Cancer Biology 2&3

CARCINOGENESIS
• Proto-oncogenes
• TUMOR SUPPRESSOR GENES
• REGULATORS OF APOPTOSIS
BASIC PRINCIPLES
• Cancer formation is initiated by damage to DNA of stem cells. The
damage
• overcomes DNA repair mechanisms, but is not lethal.
• 1. Carcinogens are agents that damage DNA, increasing the risk for cancer.
Important carcinogens include chemicals, oncogenic viruses, and radiation
• B. DNA mutations eventually disrupt key regulatory systems, allowing
for tumor promotion (growth) and progression (spread).
• 1. Disrupted systems include proto-oncogenes, tumor suppressor genes, and
regulators of apoptosis.
ONCOGENES
• A. Proto-oncogenes are essential for cell growth and differentiation;
mutations of proto-oncogenes form oncogenes that lead to unregulated
cellular growth.
• B. Categories of oncogenes include growth factors, growth factor
receptors, signal transducers, nuclear regulators, and cell cycle
regulators (Table 3.3).
• 1. Growth factors induce cellular growth (e.g., PDGFB in astrocytoma).
• 2. Growth factor receptors mediate signals from growth factors (e.g., ERBB2
[HER2/neu] in breast cancer).
ONCOGENES
3. Signal transducers relay receptor activation to the nucleus (e.g.,
ras).
I. Ras is associated with growth factor receptors in an inactive GDP-bound
state.
II. Receptor binding causes GDP to be replaced with GTP, activating ras.
III. Activated ras sends growth signals to the nucleus.
IV. Ras inactivates itself by cleaving GTP to GDP; this is augmented by GTPase
activating protein.
V. Mutated ras inhibits the activity of GTPase activating protein. This prolongs
the activated state of ras, resulting in increased growth signals.
ONCOGENES
4. Cell cycle regulators mediate progression through the cell
cycle (e.g., cyclin and cyclin-dependent kinase).
• I. Cyclins and cyclin-dependent kinases (CDKs) form a
complex which phosphorylates proteins that drive the cell
through the cell cycle.
• II. For example, the cyclinD/CDK4 complex
phosphorylates the retinoblastoma protein, which
promotes progression through the G/ S checkpoint.
References
• Page 128-140 Chapter 6

TUMOR SUPPRESSOR GENES
Regulate cell growth and, hence, decrease ("suppress")
the risk of tumor formation;
• p53 and Rb (retinoblastoma) are classic examples.

 p53 regulates progression of the cell cycle from G1 to S phase
1. In response to DNA damage, p53 slows the cell cycle and upregulates DNA repair
enzymes.
2. If DNA repair is not possible, p53 induces apoptosis.
I. p53 upregulates BAX, which disrupts Bcl2.
II. Cytochrome c leaks from the mitochondria activating apoptosis.
3. Both copies of the p53 gene must be knocked out for tumor formation (Knudson
two-hit hypothesis).
I. Loss is seen in > 50% of cancers.
II. Germline mutation results in Li-Fraumeni syndrome (2nd hit is somatic),
characterized by the propensity to develop multiple types of carcinomas and sarcomas.
Rb also regulates progression from G1 to S phase.
1. Rb "holds" the E2F transcription factor, which is necessary for transition to the S
phase.
2. E2F is released when RB is phosphorylated by the cyclinD/cyclin-dependent
kinase 4 (CDK4) complex.
3. Rb mutation results in constitutively free E2F, allowing progression through the
cell cycle and uncontrolled growth of cells.
4. Both copies of Rb gene must be knocked out for tumor formation (Knudson two-
hit hypothesis).
• I. Sporadic mutation (both hits are somatic) is characterized by unilateral retinoblastoma
• II. Germline mutation results in familial retinoblastoma (2nd hit is somatic), characterized by
bilateral retinoblastoma and osteosarcoma.
REGULATORS OF APOPTOSIS
Prevent apoptosis in normal cells, but promote apoptosis in mutated
cells whose DNA cannot be repaired (e.g., Bcl2)
l. Bcl2 normally stabilizes the mitochondrial membrane, blocking release of
cytochrome c.
2. Disruption of Bcl2 allows cytochrome c to leave the mitochondria and activate
apoptosis.
Bcl2 is overexpressed in follicular lymphoma.
1. t(l4;18) moves Bcl2 (chromosome 18) to the lg heavy chain locus (chromosome
14), resulting in increased Bcl2.
2. Mitochondrial membrane is further stabilized, prohibiting apoptosis.
3. B cells that would normally undergo apoptosis during somatic hypermutation in
the lymph node germinal center accumulate, leading to lymphoma.
OTHER IMPORTANT FEATURES OF TUMOR
DEVELOPMENT
Telomerase is necessary for cell immortality.
1. Normally, telomeres shorten with serial cell divisions, eventually resulting in
cellular senescence.
2. Cancers often have upregulated telomerase, which preserves telomeres.
Angiogenesis (production of new blood vessels) is necessary for tumor survival and
growth.
1. FGF and VEGF (angiogenic factors) are commonly produced by tumor cells.
 Avoiding immune surveillance is necessary for tumor survival.
1. Mutations often result in production of abnormal proteins, which are expressed on MHC class I.
2. CDS+ T cells detect and destroy such mutated cells.
3. Tumor cells can evade immune surveillance by downregulating expression of MHC class I
4. Immunodeficiency (both primary and secondary) increases risk for cancer.

Cancer Biology 2&3

Uploaded by

Copyright:

Available Formats

Cancer Biology 2&3

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Cancer Biology 2&3

Uploaded by

Copyright:

Available Formats

CARCINOGENESIS

• TUMOR SUPPRESSOR GENES

• Page 128-140 Chapter 6

• p53 and Rb (retinoblastoma) are classic examples.

You might also like

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.