scholarly journals An agent-based model of cancer stem cell initiated avascular tumour growth and metastasis: the effect of seeding frequency and location

2014 ◽  
Vol 11 (100) ◽  
pp. 20140640 ◽  
Author(s):  
Kerri-Ann Norton ◽  
Aleksander S. Popel
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Tumour Growth ◽  
Temporal Distribution ◽  
Growth Patterns ◽  
Metastatic Tumour ◽  
Cell Seeding ◽  
Seeding Rate ◽  
Agent Based ◽  
Cellular Quiescence

It is very important to understand the onset and growth pattern of breast primary tumours as well as their metastatic dissemination. In most cases, it is the metastatic disease that ultimately kills the patient. There is increasing evidence that cancer stem cells are closely linked to the progression of the metastatic tumour. Here, we investigate stem cell seeding to an avascular tumour site using an agent-based stochastic model of breast cancer metastatic seeding. The model includes several important cellular features such as stem cell symmetric and asymmetric division, migration, cellular quiescence, senescence, apoptosis and cell division cycles. It also includes external features such as stem cell seeding frequency and location. Using this model, we find that cell seeding rate and location are important features for tumour growth. We also define conditions in which the tumour growth exhibits decremented and exponential growth patterns. Overall, we find that seeding, senescence and division limit affect not only the number of stem cells, but also their spatial and temporal distribution.

scholarly journals Aggregated spatio-temporal division patterns emerge from reoccurring divisions of neural stem cells

2020 ◽  
Author(s):  
V. Lupperger ◽  
C. Marr ◽  
P. Chapouton
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Temporal Distribution ◽  
Adult Neural Stem Cell ◽  
Agent Based ◽  
Random Fashion ◽  
Dividing Cells ◽  
Spatio Temporal ◽  
Stem Cell Populations

AbstractThe regulation of quiescence and cell cycle entry is pivotal for the maintenance of stem cell populations. Regulatory mechanisms however are poorly understood. In particular it is unclear how the activity of single stem cells is coordinated within the population, or if cells divide in a purely random fashion. We addressed this issue by analyzing division events in an adult neural stem cell (NSC) population of the zebrafish telencephalon. Spatial statistics and mathematical modeling of over 80,000 NSCs in 36 brains revealed weakly aggregated, non-random division patterns in space and time. Analyzing divisions at two timepoints allowed us to infer cell cycle and S-phase lengths computationally. Interestingly, we observed rapid cell cycle re-entries in roughly 15% of newly born NSCs. In agent based simulations of NSC populations, this re-dividing activity sufficed to induce aggregated spatio-temporal division patterns that matched the ones observed experimentally. In contrast, omitting re-divisions lead to a random spatio-temporal distribution of dividing cells. Spatio-temporal aggregation of dividing stem cells can thus emerge from the cell’s history, regardless of possible feedback mechanisms in the population.

Colorectal cancer stem cells: Characterization and functional analysis

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4124-4124
Author(s):  
T. Yeung ◽  
J. Wilding ◽  
W. Bodmer
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Tumour Growth ◽  
Colorectal Cancer Cell Lines ◽  
Colorectal Cancer Stem Cells

