flashcards
Name the Hallmarks of cancer
Enabling characteristics:
- genome instability
- Tumour promoting inflammation
Hallmarks:
1) Self Sufficiency in Growth Signals,
2) Insensitivity to anti-growth Signals,
3) Evading Apoptosis,
4) Limitless replicative potential,
5) Sustained angiogenesis,
6) Tissue invasion and metastasis.
7) Deregulating cellular energetics
8) Avoiding immune destruction
Explain Self Sufficiency in Growth Signals,
3 ways:
1) Altering extracellular Growth Signals
- Autocrine stimulation by selfmade GFs
- Fedi et al 1997: PDGF in Glioblastomas and
TGFa in sarcomas
2) Altering Trancellular Transducers of these Signals
a) - GF receptors over expressed -> hyper-responsive
Eg: EGF-R/erbB in brest stomach and brain tumours
HER2/neu receptor in stomach and mamillary
b) - Swap to pro-growth Integrins
- BOTH can activate RAS
3) Altering intracellular Circuits of translating these to actions
- Mutant Ras that doesn’t need ongoing stimulation
- Hetrotypic singnaling is important with growth signals
from microenvironment
Explain Insensitivity to anti-growth Signals
Need to overcome:
1) Being forced into G0 by
A) Hypophosphorylated pRb blocks proliferation by
inhibiting E2F transcription factors.
- TGFb blocks phosphorylation of pRb
via Downregulation/mutation of TGFb receptors
or mutations in downstream targets
B) Integrins that are sending antigrowth signals
2) Forced into a postmiotic differentiated state.
- Mad-Max complexes induce differentiation
- c-Myc oncogene produces more Myc(promotes growth)
- Shifts balance to Myc-Max which stimulates growth and reduces differentiation.
Explain Evading Apoptosis
Survival signals: IGF and IL3
IGF stimulates P13K-AKT pathway
pTEN is a tumour suppressor that attenuates AKT
Too much IGF or loss of pTEN can mean evading apoptosis
Death signals: Fas ligand, and TNFa
- imbalance of signals, poor cell wellbeing (dna damage)
low Matrix/Cell-cell adhesion trigger apoptosis.
- Motochondria produce Cytochrome C (proAp)
(Bax Bak Bid Bim all are proAp)
- Bcl2 is antiAp as it inhibits release of Cytochrome C
(Bcl2 is upregulated via Chromosomal translocation in follicular lymphoma)
p53 upregulates bax which stimulates mitochondria to
release cytochrome C
- Fas activates caspase 8
- Cytochrome C activates caspase 9
Functional loss of p53 in over half of cancers.
Nonsignaling FAS receptor decoy found in lung and colon cancers
Necrosis can increase inflammation which is bad
Explain Limitless replicative potential
Normal cells reach senescence after 60 doublings due to shortening of telomeres
(Tumour cells die more often so need more generations)
Overcome by
1) Upregulating expression of telomerase enzyme (adds
hexanucleotide repeats to DNA ends)
2) Activating ALT mechanism which maintains them
(both strongly suppressed in normal cells)
Senescence can be induced by high oncogene expression, eg: activated ras oncogene
Explain Sustained angiogenesis
All cells reside within 1mm of capillary
Tumour change balance by altering gene transcription by
Increasing VEGF and bFGF (are pro-angiogenesis)
- Ras oncogene causes upregulation of VEGF
- Proteases can release stored bFGF
Downregulating Thrombospondin-1 (angiogenesis inhibitor)
- Loss of p53 can cause this to fall
Explain Tissue invasion and metastasis
Mets cause 90% of cancer deaths
(depend on all other hallmarks)
Needs changes in the following to occur
1) Physical coupling of cell to microenvironment
a - Cell-Cell Adhesion Molecules (CAMs) (cadherins)
help to prevent invasion.
E-cadherin(on epithelial cells) is antigrowth via beta-
catenin. Function lost in endothelial cancers.
b - Integrins ( Cell - Extracellular matrix)
Shift in integrins expressed to ones that prefer
degraded stromal components produced by proteases
2) Actions of extracellular proteases
(Matrix-degrading) protease genes upregulated (and
inhibitors downregulated) facilitating the invasion of
nearby stroma.
(many of the proteases are produced by conscripted
stromal cells and inflammatory cells)
Explain Deregulating cellular energetics
Reprogramming Energy Metabolism
Even with oxygen, cancer cells can reprogram their glucose metabolism (thus their energy production) by limiting their energy metabolism largely to glycolysis, leading to a state that has been termed “aerobic glycolysis.”
However, ∼18-fold lower efficiency of ATP production afforded by glycolysis relative to mitochondrial oxidative phosphorylation
Overcome by by upregulating glucose transporters, notably GLUT1, which substantially increases glucose import into the cytoplasm
Tumours are often hypoxic: hyopxix response leads to upregulation of glucose transporters and enzymes of the glycolytic pathway via increase the levels of the HIF1α and HIF2α transcription factors
Useful in tumours as glycolysis Intermediates can be used in biosynthetic pathways to generate nucleaslides and aminoacids required for active cell proliferation.
however could just be a result of other proliferation-inducing oncogenes, not a new hallmark
Explain Avoiding immune destruction
Immune surveillance recognises and eliminates the most developing cancer cells.
