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 neoplastic cells
• Lethal errors in metabolic pathways and DNA
  replication
• Programmed cell death
• Partial differentiation of tumor cells

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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

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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

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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
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Phorbolester, 12-O-tetradecanoylphorbol-13-acetate
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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

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• 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

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• 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

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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

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

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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

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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

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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

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• 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

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• 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

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• 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

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• 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

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THE END