Mutations in various oncogenes and/or somatic cell genes result in the malignant conversion of cells. Cells that acquire autonomous proliferative and metastatic potential are called cancer cells. Because these cells proliferate after DNA replication, each tumor cell was thought to have the same mutated genes. However, the growth rates of primary tumors and their metastatic lesions, as well as their sensitivity to drugs or radiation, may differ. These differences may also occur within tumor masses.
The Big Bang model has been proposed for the occurrence of malignant tumors. Early cancer cell development is characterized by repeating gene mutations in various clones, followed by the proliferation of these clones to form tumors. Figure 17 shows a schematic diagram of tumor growth according to the Big Bang model.
(Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366:883-892.
Sottoriva A, Kang H, Ma Z, et al. A Big Bang model of human colorectal tumor growth. Nat Genet. 2015;47:209-216.）
Assumptions for simulating the Big Bang model
* The doubling and proliferation of tumor cells is monoclonal.
* Genetic mutations within tumor cells occur early, with these cells acquiring different clonality (radiosensitivity).
* If the doubling time of each clone correlates with the doubling time of tumor volume, the latter is randomly generated, assuming a Poisson distribution with reference to published times.
* The expansion of each clone in three-dimensional space follows a normal distribution.
* The generated clones randomly acquire the radiosensitivity of seven types of cells (SCC13, SQ5, SQ20B, DU145, DLD1, SCC61, HFLIII) used in culture experiments (Table 2). The cell lines with the highest and lowest (most resistant) radiation sensitivity are HFLIII and SQ20B, respectively.
* Based on the above assumptions, a model of tumor growth in three-dimensional space can be represented by Figure 18 .
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