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| IMC Wiki | Carcinogenesis and tumour growth

Carcinogenesis and tumour growth

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Cancer is an acquired genetic disease. It is initiated by an irreversible genome damage (mutation). Tumours develop from a single genetically damaged progenitor cell in a staged process (multistep carcinogenesis).

This is best documented in the process of chemical carcinogenesis which is conceptually divided into four stages:
  1. Initiation
    • Rapid onset
    • Irreversible DNA damage
    • Modification of the biological potency of the affected cell (not neoplastic yet, but susceptible to the effect of promoters)

  2. Promotion
    • Slow development (latency period: 5-30 years!)
    • Reversible
    • Non-additive
    • Expression of altered gene products (no direct DNA damage)
    • Dose threshold
    • Increased proliferation (clonal expansion)
    • Atypical differentiation
    • Development of a pre-cancerous lesion

  3. Malignant transformation
    • Further mutations
    • Conversion of a pre-neoplastic cell into a cell with malignant phenotype (uncontrolled growth, genetic instability)
    • Inheritance of damaged genetic material to daughter cells

  4. Tumour progression
    • Tumour growth
      • Clonal growth
      • Tumour angiogenesis
      • Tumour heterogeneity
      • Cell production and loss
    • Invasion
    • Metastasis
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Molecular biology of carcinogenesis

Tumours develop through the clonal expansion of a single genetically damaged progenitor cell (monoclonal theory of carcinogenesis). Tumour evolution is a multistep process which may last for years and decades and results from progressive accumulation of genetic defects and altered gene products.
It is important to understand that the genes involved in carcinogenesis are normal constituents of the human genome and their products play a central role in the physiological regulation of cell growth, division and differentiation. Tumour development is caused by regulation errors or structural changes in this network.

All aetiological factors in carcinogenesis target regulatory genes of cell cycle, invasion and metastasis.

The following gene systems are involved in carcinogenesis:
  • Oncogenes (proto-oncogenes)
  • Tumour suppressor genes (anti-oncogenes)
  • Genes that regulate apoptosis
  • Telomerase genes
  • Genes of DNA repair
In the following, the two best-known gene systems (proto-oncogenes and tumour suppressor genes) will be presented.


Proto-oncogenes play a central role in cell proliferation control. They may be activated by different genetic mechanisms (chromosome translocations, amplifications, point mutations, other chromosome anomalies) and thus converted into cancer genes (oncogenes). Oncogenes act in a dominant fashion, i.e. cells are transformed even if only one allele is damaged.

Oncogene classes

Based on their effect, oncogene products are classified as follows:
  • Growth factors:
    PDGF (platelet-derived growth factor)
    CSF-1 (colony stimulating factor-1)
    EGF (epidermal growth factor)
    TGF-α and β (transforming growth factors), etc.
  • Growth factor receptors:
    EGFR (human epidermal growth factor receptor 1/HER1)
    HER2 (c-erbB-2/neu), etc.
  • GTP-binding proteins (intracellular signal transmission) :
    RAS family
  • Nuclear transcription factors:
    MYC family, FOS, MYB
Especially in breast cancer, the overexpression of growth factor receptor HER2 is clinically important. The prognosis for breast carcinomas with amplified HER2 oncogene is poor, presumably because tumour cells are very sensitive to smaller quantities of growth factors, and HER2 oncogene is probably one of the most important prognostic factors besides the lymph node status and the tumour size. A promising anti-HER2 antibody (Herceptin®) has recently been introduced in the therapy of metastatic breast cancer. The detection of HER2 status in breast carcinoma has therefore become a part of up-to-date molecular diagnosis.
#pic# #pic#

Overexpression of HER2 also occurs in carcinomas of the ovaries, lung, stomach, and salivary glands as well as in oral squamous cell carcinomas. Therefore, studying HER2 in different human malignancies is the target of intensive research.

Another clinically relevant oncogene for neuroblastoma is N-MYC. Gene amplification and overexpression of N-MYC is a marker of poor prognosis in this highly malignant tumour in children which also has therapeutic consequences.

