Pathophysiology of Cancer

Characteristics of Cancer Molecular Mechanisms of Growth Control Cancer Genetics Tumor/Host Interactions Clinical Application: Breast Cancer

The Nature of Cancer

Neoplasia
Unregulated accumulation of cells

Normal

Tumor

Abnormal regulation of cell growth Abnormal cell-cell interactions

Normal
Normal stem cell

Tumor
Cancer stem cell

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

Normal Stem cell Compartment Proliferative Compartment Etc.

Cell loss (apoptosis)

Cancer

Etc., Etc., Etc. Maturation Compartment

Maturation Compartment

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)

Benign

Malignant
pleomorphism abnormal nuclei mitoses loss of polarity abnormal differentiation

Invasion

Abnormal cell-substratum interaction

Invasion into adjacent structures

Dissemination (Metastases)

Penetration of vasculature Survival in circulation Survival in a new organ

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

Cancer Epidemiology
Or,

Guilt by Association

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.

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

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

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

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

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

Cancer Incidence
Obesity increases the risk of most cancers

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.