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Register a new userModeling age-specific incidence of colon cancer via niche competition
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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.
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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.
The epidemiology of lumbar degenerative spondylolisthesis (DS) remains controversial. We performed a systemic review with the aim to have a better understanding of DSs prevalence in general population. The results showed the prevalence of DS is very gender specific and age specific. Both women and men have few DS before 50 years old, after 50 years old both women and men start to develop DS, with women having a faster developing rate than men. For elderly Chinese (>=65 yrs, mean age: 72.5 yrs), large population based studies (MsOS(Hong Kong) and MrOS (Hong Kong), females n=2000 and males n=2000) showed DS prevalence was for 25.0% for women and 19.1% for men, and the prevalence F:M (women:men) ratio was 1.3:1. The published data (MsOS(USA) and MrOS(USA) studies) seem to show elderly Caucasian American has a higher DS prevalence, being approximately 60-70% higher than elderly Chinese; however the prevalence F:M ratio was similar to elderly Chinese population. Patient data showed female patients more often received treatment than men; and preliminary data show the ratio of numbers of female patients received treatment compared with men did not differ between Northeast Asians (Chinese, Japanese, and Korean) and European and American Caucasians, being around 2:1 in elderly population. The existing data also suggest that menopause may be a contributing factor for the accelerated DS development in post-menopausal
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.
Tumor growth has long been a target of investigation within the context of mathematical and computer modelling. The objective of this study is to propose and analyze a two-dimensional probabilistic cellular automata model to describe avascular solid tumor growth, taking into account both the competition between cancer cells and normal cells for nutrients and/or space and a time-dependent proliferation of cancer cells. Gompertzian growth, characteristic of some tumors, is described and some of the features of the time-spatial pattern of solid tumors, such as compact morphology with irregular borders, are captured. The parameter space is studied in order to analyze the occurrence of necrosis and the response to therapy. Our findings suggest that transitions exist between necrotic and non-necrotic phases (no-therapy cases), and between the states of cure and non-cure (therapy cases). To analyze cure, the control and order parameters are, respectively, the highest probability of cancer cell proliferation and the probability of the therapeutic effect on cancer cells. With respect to patterns, it is possible to observe the inner necrotic core and the effect of the therapy destroying the tumor from its outer borders inwards.
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.
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