Title: Cell Proliferation and Carcinogenesis
1Cell Proliferation and Carcinogenesis
- Kinetics of tumor cell population growth
- Growth fraction
- Cell loss
- Nutrient deprivation
- Immunological response against neoplastic cells
- Lethal errors in metabolic pathways and DNA
replication - Programmed cell death
- Partial differentiation of tumor cells
2Cell Proliferation and Carcinogenesis
- The role of cell proliferation in the aetiology
of neoplasia - Multistage tumor progression
- Chemically induced epidermal carcinogenesis
- Cellular necrosis, chronic inflammation, and risk
for cancer - Summary and conclusions
3Kinetics of Tumor Cell Population Growth
- Cell cycle the period from one cell division to
the next - Lewis Thomas
- The principle task of the cell division cycle
is to replicate DNA without errors during the
S-phase, and to segregate the duplicated
chromosomal DNA equally to two daughter cells
during M-phase - Most mammalian cells committed to proliferate
require between 15 to 72 hr to complete their
division cycle
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5Kinetics of Tumor Cell Population Growth
- If one cell division takes on average 24 hr, it
will produce by the end of second month 260 cells
as a result of the exponential growth rate - Around 109 cells/cm3, equivalent to over 1000 m3
of cells - In contrast, the actual doubling times of tumor
masses vary considerably, and are rarely less
than several weeks
6Kinetics of Tumor Cell Population Growth
- This discrepancy between the doubling time of a
tumor mass and the doubling time at the cellular
level may be due to - A growth fraction of less than unity
- Loss of neoplastic cells within the tumor
- A considerable fraction of a tumor comprises
non-neoplastic cells, including supportive,
infiltrative, and normal parenchymal cells
7Kinetics of Tumor Cell Population Growth
- Growth fraction
- A growth fraction of less than unity
- At any time point, only a fraction of tumor cells
are actively dividing (in most solid tumors)
8Kinetics of Tumor Cell Population Growth
- Cell loss
- A large proportion of proliferating cells is lost
within a tumor - In various animal models of carcinogenesis 40 to
80 of cells are lost in neoplasia compared to
the rates to which they are produced - Some of the following mechanisms account for the
cell loss
9Kinetics of Tumor Cell Population Growth
- Nutrient deprivation
- Tumors do not grow beyond a size of 1-2 mm3
unless they are able to attract the growth of
capillaries into the tumor - Angiogenesis prevents the necrosis of cells
within the center of the tumor mass
10Kinetics of Tumor Cell Population Growth
- Immunological response against neoplastic cells
- Most solid tumors contain a considerable number
of infiltrating T-lymphocytes, natural killer
cells, and macrophages - The proportion of these cells may account for 50
of total cells in a breast tumor
11Kinetics of Tumor Cell Population Growth
- Lethal errors in metabolic pathways and DNA
replication - Any random error in vital metabolic pathways or
in the mitotic apparatus, if occuring early or
frequently during the clonal expansion, could
lead to the inhibition of cell population growth
12Kinetics of Tumor Cell Population Growth
- Programmed cell death (APOPTOSIS)
- Increased apoptotic activity within a tumor may
balance the increased proliferation rate of the
neoplastic cells, resulting in no net growth of
the lesion - For instance, in experimental hepatic tumors,
early preneoplastic cells show much higher
apoptotic activity than in normal liver cells
13Kinetics of Tumor Cell Population Growth
- Partial differentiation of tumor cells
- Neoplastic cells within the same tumor may be
heterogeneous - The partial differentiation of tumor cells could
constantly deplete the proliferative pool of the
neoplastic cell population
14The Role of Cell Proliferation in the Aetiology
of Neoplasia
- Multistage tumor progression
- The currently accepted paradigm of carcinogenesis
is the multistage model of tumor progression - Histological alterations preceding cancer are
termed preneoplastic lesions i.e. they are
associated with an increased risk of developing
cancer
15The Role of Cell Proliferation in the Aetiology
of Neoplasia
- Clinical examples of preneoplastic lesions
dysplasia of the cervix, intestinal polyps, and
hyperplastic nodules of the cirrhotic liver - The concept of such a multistep evolution of
neoplasia has been supported by three lines of
evidence
16The Role of Cell Proliferation in the Aetiology
of Neoplasia
- Development of chemically induced cancers in
rodent tumor models - Tumor formation in transgenic mice
- Analysis of epidemiological data in man
- The current model of carcinogenesis distinguishes
three stages of tumor progression
17The Role of Cell Proliferation in the Aetiology
of Neoplasia
- In clinical terms
- Initiation latent period of the disease
- Promotion focal premalignant lesion
- Progression leads to evolution of
invasive and metastatic cancer
18Stages in Tumor Progression
Latent period of the disease
Focal premalignant lesion
Leads to evolution of invasive and metastatic
cancer
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20The Role of Cell Proliferation in the Aetiology
of Neoplasia
- Initiation (Genetic)
- Irreversible changes in the genome of previously
normal cells which makes them susceptible to
malignant transformation - Cells actively synthesizing DNA are the most
susceptible for mutagenic, genotoxic effects and
therefore to initiation - Cell division is also required for the fixation
of any genomic changes
21The Role of Cell Proliferation in the Aetiology
of Neoplasia
- Promotion (Epigenetic)
- Results from the environmental effects on
