Transcript CARCINOGENESIS - UCSD Pharmacology

CANCER:
CARCINOGENS
and
CARCINOGENESIS
BIOM 255
Drugs and Disease: The pathophysiological and
molecular bases of disease and drug therapy
March 3, 2009
Hyam Leffert, MD
OVERVIEW
Agents (molecules, radiation or viruses) that cause cancer are called
carcinogens. This causal process is called carcinogenesis.
In humans, it is generally accepted that most epithelial cancers are
caused by environmental exposure to certain kinds of chemicals.
However, carcinogenesis is clearly influenced by large numbers of
genes and non-carcinogenic environmental factors (notably diet, and
underlying inflammation).
This discussion will review basic principles of cancer and chemical
carcinogenesis, focusing upon hepatocarcinogenesis as a model
system.
We will also consider two outstanding questions:
1. What molecular events are thought to be critical for
carcinogenesis?
2. What carcinogen-targeted cells give rise to cancer?
References
1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70. [Assigned reading]
2. Balmain A, Harris CC. Carcinogenesis in mouse and human cells: parallels and
paradoxes. Carcinogenesis. 2000 Mar;21(3):371-7.
3. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nature Med. 2004; 10(8):789-799.
4. Luch A. Nature and nurture - lessons from chemical carcinogenesis. Nat Rev Cancer. 2005 Feb;5(2):11325. [Assigned reading]
5. Li HC, Stoicov C, Rogers AB, Houghton J. Stem cells and cancer: Evidence for bone marrow stem cells in
epithelial cancers. World J Gastroenterol. 2006 Jan 21;12(3):363-71.
6. Weinberg RA. The Biology of Cancer. 2007. Garland Science, New York, NY
(This recently published textbook and accompanying CD-R is in the SOM LIBRARY RESERVE)
BASIC PRINCIPLES
WHAT DO CANCERS LOOK
LIKE?
Cancerous tissues and
metastatic cancer cells (that
migrate away from primary sites)
display disorganized arrays of
normal macroscopic and
microscopic tissue structure.
Hepatocellular Carcinoma
Ovarian Carcinoma
(http://www.emanet.org/)
(from BIOM 255 lecture of S. Howell, MD)
Acute Myelogenous Leukemia
(Bone Marrow)
Breast Carcinoma
(Inflammatory)
(http://en.wikipedia.org/)
(http://www.emedicine.com/)
PROPERTIES OF CANCER CELLS
(diagram is from Reference #1)
THOUSANDS OF KNOWN CARCINOGENIC
AGENTS ARE IN THE ENVIRONMENT
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•
•
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Organic molecules (PAHs, aromatic amines)
Inorganic molecules (vinyl chloride)
Heavy metals (lead, arsenic, chromium[VI])
Viruses (HBV, HCV, HPV, HIV)
Radiation (gamma, X-ray, high energy beta)
Inert substances (asbetos)
(See Reference #2, and Reference #4 for Summary Table)
CARCINOGENESIS INVOLVES 2 STEPS
1.
INITIATION (“initiators”)
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Rapid
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Usually requires metabolic activation (procarcinogen  carcinogen)
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Sufficient to induce carcinogenesis if exposure dose is high enough
(controversial)
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Precedes promotion
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May cause mutations or epigenetic changes
2. PROMOTION (“promoters”)
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Follows initiation
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Long period of time
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Augments effects of low dose initiator
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Associated with increased survival and/or clonal expansion of initiated clones
METABOLIC ACTIVATION REQUIRES
SPECIALIZED ENZYMES: e.g. CYP450s
(receptors, co-factors and many other enzymes are also involved)
(diagram is from Reference #4)
PROPOSED CARCINOGENIC EVENTS
Genotoxic and non-genotoxic effects of carcinogens
(diagram is from Reference #4)
PROPOSED CARCINOGENIC PATHWAYS
(diagram is from Reference #1; see also Reference #3)
LIVER CANCER
Diagram of the HEPATIC LOBULE
HEPATOCARCINOGENESIS
•
Hepatocellular carcinomas (‘HCC’, parenchymal cell-like) are the most
frequent type of liver cancer.
•
Millions of people world-wide are diagnosed yearly with HCC, mostly in
Southeast Asia and Africa.
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High mortality rates with widespread metastasis (preference for lung).
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Gender preference due to endocrine status (male >> female).
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HCC is strongly associated with viral (HBV, HCV), chemical (aflatoxin-B1)
and dietary exposures (alcohol).
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Inflammation may act as a promoter of HCC.
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Non-HCC hepatic angiosarcomas are caused by exposure to vinyl chloride.
Diethylnitrosamine (DEN) metabolized by CYP2E1 induces
hepatocarcinogenesis in genetically targeted mutant mice:
Hepatocyte Ikkß-deletion, oxidative stress, cell death, liver inflammation and growth
advantages of Ikkß-deleted hepatocytes augment carcinogenesis in this animal model;
tumor suppressor(s) may also be involved.
(from Maeda S. et al. CELL 121:977-990, 2005; Koch KS et al., BBRC 380:349-354,2009)
(from Reference #5)
CARCINOGEN-TARGETED
CELLS…which one(s) ?
- The cellular target(s) of chemical carcinogens are unknown.
- The key questions are whether parenchymal cells (e.g. hepatocytes) or
non-parenchymal cells (e.g. stem cells) are the targets? Or both…?
- The answers are critical since mechanism and drug therapy studies may
be directed towards the wrong cell type(s).
- Some investigations suggest that cellular targets may also include nonresident cells that enter tissues via the blood or lymphatic system.
- Carcinogens may also alter the functions of cells that do not generate
tumors but are required for tumor cell clonal expansion and survival
(i.e. tumor progression).
HEPATOCARCINOGENESIS (HCC) LINEAGE MODELS
(Diagram is from Koch KS, Leffert HL. Normal liver progenitor cells in culture, in Stem Cells Handbook, ed. S.
Sell, Humana Press, Inc., Totowa, NJ, pp. 367-384, 2004).