208 research outputs found
On interfaces between cell populations with different mobilities
Partial differential equations describing the dynamics of cell population densities from a fluid mechanical perspective can model the growth of avascular tumours. In this framework, we consider a system of equations that describes the interaction between a population of dividing cells and a population of non-dividing cells. The two cell populations are characterised by different mobilities. We present the results of numerical simulations displaying two-dimensional spherical waves with sharp interfaces between dividing and non-dividing cells. Furthermore, we numerically observe how different ratios between the mobilities change the morphology of the interfaces, and lead to the emergence of finger-like patterns of invasion above a threshold. Motivated by these simulations, we study the existence of one-dimensional travelling wave solutions
Modeling the Effects of Space Structure and Combination Therapies on Phenotypic Heterogeneity and Drug Resistance in Solid Tumors
Histopathological evidence supports the idea that the emergence of phenotypic heterogeneity and resistance to cytotoxic drugs can be considered as a process of selection in tumor cell populations. In this framework, can we explain intra-tumor heterogeneity in terms of selection driven by the local cell environment? Can we overcome the emergence of resistance and favor the eradication of cancer cells by using combination therapies? Bearing these questions in mind, we develop a model describing cell dynamics inside a tumor spheroid under the effects of cytotoxic and cytostatic drugs. Cancer cells are assumed to be structured as a population by two real variables standing for space position and the expression level of a phenotype of resistance to cytotoxic drugs. The model takes explicitly into account the dynamics of resources and anticancer drugs as well as their interactions with the cell population under treatment. We analyze the effects of space structure and combination therapies on phenotypic heterogeneity and chemotherapeutic resistance. Furthermore, we study the efficacy of combined therapy protocols based on constant infusion and bang–bang delivery of cytotoxic and cytostatic drugs
Populational adaptive evolution, chemotherapeutic resistance and multiple anti-cancer therapies
Resistance to chemotherapies, particularly to anticancer treatments, is an increasing medical concern. Among the many mechanisms at work in cancers, one of the most important is the selection of tumor cells expressing resistance genes or phenotypes. Motivated by the theory of mutation-selection in adaptive evolution, we propose a model based on a continuous variable that represents the expression level of a resistance gene (or genes, yielding a phenotype) influencing in healthy and tumor cells birth/death rates, effects of chemotherapies (both cytotoxic and cytostatic) and mutations. We extend previous work by demonstrating how qualitatively different actions of chemotherapeutic and cytostatic treatments may induce different levels of resistance. The mathematical interest of our study is in the formalism of constrained Hamilton-Jacobi equations in the framework of viscosity solutions. We derive the long-term temporal dynamics of the fittest traits in the regime of small mutations. In the context of adaptive cancer management, we also analyse whether an optimal drug level is better than the maximal tolerated dose. © EDP Sciences, SMAI, 2013
Micro-Capsules in Shear Flow
This paper deals with flow-induced shape transitions of elastic capsules. The
state of the art concerning both theory and experiments is briefly reviewed
starting with dynamically induced small deformation of initially spherical
capsules and the formation of wrinkles on polymerized membranes. Initially
non-spherical capsules show tumbling and tank-treading motion in shear flow.
Theoretical descriptions of the transition between these two types of motion
assuming a fixed shape are at variance with the full capsule dynamics obtained
numerically. To resolve the discrepancy, we expand the exact equations of
motion for small deformations and find that shape changes play a dominant role.
