Radiobiology: Cancer Biology

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Radiobiology Cancer Biology

• 11 Dec 2008

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2008 Estimated US Cancer Cases
Men745,180
Women692,000

• 26 Breast
• 14 Lung bronchus
• 10 Colon rectum
• 6 Uterine corpus
• 4 Non-Hodgkin lymphoma
• 4 Thyroid
• 4 Melanoma of skin
• 3 Ovary
• 3 Kidney renal pelvis
• 3 Leukemia
• 23 All Other Sites

Prostate 25 Lung bronchus 15 Colon
rectum 10 Urinary bladder 7 Non-Hodgkin 5
lymphoma Melanoma of
skin 5 Kidney renal pelvis 4 Oral
cavity 3 Leukemia 3 Pancreas 3 All Other
Sites 20
Excludes basal and squamous cell skin cancers
and in situ carcinomas except urinary
bladder. Source American Cancer Society, 2008.
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Question.

• If cancers are caused by gene mutations, and if
  mutation is a random process, how can one explain
  the very wide range of incidences of cancer in
  different tissues and organs?

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Examples

• p53 mutations are found in about 50 percent of
  human cancers
• BRCA1 expressed in almost all adult tissue, but
  mutations only affect breast and ovarian ca
  incidences
• KRAS mutations are frequent in pancreatic cancer,
  but rare in melanoma
• BRAF mutations are frequent in melanoma, but rare
  in pancreatic cancer
• XP mutations are predictive of skin cancers, but
  not most other cancers

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Possible mechanisms

• Cell and tissue differences in mutation rates
• Differences in immune surveillance
• Cell and tissue specific dependence on a given
  oncogene
• Oncogenic virus gene tropism
• Tumor microenvironmental factors
• ????

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Mutation Rates

• Related to DNA replication and hence, to cell
  proliferation rates.. Law of B T ?
• Are DNA changes really random?
• Transcribed vs. untranscribed genes
• Metabolic state of cell.. Indirect vs direct DNA
  damage
• Exogenous carcinogens e.g., UV, oxidation, AHs
• Mutation spectrum studies
• Look at gene which has a lost or altered
  function.. Hence a functional bias
• Comparative approach e.g., with and without a
  suspect carcinogen.. Probably informative

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Immune surveillance

• Variation in cell surface antigen expression
  and/or availability to cytotoxic T-cells
• HLA Class I antigen expression is frequently
  abnormal in cancers
• HLA Class I-negative tumor cells have selective
  advantage
• e.g., HLA Class I defects in patients with poor
  clinical response to autologous vaccination

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Cell-specific oncongenes

• p53 widely expressed expression and processing
  influenced other genes, some are cell/tissue
  specific
• BRCA1 possible tissue-specific loss of
  heterozygosity
• Sexual dimorphisms and Multiple Endocrine
  Neoplasia Syndrome some oncogenes under hormonal
  control

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Oncogenic Virus Tropisms

• Virus genes activate (or substitute for) cell
  oncogenes EBVirus HPV HBV Kaposis Sarcoma
  Virus
• Virus entry is a cell-specific process cell
  surface receptors
• Virus replication and gene expression, may be
  cell or tissue specific

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Tumor Microenvironments

• Neovascularization
• Angiogenesis factors
• Stromal reaction
• Reponses to cancer cells paracrine growth
  factors produced by fibroblasts
• Tissue barriers and cell-adhesion molecules

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Summary

• Tissue and organ variation in cancer incidence is
  not fully understood still a research problem
• For some cases, good explanations exist, however
• Basic cell biology questions remain
• Is mutation a random process? If not, what are
  the factors that cause non-randomness?
• What happens between mutation of a gene and
  cancer development and progression in the
  organism? May be highly tissue and organ
  specific.