Tumours that do develop must have avoided this.
Non-viral induced cancers grew more quickly in immunodeficient mice [deficiencies in CD8+ cytotoxic T lymphocytes (CTLs), CD4+ Th1 helper T cells, or natural killer (NK) cells were found especially important.] Kim et al. 2007, Immunology, review of immune cells in all three phases: elimination, equilibrium, and escape.
Also weakly immunogenic cells can thereafter colonize both immunodeficient and immunocompetent hosts.
Patients with colon and ovarian tumors that are heavily infiltrated with CTLs and NK cells have a better prognosis
Immunosuppressed can develop donor derived cancers, suggesting that in Tumour-free donors, the cancer cells were held in check, in a dormant state, by a fully functional immune system. Strauss, 2010
Cancer cells may paralyze infiltrating CTLs and NK cells, by secreting TGF-β or other immunosuppressive factors,
Or via recruitment of immunosuppressive inflammatory cells (eg: T regs)
A class of tumor-infiltrating myeloid cells has been shown to suppress CTL and NK cell activity
Explain importance of Genome instability
enabling characteristic
Genes that Sense and Repair DNA damage are lost (eg. p53) This allows genome instability and accelerates the rate of further mutations.
loss of Telomeric DNA can generate karyotypic instability
LONG ANSWER:
DNA monitoring and repair enzymes ensure sequence remains pristine.
Tumour cell must acquire increased mutability in order for the process of tumour progression.
- p53 is KEY
- causes cell cycle arrest or apoptosis in response to DNA damage.
- Other genes that sense & repair DNA damage are lost
(these caretakers are Tumour Suppressors)
(* Loss of telomeric DNA in many tumors generates karyotypic instability )
Loss of function of any of these will allow genome instability and accelerate the rate at which evolving premalignant cells can accumulate favorable genotypes
(Loss of function of p53 is particularly bad as it not only enables genome instability, but also can facilitate both angiogenesis and resistance to apoptosis)
Explain Tumour promoting inflammation
enabling characteristic
Considered an enabling characteristic for its contributions to the acquisition of core hallmark capabilities by
1) Releasing ROS
2) Supplying bioactive molecules
1 - Inflammatory cells can release chemicals, notably reactive oxygen species, that are actively mutagenic for nearby cancer cells, accelerating their genetic evolution toward states of heightened malignancy.
2 - Inflammation can contribute to multiple hallmark capabilities by supplying:
Growth factors that sustain proliferative signaling, Survival factors that limit cell death,
Proangiogenic factors,
Extracellular matrix-modifying enzymes that facilitate angiogenesis, invasion, and metastasis.
Recruitment of certain myeloid cells may be doubly beneficial for the developing tumor, by directly promoting angiogenesis and tumor progression while at the same time affording a means to evade immune destruction
(“Wound healing” macrophages and neutrophils produce angiogenic, epithelial, and stromal growth factors and matrix-remodeling enzymes and are recruited and subverted to support neoplastic progression.)
Explain the Tumour Micro-Environment
Tumours are more like complex organs then a collection of homogeneous cancer cells.
Understood by studying the individual specialized cell types within it as well as the “tumor microenvironment” that they construct during the course of multistep tumorigenesis.
Formed of: Cancer Associated Fibroblasts Cancer Associated Macrophages Immune Inflammatory cells Cancer Stem Cells (CSC) Cancer cells Invasive Cancer cells Endothelial Cells Pericytes
Cancer Stem cells
Defined by ability to efficiently seed new tumours in new host tissues.
(also express markers that are expressed by the normal stem cells in that tissue)
Tumour-initiating cells proved to share transcriptional profiles with certain normal tissue stem cell populations
CSCs, like their normal counterparts, may self-renew as well as spawn more differentiated derivatives; in the case of neoplastic CSCs, these descendant cells form the great bulk of many tumors.
More resistant to therapeutic killing and, at the same time, endowed with the ability to regenerate a tumor once therapy has been halted.
Cells with properties of CSCs are more resistant to various commonly used chemotherapeutic treatments, possibly explaining tumour dormancy.
Observations like these indicate that certain tumors may acquire stromal support by inducing some of their own cancer cells to undergo various types of metamorphosis to produce stromal cell types rather than relying on recruited host cells to provide their functions.
The discovery of CSCs and biological plasticity in tumors indicates that a single, genetically homogeneous population of cells within a tumor may nevertheless be phenotypically heterogeneous due to the presence of cells in distinct states of differentiation.
How can each of the hallmarks be targeted?
- genome instability, parp inhibitors
- Tumour promoting inflammation
Self Sufficiency in Growth Signals/Insensitivity to anti-growth Signals - Targeted therapy
Evading Apoptosis - inhibition of survival proteins
Sustained angiogenesis - anti angiogenit factors
Avoiding immune destruction - Immune priming
Metabolic stress - metabolic enzyme inhibitors
Mitotic stress - Cytotoxic agents and Radiotherapy
