Both compressible and incompressible porous medium models are used in the literature to describe the mechanical properties of living tissues. These two classes of models can be related using a stiff pressure law. In the incompressible limit, the compressible model generates a free boundary problem of Hele-Shaw type where incompressibility holds in the saturated phase. Here we consider the case with a nutrient. Then, a badly coupled system of equations describes the cell density number and the nutrient concentration. For that reason, the derivation of the free boundary (incompressible) limit was an open problem, in particular a difficulty is to establish the so-called complementarity relation which allows to recover the pressure using an elliptic equation. To establish the limit, we use two new ideas. The first idea, also used recently for related problems, is to extend the usual Aronson-Bénilan estimates in $L^\infty$ to an $L^2$ setting. The second idea is to derive a sharp uniform $L^4$ estimate on the pressure gradient, independently of space dimension.
In this paper, we study a tumor growth model with nutrients. The contact inhibition for the tumor cells, presented in the model, results in the evolution of a congested tumor patch. We study the regularity of the tumor patch as the nutrients' diffusion strength $D$ diminishes. In particular, we show that for small $D>0$ the boundary of the tumor patch stays in a small neighborhood of the smooth tumor patch boundary obtained with $D=0$, uniformly with respect to the Hausdorff distance.
In this paper we study a tumor growth model with nutrients. The model presents dynamic patch solutions due to the contact inhibition among the tumor cells. We show that when the nutrients do not diffuse and the cells do not die, the tumor density exhibits regularizing dynamics. In particular, we provide contraction estimates, exponential rate of asymptotic convergence, and boundary regularity of the tumor patch. These results are in sharp contrast to the models either with nutrient diffusion or with death rate in tumor cells.
In this paper, we consider a free boundary problem modeling the growth of spherically symmetric necrotic tumors with angiogenesis and a $ω$-periodic supply $ϕ(t)$ of external nutrients. In the model, the consumption rate of the nutrient and the proliferation rate of tumor cells $S(σ)$ are both general nonlinear functions. The well-posedness and asymptotic behavior of solutions are studied. We show that if the average of $S(ϕ(t))$ is nonpositive, then all evolutionary tumors will finally vanish; the converse is also ture. If instead the average of $S(ϕ(t))$ is positive, then there exists a uniq…
Several mathematical models of tumor growth are now commonly used to explain medical observations and predict cancer evolution based on images. These models incorporate mechanical laws for tissue compression combined with rules for nutrients availability which can differ depending on the situation under consideration, in vivo or in vitro. Numerical solutions exhibit, as expected from medical observations, a proliferative rim and a necrotic core. However, their precise profiles are rather complex, both in one and two dimensions.
For tumor growth, the morphological instability provides a mechanism for invasion via tumor fingering and fragmentation. This work considers the asymptotic stability of a free boundary tumor model with a periodic supply of external nutrients. The model consists of two elliptic equations describing the concentration of nutrients and the distribution of the internal pressure in the tumor tissue, respectively. The effect of the parameter $μ$ representing a measure of mitosis on the morphological stability are taken into account. It was recently established in [25] that there exists a critical val…
In this paper, we consider a multi-layer tumor model with a periodic provision of external nutrients. The domain occupied by tumor has a different shape (flat shape) than spherical shape which has been studied widely. The important parameters are periodic external nutrients $Φ(t)$ and threshold concentration for proliferation $\widetildeσ$. In this paper, we give a complete classification about $Φ(t)$ and $\widetildeσ$ according to global stability of zero equilibrium solution or global stability of the positive periodic solution. Precisely, if $\frac{1}{T} \int_{0}^{T} Φ(t)d t\leqslant\wideti…
We consider the problem of the long time dynamics for a diffuse interface model for tumor growth. The model describes the growth of a tumor surrounded by host tissues in the presence of a nutrient and consists in a Cahn-Hilliard-type equation for the tumor phase coupled with a reaction-diffusion equation for the nutrient concentration. We prove that, under physically motivated assumptions on parameters and data, the corresponding initial-boundary value problem generates a dissipative dynamical system that admits the global attractor in a proper phase space.
We propose a diffuse interface model to describe tumor as a multicomponent deformable porous medium. We include mechanical effects in the model by coupling the mass balance equations for the tumor species and the nutrient dynamics to a mechanical equilibrium equation with phase-dependent elasticity coefficients. The resulting PDE system couples two Cahn--Hilliard type equations for the tumor phase and the healthy phase with a PDE linking the evolution of the interstitial fluid to the pressure of the system, a reaction-diffusion type equation for the nutrient proportion, and a quasistatic momen…
We introduce here a new diffuse interface thermodynamically consistent non-isothermal model for tumor growth in presence of a nutrient in a domain $Ω\subset \mathbb{R}^3$. In particular our system describes the growth of a tumor surrounded by healthy tissues, taking into account changes of temperature, proliferation of cells, nutrient consumption and apoptosis. Our aim consists in proving an existence result for weak entropy solutions to our model.
