1,721,061 research outputs found
Colon_Crypt_Model_041321.nlogo
No full textTitle: Colon_Crypt_Model_041321.nlogo
Research genre: Computer program
Creator: Axelrod, David E.
Date Created: 2021
Extent: 1 digital file (393 KB)
Intended Audience: Science
Description: Computer program that simulates and plots the dynamics of stem cells, transient amplifying cells, differentiated cells, and mutant cells in normal human colon crypts and early colon cancer. It has been calibrated with measurements of human biopsy specimens. Includes graphical user interface, detailed information text, and annotated code. Experiments can be run from the GUI without knowledge of coding, or from the Behavior Space Tool using example code or modified code. It has been used to simulate human colon cancer initiation, therapy, and prevention. Different chemotherapy or prevention intermittent dose schedules can be input. Chemotherapy of heterogeneous and drug resistant early colon cancers can be simulated. Circadian cell proliferation can be selected to investigate chronomodulated chemotherapy dose schedules. Simulated output can be saved in spreadsheet format, or as images of plots of cell numbers as function of time.
The model was developed in the application NetLogo version 5.3.1, and revisions made to also run in NetLogo version 6.2.0. The model will not run on the Web version of NetLogo. NetLogo is a multi-agent programmable modeling environment. It is authored by Uri Wilenski and developed at The Center for Connected Learning (CCL) and Computer-Based Modeling. It is multi-platform (Mac, Windows, or Linux) open source application.
NetLogo version 6.2.0, can be downloaded at http://ccl.northwestern.edu/netlogo/download.shtml. To download the computer program click on the red link “NLOGO" to the left.
Earlier versions of the model and its use have been described in the following publications: Theoret Biol Med Model. 2013;10:66-89. Cancer Chemother Pharmcol 2017;79:889-898. Converg Sci Phys Oncol 2017;3:035004. Cancer Inform 2019;18:1-8. JCO Clin Cancer Inform 2020;4:514-520. A forthcoming publication will describe results of circadian-timed chemotherapy.
Research Domain: Science
Subjects: Chronotherapy: Circadian: Colorectal cancer: Chemotherapy: Agent-based model
Rights statement: The author owns the copyright to this work
Evolution of cooperation among tumor cells
No full textThe evolution of cooperation has a well established theoretical framework based on game theory. This approach has made valuable contributions to a wide variety of disciplines, including political science, economics, and evolutionary biology. Existing cancer theory suggests that individual clones of cancer cells evolve independently from one another, acquiring all of the genetic traits or hallmarks necessary to form a malignant tumor. It is also now recognized that tumors are heterotypic, with cancer cells interacting with normal stromal cells within the issue microenvironment, including endothelial, stromal, and nerve cells. This tumor cell???stromal cell interaction in itself is a form of commensalism, because it has been demonstrated that these nonmalignant cells support and even enable tumor growth. Here, we add to this theory by regarding tumor cells as game players whose interactions help to determine their Darwinian fitness. We marshal evidence that tumor cells overcome certain host defenses by means of diffusible products. Our original contribution is to raise the possibility that two nearby cells can protect each other from a set of host defenses that neither could survive alone. Cooperation can evolve as byproduct mutualism among genetically diverse tumor cells. Our hypothesis supplements, but does not supplant, the traditional view of carcinogenesis in which one clonal population of cells develops all of the necessary genetic traits independently to form a tumor. Cooperation through the sharing of diffusible products raises new questions about tumorigenesis and has implications for understanding observed phenomena, designing new experiments, and developing new therapeutic approaches.Author manuscript. Published in final edited form as: Proc Natl Acad Sci U S A. 2006 September 5; 103(36): 13474-13479.The final published version of this article is located at: www.pnas.org/cgi/doi/10.1073/pnas.0606053103NIH U56 CA113004; to David E. AxelrodR.A. was supported by National Science Foundation (NSF) Grant SES-0240852. D.E.A. was supported by NSF Grant IIS-0312953, National Institutes of Health (NIH) Grant U56 CA113004, and New Jersey Commission on Cancer Research Grant 1076-CCR-SO. K.J.P. is an American Cancer Society Clinical Research Professor and is supported by NIH Grants CA69568, CA102872, and CA093900.NIH CA69568; to Kenneth J. PientaNIH CA102872; to Kenneth J. PientaNIH CA093900; to Kenneth J. PientaNSF SES-0240852; to Robert AxelrodNJ Commission on Cancer Research 1076-CCR-SO; to David E. AxelrodAlso available in PubMed Central. PMCID: PMC155738
A calibrated agent-based computer model of stochastic cell dynamics in normal human colon crypts useful for in silico experiments
No full textA virtual crypt has been developed that simulates the quasi-stationary stochastic cell dynamics of normal human colon crypts. It is unique in that it has been calibrated with measurements of human biopsy specimens, and it can simulate the variation of cell types in addition to the average number of each cell type. The utility of the model was demonstrated with in silico experiments that evaluated cancer therapy protocols. The model is available for others to conduct additional experiments
