Pathophysiology of Cancer

1
Pathophysiology of Cancer
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• Characteristics of Cancer
• Molecular Mechanisms of Growth Control
• Cancer Genetics
• Tumor/Host Interactions
• Clinical Application Breast Cancer

3
The Nature of Cancer
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Neoplasia Unregulated accumulation of cells
5

• Normal Tumor
• Abnormal regulation of cell growth
• Abnormal cell-cell interactions

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Normal Tumor Normal stem cell
Cancer stem cell
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Characteristics of Stem Cells

• Unlimited capacity for self-renewal
• Cellular immortality
• But relatively low rate of proliferation
• Capable of differentiation into the mature cells
  that constitute organ function
• Proliferation can be dramatic once a cell has
  committed to differentiation
• But differentiated cells have limited life-span

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Normal
Cancer
Stem cell Compartment
Proliferative Compartment
Etc. Maturation Compartment
Cell loss (apoptosis)
Etc., Etc., Etc. Maturation Compartment
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Lessons From Stem Cell Kinetics

• The growth rate of cancer cells does not exceed
  that of normal cells
• Abnormal differentiation of cancer cells results
  in a greater percentage of cells in the
  proliferative pool (at the expense of the
  maturation pool)
• Tumor (mass) growth exceeds normal growth due to
  a higher proliferative fraction and a lower rate
  of cell loss (death)

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Benign Malignant
pleomorphism abnormal nuclei
mitoses loss of polarity abnormal
differentiation
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Invasion
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Abnormal cell-substratum interaction
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Invasion into adjacent structures

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Dissemination (Metastases)
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Penetration of vasculature Survival in
circulation Survival in a new organ
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metastatic spread is not random but determined
by -pattern of venous blood flow -specific
receptors on tumor and endothelial
cells -metastatic fitness is genetically
determined
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Cancer Epidemiology

• Or,
• Guilt by Association

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Caveat epidemiology

• Studies are observational and therefore do not
  establish cause and effect
• Initial observations require confirmation and
  exclusion of confounding variables
• However, well-performed studies can provide
  valuable insights into factors that contribute to
  cancer.

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Cancer Incidence

• Cancer is a disease of aging
• Deaths increased 3x in the 7th decade compared to
  the 5th 6th decades combined
• But, cancers differ in their age-related incidence

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Cancer Incidence

• Environment affects cancer incidence
• Differences in the incidence of breast, liver,
  gastric, colon and prostate cancers in Japanese
  and US populations disappear following
  immigration (unknown factors)
• Liver cancer incidence is related to incidence of
  Hepatitis B C incidence and afflatoxin exposure
• Melanoma incidence is associated with UV exposure

21
Cancer Incidence

• Toxins affect cancer incidence
• Tobacco - lung, upper aerodigestive tract
  everything else
• Asbestos - lung, mesothelioma
• Alcohol - liver, upper aerodigestive tract
  esophagus,
• Others - see table 7-3

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Cancer Incidence

• Infectious agents
• H. pylori - gastric lymphoma adenoCA
• Papillomavirus - cervical CA
• HTLV - T-cell leukemia
• Epstein-Barr virus - lymphomas and nasopharyngeal
  cancers

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Cancer Incidence

• Genetic factors
• Specific cancer genes (addressed later)
• Unidentified genetic factors (generally a low
  level familial risk)

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Cancer Incidence

• Obesity increases the risk of most cancers

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Cancer Epidemiology Conclusions

• Cancer is the result of the cumulative effects of
  living and the interplay of environmental
  exposures and genetic predisposition
• It is likely that most risk factors act as either
  Initiators or Promoters of carcinogenesis.