In this paper, we present a rigorous mathematical analysis of a free boundary problem modeling the growth of a vascular solid tumor with a necrotic core. If the vascular system supplies the nutrient concentration $σ$ to the tumor at a rate $β$, then $\frac{\partialσ}{\partial\bf n}+β(σ-\barσ)=0$ holds on the tumor boundary, where $\bf n$ is the unit outward normal to the boundary and $\barσ$ is the nutrient concentration outside the tumor. The living cells in the nonnecrotic region proliferate at a rate $μ$. We show that for any given $ρ>0$, there exists a unique $R\in(ρ,\infty)$ such that the…
We investigate the dynamics of a nonlinear system modeling tumor growth with drug application. The tumor is viewed as a mixture consisting of proliferating, quiescent and dead cells as well as a nutrient in the presence of a drug. The system is given by a multi-phase flow model: the densities of the different cells are governed by a set of transport equations, the density of the nutrient and the density of the drug are governed by rather general diffusion equations, while the velocity of the tumor is given by Darcy's equation. The domain occupied by the tumor in this setting is a growing conti…
We study a free boundary problem modeling tumor growth with a T-periodic supply $Φ(t)$ of external nutrients. The model contains two parameters $μ$ and $\widetildeσ$. We first show that (i) zero radially symmetric solution is globally stable if and only if $\widetildeσ\ge \frac{1}{T} \int_{0}^{T} Φ(t) d t$; (ii) If $\widetildeσ<\frac{1}{T} \int_{0}^{T} Φ(t) d t$, then there exists a unique radially symmetric positive solution $\left(σ_{*}(r, t), p_{*}(r, t), R_{*}(t)\right)$ with period $T$ and it is a global attractor of all positive radially symmetric solutions for all $μ>0$. These results a…
We present and analyze new multi-species phase-field mathematical models of tumor growth and ECM invasion. The local and nonlocal mathematical models describe the evolution of volume fractions of tumor cells, viable cells (proliferative and hypoxic cells), necrotic cells, and the evolution of MDE and ECM, together with chemotaxis, haptotaxis, apoptosis, nutrient distribution, and cell-to-matrix adhesion. We provide a rigorous proof of the existence of solutions of the coupled system with gradient-based and adhesion-based haptotaxis effects. In addition, we discuss finite element discretization…
Analysis and computation of some tumor growth models with nutrient: from cell density models to free boundary dynamics
Duke University（杜克大学）；School of Mathematics and Institute of Natural Sciences, MOE-LSC, Shanghai JiaoTong University（上海交通大学数学学院与自然科学研究院）；Department of Mathematics, Computational and Data-Enabled Science and Engineering Program, State University of New York at Buffalo（纽约州立大学布法罗分校数学系、计算与数据驱动科学与工程计划）；Beijing International Center for Mathematical Research, Peking University（北京大学北京国际数学研究中心）
In this paper we study a free boundary problem modeling the growth of solid tumor spheroid. It consists of two elliptic equations describing nutrient diffusion and pressure distribution within tumor, respectively. The new feature is that nutrient concentration on the boundary is less than external supply due to a Gibbs-Thomson relation and the problem has two radial stationary solutions, which differs from widely studied tumor spheroid model with surface tension effect. We first establish local well-posedness by using a functional approach based on Fourier multiplier method and analytic semigr…
We extend previous weak well-posedness results obtained in Frigeri et al. (2017) concerning a non-local variant of a diffuse interface tumor model proposed by Hawkins-Daarud et al. (2012). The model consists of a non-local Cahn--Hilliard equation with degenerate mobility and singular potential for the phase field variable, coupled to a reaction-diffusion equation for the concentration of a nutrient. We prove the existence of strong solutions to the model and establish some high order continuous dependence estimates, even in the presence of concentration-dependent mobilities for the nutrient va…
We investigate the dynamics of a nonlinear system modeling tumor growth with drug application. The tumor is viewed as a mixture consisting of proliferating, quiescent and dead cells as well as a nutrient in the presence of a drug. The system is given by a multi-phase flow model: the densities of the different cells are governed by a set of transport equations, the density of the nutrient and the density of the drug are governed by rather general diffusion equations, while the velocity of the tumor is given by Brinkman's equation. The domain occupied by the tumor in this setting is a growing co…
We consider a diffuse interface model for tumor growth consisting of a Cahn--Hilliard equation with source terms coupled to a reaction-diffusion equation, which models a tumor growing in the presence of a nutrient species and surrounded by healthy tissue. The well-posedness of the system equipped with Neumann boundary conditions was found to require regular potentials with quadratic growth. In this work, Dirichlet boundary conditions are considered, and we establish the well-posedness of the system for regular potentials with higher polynomial growth and also for singular potentials. New diffi…