Chemoprevention of colon cancer: Advantage of intermittent pulse treatment schedules quantified by computer simulation of human colon crypts
No full textIntermittent treatment schedules have been proposed to improve the tolerance of drugs for cancer chemoprevention. However, determining a maximum tolerated dose, and the extent of the improvement, has been challenging experimentally and clinically. In order to determine the quantitative advantage of intermittent pulse treatment schedules for the chemoprevention of colon cancer we have used a computer model of human colon crypts calibrated with measurements of human biopsy specimens. In simulations, crypts were treated with an agent that increases the probability that cells, both normal and mutant, would be removed at the top of the crypt. Sulindac, which increases apoptosis at the lumen surface, is such an agent. The effect of intermittent pulse drug treatment schedules were compared with constant drug treatment schedules. Crypts treated with intermittent pulse schedules have three times the maximum tolerated dose than crypts treated with constant schedules, and have a 10 year delay in the appearance of adenomas. Intermittent treatment schedules have previously been proposed for chemoprevention. Here computer simulations have quantified the effect on human colon crypts of intermittent treatment schedules and constant treatment schedules of a chemotherapeutic drug. Intermittent pulses have an advantage, they allow an increased maximum tolerated dose, and result in an increased chemoprevention by delay.Peer reviewe
Evaluation of pathways for progression of heterogeneous breast tumors
No full textTo better understand the progression of heterogeneous breast cancers, four models of progression pathways have been evaluated. The models describe the progression through the grades of ductal carcinoma in situ (DCIS) 1, 2, and 3, and through the grades of invasive ductal carcinoma (IDC) 1, 2, and 3. The first three pathways, termed linear, nonlinear, and branched, describe DCIS as aprogenitor of IDC, and grades of DCIS progressing into grades of IDC. The fourth pathway, termed parallel, describes DCIS and IDC as diverging from a common progenitor and progressing through grades in parallel. The best transition rates for the linear, nonlinear, and branched pathways were sought using a random search in combination with a directed search based on the Nelder–Mead simplex method. Parameter values for the parallel pathway were determined with heuristic graphs. Results of computer simulation were compared with clinically observed frequencies of grades of DCIS and grades of IDC that were reported to occur together in heterogeneous tumors. Each of the four pathways could simulate frequencies that resembled, to varying degrees, the clinical observations. The parallel pathway produced the best correspondence with clinical observations. These results quantify the traditional descriptions in which grades of DCIS are the progenitors of grades of IDC. The results also raise the alternative possibility that, in some tumors with both components, DCIS and IDC may have diverged from a common progenitor
Effective Chemotherapy of Heterogeneous and Drug Resistant Early Colon Cancers by Intermittent Dose Schedules: A Computer Simulation Study
No full textPurpose The effectiveness of cancer chemotherapy is limited by intra-tumor heterogeneity, the emergence of spontaneous and induced drug resistant mutant subclones, and the maximum dose to which normal tissues can be exposed without adverse side effects. The goal of this project was to determine if intermittent schedules of the maximum dose that allows colon crypt maintenance could overcome these limitations, specifically by eliminating mixtures of drug resistant mutants from heterogeneous early colon adenomas while maintaining colon crypt function.
Methods A computer model of cell dynamics in human colon crypts was calibrated with measurements of human biopsy specimens. The model allowed simulation of continuous and intermittent dose schedules of a cytotoxic chemotherapeutic drug, as well as the drug’s effect on the elimination of mutant cells and the maintenance of crypt function.
Results Colon crypts can tolerate a 10 fold greater intermittent dose than constant dose. This allows elimination of a mixture of relatively drug sensitive and drug resistant mutant subclones from heterogeneous colon crypts. Mutants can be eliminated whether they arise spontaneously or are induced by the cytotoxic drug.
Conclusions An intermittent dose, at the maximum that allows colon crypt maintenance, can be effective in eliminating a heterogeneous mixture of mutant subclones before they fill the crypt and form an adenoma.Peer reviewedArticle also available through the publisher at http://rdcu.be/qn25
Colon_Crypt_Model_073120.nlogo
No full textComputer program that simulates and plots the dynamics of stem cells, transient amplifying cells, differentiated cells, and mutant cells in normal human colon crypts and early colon cancer. It has been calibrated with measurements of human biopsy specimens. Includes graphical user interface, detailed information text, and annotated code. Experiments can be run from the GUI without knowledge of coding, or from the Behavior Space Tool using example code or modified code. Has been used to simulate human colon cancer initiation, therapy, and prevention.