We classify the dynamical phase transitions and obtain numerical and analytical
results for the phase boundaries as a function of viscosity contrast, shear and
elongational flow rate. We conclude with perspectives on timedependent flow, on
shear-induced unbinding from surfaces, on the role of thermal fluctuations, and
on applying the concepts of stochastic thermodynamics to these systems.Comment: 34 pages, 15 figure
Emergence of Anti-Cancer Drug Resistance: Exploring the Importance of the Microenvironmental Niche via a Spatial Model
Practically, all chemotherapeutic agents lead to drug resistance. Clinically,
it is a challenge to determine whether resistance arises prior to, or as a
result of, cancer therapy. Further, a number of different intracellular and
microenvironmental factors have been correlated with the emergence of drug
resistance. With the goal of better understanding drug resistance and its
connection with the tumor microenvironment, we have developed a hybrid
discrete-continuous mathematical model. In this model, cancer cells described
through a particle-spring approach respond to dynamically changing oxygen and
DNA damaging drug concentrations described through partial differential
equations. We thoroughly explored the behavior of our self-calibrated model
under the following common conditions: a fixed layout of the vasculature, an
identical initial configuration of cancer cells, the same mechanism of drug
action, and one mechanism of cellular response to the drug. We considered one
set of simulations in which drug resistance existed prior to the start of
treatment, and another set in which drug resistance is acquired in response to
treatment. This allows us to compare how both kinds of resistance influence the
spatial and temporal dynamics of the developing tumor, and its clonal
diversity. We show that both pre-existing and acquired resistance can give rise
to three biologically distinct parameter regimes: successful tumor eradication,
reduced effectiveness of drug during the course of treatment (resistance), and
complete treatment failure
Mouse p53-deficient cancer models as platforms for obtaining genomic predictors of human cancer clinical outcomes
Mutations in the TP53 gene are very common in human cancers, and are associated with poor clinical outcome. Transgenic mouse models lacking the Trp53 gene or that express mutant Trp53 transgenes produce tumours with malignant features in many organs. We previously showed the transcriptome of a p53-deficient mouse skin carcinoma model to be similar to those of human cancers with TP53 mutations and associated with poor clinical outcomes. This report shows that much of the 682-gene signature of this murine skin carcinoma transcriptome is also present in breast and lung cancer mouse models in which p53 is inhibited. Further, we report validated gene-expression-based tests for predicting the clinical outcome of human breast and lung adenocarcinoma. It was found that human patients with cancer could be stratified based on the similarity of their transcriptome with the mouse skin carcinoma 682-gene signature. The results also provide new targets for the treatment of p53-defective tumours
Influence of shear flow on vesicles near a wall: a numerical study
We describe the dynamics of three-dimensional fluid vesicles in steady shear
flow in the vicinity of a wall. This is analyzed numerically at low Reynolds
numbers using a boundary element method. The area-incompressible vesicle
exhibits bending elasticity. Forces due to adhesion or gravity oppose the
hydrodynamic lift force driving the vesicle away from a wall. We investigate
three cases. First, a neutrally buoyant vesicle is placed in the vicinity of a
wall which acts only as a geometrical constraint. We find that the lift
velocity is linearly proportional to shear rate and decreases with increasing
distance between the vesicle and the wall. Second, with a vesicle filled with a
denser fluid, we find a stationary hovering state. We present an estimate of
the viscous lift force which seems to agree with recent experiments of Lorz et
al. [Europhys. Lett., vol. 51, 468 (2000)]. Third, if the wall exerts an
additional adhesive force, we investigate the dynamical unbinding transition
which occurs at an adhesion strength linearly proportional to the shear rate.Comment: 17 pages (incl. 10 figures), RevTeX (figures in PostScript
Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy
<p>Abstract</p> <p>Background</p> <p>The epidermal specific ablation of <it>Trp53 </it>gene leads to the spontaneous development of aggressive tumors in mice through a process that is accelerated by the simultaneous ablation of <it>Rb </it>gene. Since alterations of p53-dependent pathway are common hallmarks of aggressive, poor prognostic human cancers, these mouse models can recapitulate the molecular features of some of these human malignancies.</p> <p>Results</p> <p>To evaluate this possibility, gene expression microarray analysis was performed in mouse samples. The mouse tumors display increased expression of cell cycle and chromosomal instability associated genes. Remarkably, they are also enriched in human embryonic stem cell gene signatures, a characteristic feature of human aggressive tumors. Using cross-species comparison and meta-analytical approaches, we also observed that spontaneous mouse tumors display robust similarities with gene expression profiles of human tumors bearing mutated TP53, or displaying poor prognostic outcome, from multiple body tissues. We have obtained a 20-gene signature whose genes are overexpressed in mouse tumors and can identify human tumors with poor outcome from breast cancer, astrocytoma and multiple myeloma. This signature was consistently overexpressed in additional mouse tumors using microarray analysis. Two of the genes of this signature, AURKA and UBE2C, were validated in human breast and cervical cancer as potential biomarkers of malignancy.</p> <p>Conclusions</p> <p>Our analyses demonstrate that these mouse models are promising preclinical tools aimed to search for malignancy biomarkers and to test targeted therapies of prospective use in human aggressive tumors and/or with p53 mutation or inactivation.</p
Interactions between proteins bound to biomembranes
We study a physical model for the interaction between general inclusions
bound to fluid membranes that possess finite tension, as well as the usual
bending rigidity. We are motivated by an interest in proteins bound to cell
membranes that apply forces to these membranes, due to either entropic or
direct chemical interactions. We find an exact analytic solution for the
repulsive interaction between two similar circularly symmetric inclusions. This
repulsion extends over length scales of order tens of nanometers, and contrasts
with the membrane-mediated contact attraction for similar inclusions on
tensionless membranes. For non circularly symmetric inclusions we study the
small, algebraically long-ranged, attractive contribution to the force that
arises. We discuss the relevance of our results to biological phenomena, such
as the budding of caveolae from cell membranes and the striations that are
observed on their coats.Comment: 22 pages, 2 figure
- …