4124 Background: Cancer stem cells are defined as cells within a tumour that are able to self-renew and differentiate into all cell lineages within that tumour. With our extensive panel of colorectal cell lines, our aims are: 1) To characterise and isolate cancer stem cells based on stem cell markers, morphological appearances and the ability to form multiple lineages; 2) To understand how cancer stem cells drive tumour growth and progression. Methods: 1) Fluorescent Activated Cell Sorting (FACS); 2) In vitro soft agar clonogenic and Matrigel differentiation assays; 3) In vivo tumourigenic NOD/SCID mice assay; 4) Confocal immunofluorescence imaging. Results: 1) A subpopulation of cells can differentiate into crypt-like megacolonies, retaining the ability to self-renew and differentiate. SW1222 cell line forms heterogeneous colonies when single cells are plated in Matrigel. Megacolonies can both self-renew and form terminally differentiated small colonies, whereas small colonies cannot form megacolonies. Megacolonies develop crypt-like structures and increase their expression of differentiation markers (CDX-1, CK-20) over time. Experiments are currently under way to confirm that cells from megacolonies are able to initiate tumours in NOD/SCID mice. Some cell lines retain the ability to differentiate into both neuroendocrine and epithelial lineages. 2) CD44+CD24+ enriches for the cancer stem cell population. Colorectal cancer cell lines HCT116, HT29, LS180, LS174T and SW1222 express both CD44 and CD24. The CD44+CD24+ subpopulation is the most clonogenic. In SW1222, CD44+CD24+ cells enrich for megacolonies and can reform all four CD44/CD24 subpopulations. 3) Hypoxia reduces differentiation, increases stem-like phenotype and enhances clonogenicity. Hypoxia increases the proportion of undifferentiated colorectal cancer cells when plated on Matrigel and increases clonogenicity. Conclusions: 1) Colorectal cancer cell lines contain subpopulations of cells that have the ability to self-renew, differentiate and drive tumour growth, and may be characterised by their cell surface markers and colony morphology. 2) CD44+CD24+ can be used as markers for colorectal cancer stem cells. 3) Hypoxia increases the stem-like phenotype of cancer cells, reduces differentiation and increases clonogenicity. No significant financial relationships to disclose.

scholarly journals Estimating stem cell fractions in hierarchically organized tumors

2015 ◽  
Author(s):  
Benjamin Werner ◽  
Jacob G Scott ◽  
Andrea Sottoriva ◽  
Alexander RA Anderson ◽  
Arne Traulsen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Tumor Growth ◽  
Treatment Strategies ◽  
Exact Result ◽  
Growth Patterns ◽  
Cell Fractions ◽  
Tumor Types

Cancers arise as a result of genetic and epigenetic alterations. These accumulate in cells during the processes of tissue development, homeostasis and repair. Many tumor types are hierarchically organized and driven by a sub-population of cells often called cancer stem cells. Cancer stem cells are uniquely capable of recapitulating the tumor and can be highly resistant to radio- and chemotherapy treatment. We investigate tumor growth patterns from a theoretical standpoint and show how significant changes in pre- and post-therapy tumor dynamics are tied to the dynamics of cancer stem cells. We identify two characteristic growth regimes of a tumor population that can be leveraged to estimate cancer stem cell fractions in vivo using simple linear regression. Our method is a mathematically exact result, parameter free and does not require any microscopic knowledge of the tumor properties. A more accurate quantification of the direct link between the sub-population driving tumor growth and treatment response promises new ways to individualize treatment strategies.

scholarly journals Reoccurring neural stem cell divisions in the adult zebrafish telencephalon are sufficient for the emergence of aggregated spatiotemporal patterns

PLoS Biology ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. e3000708
Author(s):  
Valerio Lupperger ◽  
Carsten Marr ◽  
Prisca Chapouton
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cell ◽  
Agent Based ◽  
Brain Hemispheres ◽  
Random Fashion ◽  
Dividing Cells ◽  
Stem Cell Divisions ◽  
Stem Cell Populations

Regulation of quiescence and cell cycle entry is pivotal for the maintenance of stem cell populations. Regulatory mechanisms, however, are poorly understood. In particular, it is unclear how the activity of single stem cells is coordinated within the population or if cells divide in a purely random fashion. We addressed this issue by analyzing division events in an adult neural stem cell (NSC) population of the zebrafish telencephalon. Spatial statistics and mathematical modeling of over 80,000 NSCs in 36 brain hemispheres revealed weakly aggregated, nonrandom division patterns in space and time. Analyzing divisions at 2 time points allowed us to infer cell cycle and S-phase lengths computationally. Interestingly, we observed rapid cell cycle reentries in roughly 15% of newly born NSCs. In agent-based simulations of NSC populations, this redividing activity sufficed to induce aggregated spatiotemporal division patterns that matched the ones observed experimentally. In contrast, omitting redivisions leads to a random spatiotemporal distribution of dividing cells. Spatiotemporal aggregation of dividing stem cells can thus emerge solely from the cells’ history.

