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Cell Proliferation and Carcinogenesis

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Cell Proliferation and Carcinogenesis Kinetics of tumor cell population growth Growth fraction Cell loss Nutrient deprivation Immunological response against ... – PowerPoint PPT presentation

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Title: Cell Proliferation and Carcinogenesis


1
Cell 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

2
Cell 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

3
Kinetics 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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Kinetics 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

6
Kinetics 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

7
Kinetics 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)

8
Kinetics 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

9
Kinetics 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

10
Kinetics 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

11
Kinetics 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

12
Kinetics 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

13
Kinetics 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

14
The 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

15
The 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

16
The 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

17
The 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

18
Stages in Tumor Progression
Latent period of the disease
Focal premalignant lesion
Leads to evolution of invasive and metastatic
cancer
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The 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

21
The 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

22
The 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

23
The 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

24
The 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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Dimethylbenzaanthracene
Hydrocarbons and alkylating agents
27
Phorbolester, 12-O-tetradecanoylphorbol-13-acetate
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29
The 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

32
The 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

33
A multistep molecular event model for the
development of familial adenomatous polyposis, a
colorectal cancer
Genetic changes
Epigenetic changes
34
The 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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The 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

38
The 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

39
The 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

40
Summary 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

45
THE END
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