initiated cells - It is manifested by the acquisition of
premalignant phenotypic changes including
atypical cellular morphology and progressive
growth
22The Role of Cell Proliferation in the Aetiology
of Neoplasia
- Such premalignant cell populations are often the
result of clonal expansion and have an increased
risk for cancer - Diverse groups of molecules including various
chemicals (phorbol esters) and growth factors can
induce promotion of initiated cells - Many tumor promoters are mitogenic, nonmutagenic,
and others prevent apoptosis
23The Role of Cell Proliferation in the Aetiology
of Neoplasia
- The promotion stage is reversible
- Ample clinical observations indicate that
differentiation and regression is also common in
premalignant, precursor lesions of human neoplasia
24The Role of Cell Proliferation in the Aetiology
of Neoplasia
- Progression (More mutations, epigenetic)
- This phase is characterized by acquisition of
malignant phenotypic changes - Characteristic changes include invasiveness,
metastatic competence, tendency for autonomous
growth, and often increased karyotypic
instability
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26Dimethylbenzaanthracene
Hydrocarbons and alkylating agents
27Phorbolester, 12-O-tetradecanoylphorbol-13-acetate
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29The Role of Cell Proliferation in the Aetiology
of Neoplasia
- Carcinogenesis, according to the multi-stage
model of neoplasia, is regarded as a progressive
accumulation of genetic errors and phenotypic
abnormalities - Stage-specific genetic changes have not been
consistently detected - The total accumulation of changes rather than
their order is responsible for determining the
tumors biological properties
30- The huge number of genetic abnormalities
accumulated by neoplastic cells is mainly due to
the effect of high cellular proliferation rates
in tumors - Cell division triggers mitotic recombination,
gene conversion, inversion, and non-disjunction
of chromosomes
31- The time interval for DNA repair in mitosis is
short - If random mutations in particular genes confer a
selective growth advantage, a clonal expansion of
the mutant cell population occurs - This clonal expansion, in turn, creates an
enlarged population of target cells for the next
mutagenic event
32The Role of Cell Proliferation in the Aetiology
of Neoplasia
- The following lines of experimental and clinical
evidence support the multi-stage model of
carcinogenesis - Mouse chemical model of epidermal
carcinogenesis - Human cancers Goldesteins multi- step model
of cancer (colorectal cancer) FAP Familial
Adenomatous Polyposis
33A multistep molecular event model for the
development of familial adenomatous polyposis, a
colorectal cancer
Genetic changes
Epigenetic changes
34The Role of Cell Proliferation in the Aetiology
of Neoplasia
- Cellular necrosis, chronic inflammation, and
risk for cancer - It can be generalized that any chronically toxic
agent which also evokes regenerative cell
proliferation in a tissue, increases the risk for
cancer - Epidemiological studies have identified several
risk factors for a variety of human cancers
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37The Role of Cell Proliferation in the Aetiology
of Neoplasia
- Cellular necrosis, induced by toxic agents, is
frequently associated with local chronic
inflammation - Under certain clinical conditions, chronic
inflammation itself is associated with a higher
risk for cancer formation i.e. chronic active
tuberculosis is associated with an increased risk
for adenocarcinoma formation in the lung
38The Role of Cell Proliferation in the Aetiology
of Neoplasia
- Prolonged irritation by mechanical trauma and
subsequent regenerative cell division is also
associated with increased cancer incidence of the
tissue involved i.e. gallbladder cancer is
associated with prior history of gallstones
39The Role of Cell Proliferation in the Aetiology
of Neoplasia
- Chronic ulcerative colitis is a risk factor for
colon cancer - These examples have a common denominator,
increased cellular proliferation, but do not
exclude the importance of other mechanisms in
tumorigenesis
40Summary and Conclusions
- Unlimited growth potential is a prerequisite of
the malignant phenotype - However, cellular proliferation is not an
exclusive feature of neoplastic cells, but
frequently encountered in a variety of
physiological and pathological conditions
41- Increased proliferative capacity of cells
contributes to a higher risk of cancer formation
by multiple mechanisms - Proliferating cells are more susceptible for
genomic changes - Clonal expansion of initiated cells is an
important element of tumor promotion
42- However, elegant experiments on transgenic mice
have demonstrated that cellular proliferation
alone is not sufficient to cause cancer - Autonomous tumor growth, angiogenesis,
metastasis, together with increased genomic
instability drive tumor progression under the
selective pressure of environmental selection
43- Transgenic mice constitutively expressing
Transforming Growth Factor ? (TGF?), a potent
mitogen for various cell types, developed
epithelial hyperplasia in multiple tissues - However, tumors were only common in the liver and
mammary glands, demonstrating that further
changes are necessary for tumorigenic
transformation
44- The incidence of colon carcinoma (in the US) is
100 times higher than the occurrence of small
bowel cancers, although the cell turnover is
considerably higher in the small intestine - The above observations do not invalidate the
importance of cell proliferation in
tumorigenesis, but rather shows our imperfect
understanding of the whole process
45THE END