scholarly journals Airbrushed Nanofibrous Membranes to Control Stem Cell Infiltration In 3D Printed Scaffolds

2021 ◽  
Author(s):  
Chya-Yan Liaw ◽  
Shawn Huynh ◽  
Christina Gedeon ◽  
Shen Ji ◽  
Caroline D’souza ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Infiltration ◽  
Cell Seeding ◽  
Feature Size ◽  
Polymeric Biomaterials ◽  
3D Printed ◽  
Fibrous Membranes ◽  
Hybrid Scaffolds ◽  
Seeding Efficiency

Extrusion-based 3D printing of polymeric biomaterials has emerged as a promising approach for the fabrication of complex tissue engineering constructs. However, the large pore and feature size lead to low cell seeding efficiency and limited control of spatial distribution of cells within the scaffolds. We developed hybrid scaffolds that are composed of 3D printed layers and airbrushed fibrous membranes. Airbrushing time was adjusted to fabricate low (L), medium (M), and high (H) density membranes to effectively control stem cell infiltration. When two distinct populations of stem cells were seeded from top or bottom of the scaffolds, scaffolds composed of LLL membranes showed gradual mixing of the cells with depth whereas LHL membranes led to two distinct regions of cells separated by the H membrane. Our results demonstrate that fibrous membranes incorporated within 3D printed layers enable user-defined and spatially controlled cell compositions within hybrid scaffolds.

scholarly journals Agent-Based Deterministic Modeling of the Bone Marrow Homeostasis

2016 ◽  
Vol 2016 ◽  
pp. 1-12
Author(s):  
Manish Kurhekar ◽  
Umesh Deshpande
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Deterministic Model ◽  
Model Parameters ◽  
Agent Based Simulation ◽  
Hematopoietic Stem ◽  
Agent Based ◽  
Differentiated Cells ◽  
Stem Cell Populations

Modeling of stem cells not only describes but also predicts how a stem cell’s environment can control its fate. The first stem cell populations discovered were hematopoietic stem cells (HSCs). In this paper, we present a deterministic model of bone marrow (that hosts HSCs) that is consistent with several of the qualitative biological observations. This model incorporates stem cell death (apoptosis) after a certain number of cell divisions and also demonstrates that a single HSC can potentially populate the entire bone marrow. It also demonstrates that there is a production of sufficient number of differentiated cells (RBCs, WBCs, etc.). We prove that our model of bone marrow is biologically consistent and it overcomes the biological feasibility limitations of previously reported models. The major contribution of our model is the flexibility it allows in choosing model parameters which permits several different simulations to be carried out in silico without affecting the homeostatic properties of the model. We have also performed agent-based simulation of the model of bone marrow system proposed in this paper. We have also included parameter details and the results obtained from the simulation. The program of the agent-based simulation of the proposed model is made available on a publicly accessible website.

335 GENE THERAPEUTIC EFFECT OF ENGINEERED STEM CELLS EXPRESSING CYTOSINE DEAMINASE AND INTERFERON-B AGAINST ENDOMETRIAL CANCER IN A XENOGRAFT MOUSE MODEL

2015 ◽  
Vol 27 (1) ◽  
pp. 256
Author(s):  
B.-R. Yi ◽  
K.-C. Choi
Keyword(s):  
Stem Cells ◽  
Endometrial Cancer ◽  
Stem Cell ◽  
Therapeutic Effect ◽  
Tumour Growth ◽  
Cytosine Deaminase ◽  
Scid Mice ◽  
Tumour Mass ◽  
Rt Pcr ◽  
Ishikawa Cells