Different chemotherapy or prevention intermittent dose schedules can be input. Chemotherapy of heterogeneous and drug resistant early colon cancers can be simulated. Circadian cell proliferation can be selected to investigate chronomodulated chemotherapy dose schedules. Simulated output can be saved in spreadsheet format, or as images of plots of cell numbers as function of time. It runs on the open-source multi-platform NetLogo application version 5.3.1 available at https://ccl.northwestern.edu/netlogo/index.shtml. Described in the following publications: Theoret Biol Med Model. 2013;10:66-89. Cancer Chemother Pharmcol 2017;79:889-898. Converg Sci Phys Oncol 2017;3:035004. Cancer Inform 2019;18:1-8. JCO Clin Cancer Inform 2020;4:514-520.
A forthcoming publication will describe results of circadian-timed chemotherapy.
To download the computer program click on the red link “Download file" to the left
Data Files, Chronotherapy
No full textOutput of chronotherapy simulated with NetLogo computer program Colon_Crypt_Model_073120. The model is described in a separate file. Each data file is the result of cytotoxic chemotherapy during a different 4 hour period during the day.
The file names (Data Analysis…) indicate the date that they were generated (073120 is Aug. 31, 2020), the time step that circadian cell proliferation was initiated (Circad), the time step the chemotherapy was initiated (Chemo), and the time steps (Phase) that chemotherapy was active.
Data in each column include the following, A: run number, with the number of time steps when mutants were initiated and the number of time steps that chemotherapy was initiated; B: whether or not the mutants overflowed the crypt and the mutants were not eliminated from the crypt (cured); C: the time step at which the mutants were eliminated from the crypt (cured); D: time steps between the time that chemotherapy was on and the time that mutants were cured; E: time to cure mutants in hours, assuming one time step equals four hours.; F: time to cure mutants in days; G: time of day, in hours, when chemotherapy was initiated.
A forthcoming publication will describe the computer program and simulation results of circadian-timed chemotherapy
Ecological therapy for cancer: Defining tumors utilizing an ecosystem paradigm suggests new opportunities for novel cancer treatments
No full textWe propose that there is an opportunity to devise new cancer therapies based on the recognition that tumors have properties of ecological systems. Traditionally, localized treatment has targeted the cancer cells directly by removing them (surgery) or killing them (chemotherapy and radiation). These modes of therapy have not always been effective because many tumors recur after these therapies, either because not all of the cells are killed (local recurrence) or because the cancer cells had already escaped the primary tumor environment (distant recurrence). There has been an increasing recognition that the tumor microenvironment contains host noncancer cells in addition to cancer cells, interacting in a dynamic fashion over time. The cancer cells compete and/or cooperate with nontumor cells, and the cancer cells may compete and/or cooperate with each other. It has been demonstrated that these interactions can alter the genotype and phenotype of the host cells as well as the cancer cells. The interaction of these cancer and host cells to remodel the normal host organ microenvironment may best be conceptualized as an evolving ecosystem. In classic terms, an ecosystem describes the physical and biological components of an environment in relation to each other as a unit. Here, we review some properties of tumor microenvironments and ecological systems and indicate similarities between them. We propose that describing tumors as ecological systems defines new opportunities for novel cancer therapies and use the development of prostate cancer metastases as an example.We refer to this as “ecological therapy” for cancer
Determining the control networks regulating stem cell lineages in colonic crypts
No full textThe question of stem cell control is at the center of our understanding of tissue functioning, both in healthy and cancerous conditions. It is well accepted that cellular fate decisions (such as divisions, dif- ferentiation, apoptosis) are orchestrated by a network of regulatory signals emitted by different cell pop- ulations in the lineage and the surrounding tissue. The exact regulatory network that governs stem cell lineages in a given tissue is usually unknown. Here we propose an algorithm to identify a set of candi- date control networks that are compatible with (a) measured means and variances of cell populations in different compartments, (b) qualitative information on cell population dynamics, such as the existence of local controls and oscillatory reaction of the system to population size perturbations, and (c) statistics of correlations between cell numbers in different compartments. Using the example of human colon crypts, where lineages are comprised of stem cells, transit amplifying cells, and differentiated cells, we start with a theoretically known set of 32 smallest control networks compatible with tissue stability. Utilizing near-equilibrium stochastic calculus of stem cells developed earlier, we apply a series of tests, where we compare the networks’ expected behavior with the observations. This allows us to exclude most of the networks, until only three, very similar, candidate networks remain, which are most compatible with the measurements. This work demonstrates how theoretical analysis of control networks combined with only static biological data can shed light onto the inner workings of stem cell lineages, in the absence of direct experimental assessment of regulatory signaling mechanisms. The resulting candidate networks are dom- inated by negative control loops and possess the following properties: (1) stem cell division decisions are negatively controlled by the stem cell population, (2) stem cell differentiation decisions are negatively controlled by the transit amplifying cell population.Peer reviewe
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