Oncogenes, Tumor Suppressors, and the Cell Cycle

Radiobiology2012

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.

Impact of Transformation on the Cell Cycle

Many physical and chemical insults can activate a proto-oncogene

Several Molecular Mechanisms to activate a proto-oncogene

Cytogenetics identified the “Philadelphia Chromosome”

Peter Nowell at PennFound a small Ch22 in patients with CML

Identification of activated oncogenes experimentally

H-ras V12D identified in 1983

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

Tumor Suppressors require “Two-Hit” inactivation

One allele may be lost in the germ line

LFS can result in many types of cancer

Cancer Predisposition Syndromes helped identify Tumor Suppressor Genes

Loss of Heterozygosity can Remove the Normal allele and result in functional loss

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)

Function of oncogenes in normal growth signal processes

Function of oncogenes in blocking normal death signals

MYC can drive several processes

Cancer is a multi-step process

Colon Cancer Moleculr Oncogenesis – Vogelstein and Kinzler

“Mutator” phenotype can accelerate Multi-Hits needed for Transformation

DNA metabolism obiously important to maintain integrity of the genome

Metastatic spread requires additional genetic changes

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

Radiation Response impacts the Cell Cycle Machinery

Deckbar et al Crit Rev Biochem2011

G1 ArrestAfter XRT

G2/M arrest after XRT

Deckbar et al Crit Rev Biochem2011

DNA Repair–Deficiency can result in tumor predisposition

Loss of ATM predisposes to Radiation-induced Cancers

Mutations in Mismatch Repair genes causes Predisposition to CRC

Radiation also impacts Lipid Second Messenger Signaling

Fuchs and Kolesnik model

NF-κB pathway is also Stress-Responsive

Pro-Survival Signals

Aid Tumor Cell Growth

Summary

• Cancer is a multistep process• Gain of oncogenic function or loss of tumor

suppressor function impacts many cellular processes (cell cycle, apoptosis, senescence)

• Some genetic events that contribute to cancer formation can also influence response to DNA damage dependent therapy