Cancer may arise not only by activation of growth-promoting oncogenes, but also by inactivation of tumour suppressor genes (anti-oncogenes). In contrast to oncogenes, tumour suppressor genes code proteins which inhibit cell growth and proliferation. These genes act in a recessive fashion, i.e. both alleles of a pair of chromosomes must be inactivated for the development of a malignant tumour.

The prototype of tumour suppressor genes is the retinoblastoma (Rb) gene which is involved in the genesis of a rare, partly familial, partly sporadic malignant tumour of childhood. The inactivation of both alleles of Rb results in loss of the cell cycle regulatory function of the protein product and in the development of retinoblastoma.

The unravelling of this mechanism lead to the proposal of the so-called two hit hypothesis [Alfred Knudson; 1971] of the mechanism of action of tumour suppressor genes:
  1. The first hit (mutation) inactivates one allele of the Rb gene (either inherited in the germ line, or acquired)
  2. The second hit destroys the second allele resulting in a loss of heterozygosity (LOH) and malignant transformation of the cell.
Inactivation of the Rb gene may also occur in other types of malignancies such as osteosarcoma, lung, and breast carcinomas. This indicates, that the RB gene product has a universal function in cells independent of cell type. Now we know that the RB gene products is a nuclear phosphoprotein which controls the cell cycle at the G1/S checkpoint (see fig. 5).

The most significant tumour suppressor gene is p53. Mutations of this gene, located at the short arm of chromosome 17 [17p13.1], are the most common genetic alterations encountered in human malignancies. In over 50% of all human cancers, the p53 protein is either missing, or a mutation of the p53 gene can be observed. P53 mutations in the germ line may lead to familial accumulation of certain malignant tumours (Li-Fraumeni-Syndrom).

The main task of the normal p53-gene product (wild type=WT) is to maintain the integrity of the genome. In normal cells, there is only a small amount of p53 protein with a short half-life. DNA damage activates p53 and the amount of p53 protein in the cell will also be increased. P53 activation may have two completely different consequences:
  1. Early in the cell cycle, activated p53 blocks the cell cycle at the G1/S checkpoint to give the cell time to repair DNA before dividing (see fig. 5).
  2. If the DNA cannot be repaired during the pause, p53 triggers programmed cell death (apoptosis).
The molecular mechanisms of how p53 decides in which direction the cell will be driven are still not completely understood. P53 has no direct influence on the cell cycle; it acts as a transcription factor. The wild type p53 protein can bind to different parts of the DNA and thus activate the expression of corresponding target genes.

Effector genes of p53:
  1. WAF1/p21, cell cycle arrest
  2. mdm-2, negative feedback regulator of p53,
  3. GADD-45, DNA repair, and
  4. BAX/bcl-2 system, important for regulation of apoptosis

Activation of normal wild type p53 protein leads to cell cycle arrest in the G1 phase and induction of DNA repair. With irreparable DNA injury, p53 induces apoptosis. In cells with loss or mutations of p53, DNA damage does not induce cell cycle arrest or DNA repair, with consequent proliferation of genetically damaged cells and potential development of a malignant tumour.

The number of newly discovered tumour suppressor genes is rapidly increasing. Some of them are demonstrated in the following table:

Gene Locus Function Tumour
17p13.1 Checkpoint in the cell cycle,
inducer of apoptosis
In >50% of
malignant tumours
13q14 Regulator of cell cycle
and gene activity
(deleted in colon cancer)
18q21.3 Cell-adhesion,
signal transduction
Colon cancer
(adenomatous polyposis coli)
5q25 Microtubule complexing Colon cancer
(Wilm's tumour 1)
11p13 Regulator of gene activity Wilm's tumour
type 1)
17q11 Regulator of p21 (RAS-protein) Neurofibromatosis
type 1
suppressor-1/ p16/ CDKN2)
9p21-22 CDK-inhibitor,
rRegulator of cell cycle
Breast cancer,
pancreas cancer,
BRCA1 17q21 Transcription factor Breast-, ovarial-,
prostate cancers
BRCA2 13q12-13 Transcription factor Breast-, ovarial-,
prostate cancers
E-cadherin 16q21-22 Cell adhesion, signal transduction Gastric cancer, squamous cell carcinoma,
oral cancer

The cell cycle and its control

The sequence of processes between two mitotic cell divisions is referred to as the cell cycle. The phase in which mitosis actually occurs is referred to as M-phase, the rest is as interphase. The interphase is subdivided into G1, S and G2 phases. The progress of the cell cycle is controlled at specific checkpoints where the accuracy of the previous phases is verified. There are three checkpoints within the cell cycle that decide upon the continuation of the cycle.

