Hallmarks of cancer

1. Hallmarks of cancer
Mohammed Fathy Bayomy, MSc, MD
Lecturer
Clinical Oncology & Nuclear Medicine
Faculty of Medicine
Zagazig University

3. Self-Sufficiency in Growth Signals
 Normal cells require mitogenic growth signals to proliferate. These
signals are transmitted by transmembrane receptors, which bind
ligands such as diffusible growth factors, extracellular matrix
components, & cell–cell adhesion/ interaction molecules
 In cancer cells, dependency on growth signals is lost by alterations
in extracellular growth signals, transcellular transducers or the
intracellular circuits

4.  Cancer cells may:
* Synthesize growth factors (autocrine stimulation), e.g.
platelet-derived growth factor (PDGF) & transforming growth
factor α (TGF-α)
* Overexpress receptors, e.g. epidermal growth factor receptor
(EGFR)
* Show ligand-independent receptor activation by structural
changes
* Express different extracellular receptors
* Contain intrinsically active intracellular pathways

5. Insensitivity to antigrowth signals
 In normal tissues, multiple antiproliferative signals operate to
maintain tissue homeostasis. These signals include soluble growth
inhibitors and immobilized inhibitors embedded in extracellular
matrix & on surfaces of surrounding cells. Antiproliferative
signals are perceived by transmembrane cell surface receptors
coupled to intracellular signaling circuits

6.  Antiproliferative signals cause:
* Transition of cell out of cell cycle to resting state (G0).
Antiproliferative signals are funneled through retinoblastoma
protein (pRb). In cancer, disruption of the pRb pathway
renders cells insensitive to antiproliferative signals.
* Cell differentiation is a complex mechanism. One of factors of
differentiation is MYC oncogene. Myc protein associates with
another factor, Max. Max also associates with group of Mad
transcription factors, & this complex induces differentiation. If
MYC overexpression is present, balance is impaired & Myc–
Max complexes impair differentiation

7. Evading apoptosis
 Tumor growth is balance between cell proliferation & programmed
cell death (apoptosis). Apoptosis is complex process, with
disruption of cell membranes, extrusion of cytosol, degradation of
chromosomes, & fragmentation of nucleus
 Apoptotic machinery consists of sensors & effectors:
* Sensors
- These monitor extra- & intracellular environment for damage
- They regulate effectors.
- They are influenced by survival (insulin-like growth factor I & II
(IGF-I, -II) & interleukin-3 (IL-3)), death factors (Fas ligand&
tumor necrosis factor α (TNF-α))

8. * Effectors: Most pro-apoptotic signals have influence on
mitochondria, which release cytochrome c
- Pro-apoptotic signal proteins: Bax, Bak, Bid, Bim, p53
- Anti-apoptotic signals: Bcl-2, Bcl-xL, Bcl-w.
 These signals release number of intracellular proteases (caspases)
that execute death program through selective destruction of
subcellular structures, organelles, & genome
 Resistance to apoptosis in cancer may be by loss of pro-apoptotic
regulator (e.g. mutation of TP53 tumor suppressor gene) or by
abrogation of death signal (e.g. upregulation of non-functional
decoy receptor for Fas)

9. Limitless replicative potential
 Normal cells have limited replicative potential, &, after number of
divisions, they stop growing (senescence). Mechanism of
senescence is due to limited number of telomeres, restricting
number of divisions
 Telomere maintenance is present in almost all cancer cells, by
upregulation of enzyme telomerase, which adds hexanucleotide
repeats to end of telomeric DNA

10. Sustained Angiogenesis
 Vasculature supplies oxygen and nutrients, which are essential for
cell function and survival
 Growth of new blood vessels (angiogenesis) is regulated by anti-
angiogenic & angiogenic factors (e.g. vascular endothelial growth
factor (VEGF) & fibroblast growth factor 1 & 2 (FGF-1 & -2))
 Tumors are able to activate angiogenic switch by changing this
balance & recruit blood vessels

11. Tissue invasion & metastasis
 Cancer cell invasion & metastasis are due to changes in physical
coupling of cells to their microenvironment & activation of
extracellular proteases
* Interference with microenvironment: several classes of
proteins are involved in interaction of cells with
microenvironment, including cell–cell adhesion molecules
(CAMs: e.g. immunoglobulins & cadherins) & integrins,
which link cells to extracellular matrix substrates

12. - E-cadherin is expressed on epithelial cells. Coupling between
cells by E-cadherin bridges results in transmission of
antigrowth & other signals. E-cadherin function is lost in cancer
cells
- Neural cell adhesion molecule (NCAM) is immunoglobulin
with highly adhesive isoform that is changed to a poorly
adhesive form in certain cancer types (e.g. Wilms’ tumor,
neuroblastoma, & small cell lung cancer) or has reduced overall
expression level (e.g. in pancreatic & colorectal cancer)
- Growing tumor cells express different integrins that interfere
with extracellular matrix, enabling cancer cells to evade control
by extracellular matrix compounds

13. * Extracellular proteases: in cancer, protease genes are
upregulated, protease inhibitor genes are downregulated, &
inactive zymogen forms of proteases are converted into active
enzymes