Neoplasia 5
Dr. Hiba Wazeer Al Zou’bi
3- Evasion of Cell death
• Extrinsic pathway: through binding of receptors as
CD95 (Fas) to its ligand (FasL) ultimately activating
several CASPASES → Apoptosis.
– Some tumors have ↓levels of CD95 → ↓
Apoptosis
• Intrinsic pathway: Mutations in genes of BCL-2
(Antiapoptosis)
- Activated by t. (18;14) - Follicular B cell Lymphoma
4-Limitless replicative potential(Telomeres)
• Specialized structures at the end of
chromosomes which are shortened after each
division
• Shortening is prevented by TELOMERASE
Majority of cancers  telomerase
5- Genomic instability due to defective
DNA Repair Genes
1- Nucleotide excision repair genes
• Damage by U-V light: Defective in Xeroderma
Pigmentosum
2-Mismatch repair genes: repair errors in pairing of
nucleotides during cell division (Spell Checkers)
- Defective in: ( HNPCC) (Hereditary
Nonpolyposis Colonic Ca.)
- HNPCC shows: Microsatellite Instability (MSI):
changes in length of short tandem repeating sequences
throughout the genome.
3- Homologous Recombination:
- Syndromes involving defects in the
homologous recombination DNA repair system :
• Bloom syndrome, ataxia-telangiectasia, and
Fanconi anemia— characterized by
hypersensitivity to DNA-damaging agents, such as
ionizing radiation.
- BRCA1 and BRCA2, mutated in 50% of familial
breast cancers.
6- Development of sustained
angiogenesis
-
Tumors cannot enlarge beyond 1 to 2 mm in diameter unless
they are vascularized.
Effects of vascularization:
1. It supplies needed nutrients and oxygen
2. Is required for tumor metastasis
3. Newly formed endothelial cells secret growth factors
 vascular density = Poor prognosis
Angiogenic Factors:
1. Hypoxia-Inducible Factor (HIF-1) Induce
transcription of VEGF
2. VEGF : increases the expression of ligands that
activate the Notch signaling pathway, which
regulates the branching and density of the new
vessels.
3. Proteases from tumor or stroma can release the
angiogenic basic FGF stored in the ECM
Anti- Angiogenesis:
1.
Thrombospondin1(TSP-1) produced by stromal fibroblasts
and induced by P53, so Inactivation of P53  Angiogenesis
VHL protein (Tumor supressor gene) in normoxic state
destroys HIF-1   No VEGF
-In hypoxic conditions, such as in a tumor that has reached a
critical size, the lack of oxygen prevents HIF-1  recognition by
VHL.
-Germ line mutation of VHL  von Hippel-Lindau Syndrome 
hereditary renal CA, hemangiomas in CNS, renal cyst.
2.
3. Angiogenesis inhibitors
7- Ability to invade & metastasize
Occurs in two phases:
• 1- Invasion of extracellular matrix
• 2- Vascular dissemination and homing of
tumor cells
1- Mechanism of invasion of ECM:
1- Detachment of tumor cells
- E-cadherin function is lost in almost all epithelial cancers,
either:
• by mutational inactivation of E-cadherin genes
• by activation of β-catenin genes
• or by inappropriate expression of the SNAIL and TWIST
transcription factors, which suppress E-cadherin
expression.
2- Degradation of ECM by proteases :
Matrix Metalloproteinase (MMPs): Cathepsin D, Type IV
collagenase
3- Attachment of tumor cells to extracellular
matrix
4- Locomotion:
- Potentiated and directed by tumor
derived cytokines e.g. Autocrine motility
factor
- Stromal cells produce paracrine effectors
of cell motility e.g. HGF
2- Vascular dissemination and
homing:
• Extravasation of free tumor cells or tumor emboli involves
adhesion to the vascular endothelium, followed by egress
through the basement membrane into the organ parenchyma
by mechanisms similar to those involved in invasion.
• The site of extravasation and the organ distribution of
metastases generally can be predicted by the location of
the primary tumor and its vascular or lymphatic
drainage
• In many cases, the natural pathways of drainage do not
readily explain the distribution of metastases (Tropism)
probably due to activation of adhesion or chemokine
receptors whose ligands are expressed by endothelial cells
at the metastatic site.
8- Reprogramming Energy Metabolism
• Even in the presence of ample oxygen, cancer
cells shift their glucose metabolism away from
the oxygen-hungry but efficient mitochondria to
glycolysis ( Warburg effect , aerobic glycolysis)
• Aerobic glycolysis is less efficient than
mitochondrial oxidative phosphorylation,
producing 2 molecules of ATP per molecule of
glucose, versus 36.
• But tumors that adopt aerobic glycolysis, such as
Burkitt lymphoma, are the most rapidly growing
of human cancers.
• In rapidly growing cells glucose is the primary source
of the carbons that are used for synthesis of lipids
(needed for membrane assembly) as well as other
metabolites needed for nucleic acid synthesis. This
pattern of glucose carbon use is achieved by shunting
pyruvate toward biosynthetic pathways at the expense
of the oxidative phosphorylation pathway and ATP
generation.
• The “glucose hunger” of such tumors is used to
visualize tumors by positron emission tomography
(PET) scanning, in which the patient is injected with
18F-fluorodeoxyglucose, a nonmetabolizable derivative
of glucose.
• Most tumors are PET-positive.
9- Evasion of the Immune System
• The ability of tumors to evade destruction by
the immune system.
• Will be discussed in the next lecture.
10- Tumor-Promoting Inflammation as
Enabler of Malignancy
1- Persistent chronic inflammation in response to microbial infections or as
part of an autoimmune reaction.
- In chronic tissue injury, there is a compensatory proliferation of cells in an
attempt to repair the damage aided by growth factors, cytokines,
chemokines, and other bioactive substances
- Persistent cell replication and reduced apoptosis place the cells at risk of
acquiring mutations in one or more of the genes involved in
carcinogenesis.
- In addition, inflammatory cells such as neutrophils can contribute to
carcinogenesis by secretion of reactive ROS, which in turn can inflict
additional DNA damage in rapidly dividing cells.
- Increased risk of cancer in patients affected by Barrett esophagus,
ulcerative colitis, H. pylori gastritis, hepatitis B and C, and chronic
pancreatitis.
2- When inflammation occurs in response to
tumors.
• Virtually every tumor contains cells of the
immune system.
• Inflammatory reaction represents an attempt
by the host to destroy the tumor, but these
cells can exert tumor-promoting activity by
producing growth factors and inflicting
additional DNA damage