Cell cycle checkpoints

Checkpoint Description Parameters controlled by the cell which can stop the cell cycle
G1 /S Control of entry into the G1 phase,
Major checkpoint,
Site of action of Rb1
(retinoblastoma protein 1)
Unfavourable external conditions
(shortage in nutrients) -
Critical cell size not achieved -
DNA damage
G2 /M Control of entry into mitosis Critical cell size not achieved -
DNA damage -
DNA not completely replicated
M Control during mitosis Mitotic spindles not correctly formed

Some cells, however, do not divide or have temporarily excited the cell cycle. They are in the G0 phase. Exit from and re-entry into the cell cycle occur at a restriction point in the early G1 phase (G0/G1). At this checkpoint, the p53 tumour suppressor system guards the integrity of the genome.

Pathological and genetic model of multistep carcinogenesis

The evolution of a malignant tumour is documented best in epithelial tissues. This theory presumes that malignant tumours arise from a single transformed cell and develop through morphologically and clinically detectable pre-cancerous stages.

Two well known models are:
  1. Adenoma-carcinoma sequence in colorectal cancers (Fearon ER, Vogelstein B; 1990)
  2. Dysplasia (intraepithelial neoplasia) carcinoma sequence in carcinomas of the uterine cervix
The genetic model for the development and progression of squamous cell carcinomas in the head and neck region is demonstrated schematically in the following figure.

Stages of tumour growth

Malignant tumours usually arise from a transformed somatic cell (clonal development theory).
  1. Growth along the basement membrane (in situ carcinoma)
    • Clonal evolution
    • Angiogenesis
    • Tumour cell heterogeneity
  2. Permeation of the basement membrane
    Adhesion → Invasion → Permeation of basement membrane
  3. Passage of tumour cells through the interstitium towards the vessels (infiltrative growth).
    • Loosening of tumour cell cohesion
    • Derangement of cell adhesion
    • Loss of contact inhibition
    • Enzymatic degradation of extracellular matrix
    • Active locomotion
    • Damage to adjacent healthy tissues
  4. Invasion
    • Infiltration into the vessels
  5. Tumour dissemination
    • Circulating tumour cells
    • Interaction with the immune system/macrophages (elimination of 99.9% of tumour cells)
    • Tumour cells wrapped in an embolus
  6. Adhesion to endothelium/basement membrane Extravasation
    • Arrest of tumour cells in capillary bed
  7. Metastasis
    • Mechanical-haemodynamical hypothesis
    • "Seed and soil" theory (Paget 1889); Significance of microenvironment in settlement of metastatic tumour cells
    • Organotropy of metastasis
      1. Negative organ disposition (heart, skeletal muscle, spleen)
      2. Positive organ disposition (lungs, liver, skeleton)
    • Angiogenesis Metastasis Micrometastasis (<2mm) Macrometastasis (>2mm)
    • Metastatic pathways:
      1. Lymphatic
      2. Haematogenous
      3. Cavitary


  • Califano J, van der Riet P, Westra W, Nawroz H, Clayman G, Piantadosi S, Corio R, Lee D, Greenberg B, Koch W, Sidransky D (1996), Genetic progression model for head and neck cancer: implications for field cancerization, Cancer Res. 1996 Jun 1;56(11):2488-92
  • Fearon ER, Vogelstein B (1990)   A genetic model for colorectal tumorigenesis   Cell. 1990 Jun 1;61(5):759-67
  • Knudson AG Jr. (1971)   Mutation and cancer: statistical study of retinoblastoma   Proc Natl Acad Sci U S A. 1971 Apr;68(4):820-3
  • Kumar V, Cotran RS, Robbins SL (1993)   Grundlagen der Allgemeinen Pathologie   Gustav Fischer Verlag Stuttgart-Jena-New York 1993
  • Paget S (1889)   The distribution of secondary growths in cancer of the breast   Lancet 1889; 1:571