To generate an animal model of endometrial cancer, Ishikawa cells (2 × 106 cells) were implanted via subcutaneous injection into SCID mice. In order to evaluate the therapeutic effect on tumour growth, human neural stem cells (HB1.F3), transduced with genes expressing cytosine deaminase (CD) and interferon-β (IFN-b), were labelled with the membrane dye stained with CM-DiI and were injected nearby into the tumour masses (250 mm3) in these SCID mice (n = 24). Two days after stem cell injections, 5-fluorocytosine (5-FC) was intraperitoneally injected (500 mg kg–1 per day) for 14 consecutive days. Mice were sacrificed at 48 h after the last treatment with 5-FC delivered by intraperitoneal injection for 14 days. Results demonstrated that tumour mass growth in mice treated with stem cells and 5-FC was significantly inhibited (450 mm3 ± 52) in comparison to that of nontreated mice (1400 mm3 ± 124; P < 0.01). We confirmed that injected stem cells migrated to the tumour masses by visualising the red-coloured cells in the endometrial cancer masses. The RT-PCR analysis showed that the VEGF gene was highly expressed in endometrial cancer cells, while migration-induced uPA, SDF-1, SCF, MCP-1, IL-6, and IL-8 genes were moderately expressed in these tumour cells. Histological analysis of tumour masses showed that the aggressive nature of endometrial tumour masses, determined by labelled stem cells, was inhibited in treated mice. A further analysis showed that expression of proliferating nuclear antigen (PCNA) was significantly decreased in tumour masses from treated mice. To evaluate the effect of 5-FU on Ishikawa cells, 5-FU (1.0 mg mL–1) was added to in vitro-cultured cells and the levels of IFN-a/b receptor 2 (IFNAR2) and BAX, a proapoptotic genes, were detected by RT-PCR. In these cells, IFNAR2 and BAX genes were significantly increased by the addition of 5-FU. Taken together, these results indicate that co-expression of CD and IFN-b significantly inhibited the growth of endometrial tumour masses in the presence of 5-FC, and 5-FU and IFN-b inhibits tumour growth by inhibition of DNA synthesis and enhancing the apoptotic cascade, respectively. We provide evidence to support the efficacy of therapeutic stem cell-based immuno-therapy involving the targeted expression of CD and IFN-b genes at endometrial cancer sites.This work was supported by a National Research Foundation of Korea (NRF) grant (2013R1A1A2059092) funded by the Ministry of Education, Science and Technology (MEST) of the Republic of Korea government.

57 Primordial germ cell distribution in the horse fetal gonad

2020 ◽  
Vol 32 (2) ◽  
pp. 154
Author(s):  
D. Scarlet ◽  
U. Reichart ◽  
G. Podico ◽  
R. Ellerbrock ◽  
I. Canisso ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Germ Cell ◽  
Primordial Germ Cell ◽  
Temporal Distribution ◽  
Germline Stem Cell ◽  
Female Gonad ◽  
Specific Marker ◽  
Cortical Region ◽  
Germ Cell Differentiation

