Cancer is consequence of abnormal increased cell growth
and/or decreased cell death
• Normal tissue homeostasis balances cell growth and death to maintain constant mass
• Normal tissue hypertrophy can come from increased cell number (pregnant uterus), or increased cellular mass (exercising muscle)
• Normal tissue regeneration can be physiologically necessary (bone marrow, gut epithelium, skin) or in response to damage (liver regeneration)
Cancer cell dynamics are not under normal processes of cell control
• Oncogenes (activated proto-oncogenes) are generalized as drivers of tumor cell division
• Tumor Suppressors are generalized as brakes to cellular division
• Therefore oncogenic transformation combines activation of proto-oncogenes and loss of tumor suppressors to drive cell proliferation.
Cytogenetics identified the “Philadelphia Chromosome”
Peter Nowell at PennFound a small Ch22 in patients with CML
Cell Fusion Identified the concept of “The Tumor Supressor Gene”
Heterokaryon has more “Normal”Cellular phenotype
Some normal gene was lost in cancer cell?
Cancer Cell
Normal Cell
PEG or Virus
How do Oncogenes and tumor suppressor disrupt normal functions?
• Ocogenes:– Stimulate the cell cycle (ras)– Inhibit death (Apoptotic) signalling (bcl2)– Drive metastatic growth (Met)
• Tumor suppressors– Release brakes in the Cell Cycle (p53/Rb)– Release brakes on growth factor signals (PTEN)– Modulate response to stress (VHL)– Increased survival signals (APC)
“Mutator” phenotype can accelerate Multi-Hits needed for Transformation
DNA metabolism obiously important to maintain integrity of the genome
Senescence can also block cellular transformation
Normal fibroblastsHave finite numberOf divisions before Permanent Arrest
Genomic Instability can accelerate Tumor formation
• DNA damage can be:– Properly repaired without consequences– Non-repaired that can lead to cell death– Mis-repaired contributes to alterations in gene
sequence or expression