Abstract
The development of cancer is a multistep process in which cells increase in malignancy through progressive alterations. Such altered cells compete with wild-type cells and have to establish within a tissue in order to induce tumor formation. The range of this competition and the tumor-originating cell type which acquires the first alteration is unknown for most human tissues, mainly because the involved processes are hardly observable, aggravating an understanding of early tumor development. On the tissue scale, one observes different progression types, namely with and without detectable benign precursor stages. Human epidemiological data on the ratios of the two progression types exhibit large differences between cancers. The idea of this study is to utilize data of the ratios of progression types in human cancers to estimate the homeostatic range of competition in human tissues. This homeostatic competition range can be interpreted as necessary numbers of altered cells to induce tumor formation on the tissue scale. For this purpose, we develop a cell-based stochastic model which is calibrated with newly-interpreted human epidemiological data. We find that the number of tumor cells which inevitably leads to later tumor formation is surprisingly small compared to the overall tumor and largely depends on the human tissue type. This result points toward the existence of a tissue-specific tumor-originating niche in which the fate of tumor development is decided early and long before a tumor becomes detectable. Moreover, our results suggest that the fixation of tumor cells in the tumor-originating niche triggers new processes which accelerate tumor growth after normal tissue homeostasis is voided. Our estimate for the human colon agrees well with the size of the stem cell niche in colonic crypts. For other tissues, our results might aid to identify the tumor-originating cell type. For instance, data on primary and secondary glioblastoma suggest that the tumors originate from a cell type competing in a range of 300 – 1,900 cells.
Highlights
Cancer development is a multistep process in which cells acquire a certain number of progressive epigenetic and genetic alterations [1]
In our cell-based model, we only regard the last step within the neutral phase and the first step within the selection phase such that we obtain a two-step process. This coarse-grained approach is appropriate for our purpose since we are only interested in modeling tumor progression patterns and not quantities which are largely influenced by the precise number of steps, e.g., the time-scale of tumor development or intra-tumor heterogeneity
The parameter N in our model describes the homeostatic range of this competition
Summary
Cancer development is a multistep process in which cells acquire a certain number of progressive epigenetic and genetic alterations [1]. This multistep process can be divided into a neutral and a selection phase. The progeny of the tumor-originating cell competes with wild-type cells within normal tissue homeostasis. In order to induce tumor formation, the progeny of the tumor-originating cell has to establish within the tissue. This establishment is achieved by clonal expansion to a sufficiently large cell population [8]. There is experimental evidence that this establishment is characterized by an outcompetition of wild-type cells within the homeostatic range of competition, e.g., the human colon [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