Germ cell development and differentiation is a complex process associated with down-regulation of stem cell-associated genes and up-regulation of markers of germ cell differentiation and meiosis. In horses, putative primordial germ cells (PGCs) were identified outside the gonads starting 20 days after ovulation (Curran et al. 1997 Equine Vet. J. Suppl. 25, 72-76). However, no information is available after the time when these cells enter the gonad. The aim of this study was to identify, localise, and quantify PGCs in fetal male and female gonads. Twelve (5 males and 7 females) equine fetuses were collected transcervically 60 days after ovulation. Fetuses were entirely fixed in formaldehyde and gonads were subsequently localised. Fetal gonads underwent multiplex immunofluorescence staining for pre-meiotic germ cell marker LIN28, stem-cell associated marker CD117, and cell proliferation marker Ki67. Specificity of the primary antibodies for equine samples has been first validated. Quantification of fluorescence positive areas for LIN28, CD117, and Ki67 in the fetal gonads was done using a macro for ImageJ. Furthermore, we analysed the co-localization of above-mentioned markers using the same macro. Statistical comparison for differences between males and females was performed using non-parametric tests. In both sexes, PGCs proliferated as determined by double immunofluorescence of Ki67 and LIN28. Protein expression of LIN28 and Ki67 was highly correlated (r=0.92; P=0.003). In the fetal female gonad, PGCs were organised in cord-like structures localised in the cortical region, but there were also LIN28+ cells in the surface germinal epithelium. In the fetal male gonad, PGCs were restricted to the already developed tubular structures. Fewer LIN28+ cells (3.0±0.4% vs. 4.5±0.3%; P&lt;0.05) were present in female than in male gonads. The distribution pattern of the stem cell factor receptor CD117 was similar to LIN28, as 86.8±3.2% of LIN28+ cells in females and 84.6±4.7% in males were also CD117+. However, immunofluorescent co-localization analysis revealed a subpopulation of CD117+ cells (43.1±8.1% in females and 46.1±6.1% in males), which did not show an overlap with LIN28. These were presumably stem cells localised in the medullar area of the gonad. In summary, we analysed for the first time spatial distribution of PGCs in fetal equine gonads. We demonstrated LIN28 to be a specific marker for PGCs also in the horse gonad, which is in agreement with the situation in human and other species. Furthermore, we identified stem cells and described their localization in the fetal equine gonad. Nevertheless, the temporal distribution of PGC and stem cells in the developing horse gonad and the role of LIN28 in the maintenance of the germline stem cell state still need to be investigated.

scholarly journals Predicting pattern formation in embryonic stem cells using a minimalist, agent-based probabilistic model

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Minhong Wang ◽  
Athanasios Tsanas ◽  
Guillaume Blin ◽  
Dave Robertson
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Pattern Formation ◽  
Embryonic Stem ◽  
Agent Based ◽  
Agent Based Modelling ◽  
Random Models ◽  
The Many ◽  
Modelling Approach

Abstract The mechanisms of pattern formation during embryonic development remain poorly understood. Embryonic stem cells in culture self-organise to form spatial patterns of gene expression upon geometrical confinement indicating that patterning is an emergent phenomenon that results from the many interactions between the cells. Here, we applied an agent-based modelling approach in order to identify plausible biological rules acting at the meso-scale within stem cell collectives that may explain spontaneous patterning. We tested different models involving differential motile behaviours with or without biases due to neighbour interactions. We introduced a new metric, termed stem cell aggregate pattern distance (SCAPD) to probabilistically assess the fitness of our models with empirical data. The best of our models improves fitness by 70% and 77% over the random models for a discoidal or an ellipsoidal stem cell confinement respectively. Collectively, our findings show that a parsimonious mechanism that involves differential motility is sufficient to explain the spontaneous patterning of the cells upon confinement. Our work also defines a region of the parameter space that is compatible with patterning. We hope that our approach will be applicable to many biological systems and will contribute towards facilitating progress by reducing the need for extensive and costly experiments.

Germ cell tumour growth patterns originating from clear cell carcinomas of the ovary and endometrium: a comparative immunohistochemical study favouring their origin from somatic stem cells

2017 ◽  
Vol 72 (4) ◽  
pp. 634-647 ◽  
Author(s):  
Francisco F Nogales ◽  
Jaime Prat ◽  
Maolly Schuldt ◽  
Nelly Cruz-Viruel ◽  
Baljeet Kaur ◽  
...  
Keyword(s):  
Stem Cells ◽  
Germ Cell ◽  
Tumour Growth ◽  
Clear Cell ◽  
Immunohistochemical Study ◽  
Germ Cell Tumour ◽  
Growth Patterns ◽  
Cell Tumour ◽  
Somatic Stem Cells
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