A stochastic model of cancer initiation including a bystander effect.
A stochastic model of cancer initiation is considered. The model is used to evaluate whether a bystander effect may be important in the pre-malignant and malignant stages of carcinogenesis, and furthermore, on the basis of epidemiological data, to estimate the mutation rates of genes involved in the development of oral leukoplakias. The bystander effect is defined here as the capability of oncogenic mutations to increase the mutation probability of neighbouring (bystander) cells, thus leading potentially to a cascade of neighbouring mutated and neoplastic cells as a pre-stage in the development to leukoplakias and cancer. We find that incidence data for oral cancer are indeed in accordance with a significant bystander effect, operating either alone or in combination with genomic instability in the early stages of carcinogenesis, i.e. the development of neoplasia. Simulations performed gave a picture of how mutations and neoplasia may spread in a tissue, to form characteristic leukoplakias with a core of neoplastic cells. The model also showed that the probability of finding at least one neoplastic cell in the tissue after a given number of years is more sensitive to changes in genomic instability within the cell itself than to changes in a bystander effect. Based on epidemiological data we also calculate the maximum number of oncogenic genes that may be involved in the bystander effect and development of genomic instability. Even if capable of explaining the initial development of oncogenic mutations towards neoplastic cells, the bystander model could not reproduce the observed incidence rates of leukoplakia without assuming a carcinogen mutation probability per cell per year of neoplastic cells practically equal to one. This means that the bystander effect, to be of substantial importance in the final development of neoplastic cells towards leukoplakias, requires a very significant increase in mutation probabilities for bystanders to neoplastic cells. Alternatively, additional mechanisms such as abnormal cell differentiation and uncontrolled proliferation and apoptotis in the neoplastic stage may be of major importance during the development to cancerization.
Østby
Ivar
I
CIGENE-Centre for Integrative Genetics, Norwegian University of Life Sciences, P.O. Box 5003, N-1342 Aas, Norway. ivar.ostby@umb.no
Øyehaug
Leiv
L
Steen
Harald B
HB
D024201:Bystander Effect; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D003198:Computer Simulation; D006801:Humans; D007972:Leukoplakia, Oral / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008954:Models, Biological; D009154:Mutation; D013269:Stochastic Processes