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Register a new userNew Insights into Initiation of Colon and Intestinal Cancer: The Significance of Central Stem Cells in the Crypt
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Added by
Ali Mahdipour Shirayeh
Publication date
2016
fields
Biology
and research's language is
English
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Rapidly dividing tissues, like intestinal crypts, are frequently chosen to investigate the process of tumor initiation, because of their high rate of mutations. To study the interplay between normal and mutant as well as immortal cells in the human colon or intestinal crypt, we developed a 4-compartmental stochastic model for cell dynamics based on current discoveries. Recent studies of the intestinal crypt have revealed the existence of two stem cell groups. Therefore, our model incorporates two stem cell groups (central stem cells (CeSCs) and border stem cells (BSCs)), plus one compartment for transit amplifying (TA) cells and one compartment of fully differentiated (FD) cells. However, it can be easily modified to have only one stem cell group. We find that the worst-case scenario occurs when CeSCs are mutated, or an immortal cell arises in the TA or FD compartments. The probability that the progeny of a single advantageous CeSC mutant will take over the entire crypt is more than $0.2$, and one immortal cell always causes all FD cells to become immortals.Moreover, when CeSCs are either mutants or wild-type (w.t.) individuals, their progeny will take over the entire crypt in less than 100 days if there is no immortal cell. Unexpectedly, if the CeSCs are wild-type, then non-immortal mutants with higher fitness are washed out faster than those with lower fitness. Therefore, we suggest one potential treatment for colon cancer might be replacing or altering the CeSCs with the normal stem cells.
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Since the discovery of a cancer initiating side population in solid tumours, studies focussing on the role of so-called cancer stem cells in cancer initiation and progression have abounded. The biological interrogation of these cells has yielded volumes of information about their behaviour, but there has, as of yet, not been many actionable generalised theoretical conclusions. To address this point, we have created a hybrid, discrete/continuous computational cellular automaton model of a generalised stem-cell driven tissue and explored the phenotypic traits inherent in the inciting cell and the resultant tissue growth. We identify the regions in phenotype parameter space where these initiating cells are able to cause a disruption in homeostasis, leading to tissue overgrowth and tumour formation. As our parameters and model are non-specific, they could apply to any tissue cancer stem-cell and do not assume specific genetic mutations. In this way, our model suggests that targeting these phenotypic traits could represent generalizable strategies across cancer types and represents a first attempt to identify the hallmarks of cancer stem cells.
Cancer development is a multistep process often starting with a single cell in which a number of epigenetic and genetic alterations have accumulated thus transforming it into a tumor cell. The progeny of such a single benign tumor cell expands in the tissue and can at some point progress to malignant tumor cells until a detectable tumor is formed. The dynamics from the early phase of a single cell to a detectable tumor with billions of tumor cells are complex and still not fully resolved, not even for the well-known prototype of multistage carcinogenesis, the adenoma-adenocarcinoma sequence of colorectal cancer. Mathematical models of such carcinogenesis are frequently tested and calibrated based on reported age-specific incidence rates of cancer, but they usually require calibration of four or more parameters due to the wide range of processes these models aim to reflect. We present a cell-based model, which focuses on the competition between wild-type and tumor cells in colonic crypts, with which we are able reproduce epidemilogical incidence rates of colon cancer. Additionally, the fraction of cancerous tumors with precancerous lesions predicted by the model agrees with clinical estimates. The match between model and reported data suggests that the fate of tumor development is dominated by the early phase of tumor growth and progression long before a tumor becomes detectable. Due to the focus on the early phase of tumor development, the model has only a single fit parameter, the replacement rate of stem cells in the crypt. We find this rate to be consistent with recent experimental estimates.
Compiled data for the stem cell numbers, Ns, and division rates, ms, is reanalized in order to show that we can distinguish two groups of human tissues. In the first one, there is a relatively high fraction of maintenance (stem and transit) cells in the tissue, but the division rates are low. The second group, on the other hand, is characterized by very high transit cell division rates, of around one division per day. These groups do not have an embrionary origin. We argue that their properties arise from a combination of the needs of tissue homeostasis (in particular turnover rate) and a bound on cancer risk, which is roughly a linear function of the product Ns ms. The bound on cancer risk leads to a threshold at ms = 8/year, where the fraction of stem cells falls down two orders of magnitude.
The growth of several biological tissues is known to be controlled in part by local geometrical features, such as the curvature of the tissue interface. This control leads to changes in tissue shape that in turn can affect the tissues evolution. Understanding the cellular basis of this control is highly significant for bioscaffold tissue engineering, the evolution of bone microarchitecture, wound healing, and tumour growth. While previous models have proposed geometrical relationships between tissue growth and curvature, the role of cell density and cell vigor remains poorly understood. We propose a cell-based mathematical model of tissue growth to investigate the systematic influence of curvature on the collective crowding or spreading of tissue-synthesising cells induced by changes in local tissue surface area during the motion of the interface. Depending on the strength of diffusive damping, the model exhibits complex growth patterns such as undulating motion, efficient smoothing of irregularities, and the generation of cusps. We compare this model with in-vitro experiments of tissue deposition in bioscaffolds of different geometries. By accounting for the depletion of active cells, the model is able to capture both smoothing of initial substrate geometry and tissue deposition slowdown as observed experimentally.
The maintenance of the proliferative cell niche is critical to epithelial tissue morphology and function. In this paper we investigate how current modelling methods can result in the erroneous loss of proliferative cells from the proliferative cell niche. Using an established model of the inter-follicular epidermis we find there is a limit to the proliferative cell densities that can be maintained in the basal layer (the niche) if we do not include additional mechanisms to stop the loss of proliferative cells from the niche. We suggest a new methodology that enables maintenance of a desired homeostatic population of proliferative cells in the niche: a rotational force is applied to the two daughter cells during the mitotic phase of division to enforce a particular division direction. We demonstrate that this new methodology achieves this goal. This methodology reflects the regulation of the orientation of cell division.
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