Existence and uniqueness of solutions for a class of models for stress-modulated growth is proven in one spatial dimension. The model features the multiplicative decomposition of the deformation gradient $F$ into an elastic part $F_e$ and a growth-related part $G$. After the transformation due to the growth process, governed by $G$, an elastic deformation described by $F_e$ is applied in order to restore the Dirichlet boundary conditions and therefore the current configuration might be stressed with a stress tensor $S$. The growth of the material at each point in the reference configuration is…
We propose a new type of diffuse interface model describing the evolution of a tumor mass under the effects of a chemical substance (e.g., a nutrient or a drug). The process is described by utilizing the variables $φ$, an order parameter representing the local proportion of tumor cells, and $σ$, representing the concentration of the chemical. The order parameter $φ$ is assumed to satisfy a suitable form of the Cahn-Hilliard equation with mass source and logarithmic potential of Flory-Huggins type (or generalizations of it). The chemical concentration $σ$ satisfies a reaction-diffusion equation…
This paper is concerned with a nonlinear free boundary problem modeling the growth of spherically symmetric tumors with angiogenesis, set with a Robin boundary condition. In which, both nonnecrotic tumors and necrotic tumors are taken into consideration. The well-posedness and asymptotic behavior of solutions are studied. It is shown that there exist two thresholds, denoted by $\tildeσ$ and $σ^*$, on the surrounding nutrient concentration $\barσ$. If $\barσ\leq\tildeσ$, then the considered problem admits no stationary solution and all evolutionary tumors will finally vanish, while if $\barσ>\t…
We consider a phase-field model of prostate cancer growth with chemotherapy and antiangiogenic therapy effects which is introduced in [2]. It is comprised of phase-field equation to describe tumor growth, which is coupled to a reaction-diffusion type equation for generic nutrient for the tumor. An additional equation couples the concentration of prostate-specific antigen (PSA) in the prostatic tissue and it obeys a linear reaction-diffusion equation. The system completes with homogeneous Dirichlet boundary conditions for the tumor variable and Neuman boundary condition for the nutrient and the…
In this paper, we study a distributed optimal control problem for a diffuse interface model for tumor growth. The model consists of a Cahn-Hilliard type equation for the phase field variable coupled to a reaction diffusion equation for the nutrient and a Brinkman type equation for the velocity. The system is equipped with homogeneous Neumann boundary conditions for the tumor variable and the chemical potential, Robin boundary conditions for the nutrient and a "no-friction" boundary condition for the velocity. The control acts as a medication by cytotoxic drugs and enters the phase field equati…
We study a free boundary problem modelling the growth of non-necrotic tumors with fluid-like tissues. The fluid velocity satisfies Stokes equations with a source determined by the proliferation rate of tumor cells which depends on the concentration of nutrients, subject to a boundary condition with stress tensor effected by surface tension. It is easy to prove that this problem has a unique radially symmetric stationary solution. By using a functional approach, we prove that there exists a threshold value $γ_*>0$ for the surface tension coefficient $γ$, such that in the case $γ>γ_*$ this radia…
In the present contribution we study the sliding mode control (SMC) problem for a diffuse interface tumor growth model coupling a viscous Cahn-Hilliard type equation for the phase variable with a reaction-diffusion equation for the nutrient. First, we prove the well-posedness and some regularity results for the state system modified by the state-feedback control law. Then, we show that the chosen SMC law forces the system to reach within finite time the sliding manifold (that we chose in order that the tumor phase remains constant in time). The feedback control law is added in the Cahn-Hilliar…
In this paper, we establish a reaction-diffusion-advection partial differential equation model to describe the growth of algae depending on both nutrients and inorganic carbon in a poorly mixed water column. Nutrients from the water bottom and inorganic carbon from the water surface form an asymmetric resource supply mechanism on the algal growth. The existence and stability of semi-trivial steady state and coexistence steady state of the model are proved, and a threshold condition for the regime shift from extinction to survival of algae is established. The influence of environmental paramete…
Models of tumor growth, now commonly used, present several levels of complexity, both in terms of the biomedical ingredients and the mathematical description. The simplest ones contain competition for space using purely fluid mechanical concepts. Another possible ingredient is the supply of nutrients through vasculature. The models can describe the tissue either at the level of cell densities, or at the scale of the solid tumor, in this latter case by means of a free boundary problem. Our first goal here is to formulate a free boundary model of Hele-Shaw type, a variant including growth terms,…
In this paper, we study a distributed optimal control problem for a diffuse interface model for tumor growth. The model consists of a Cahn-Hilliard type equation for the phase field variable coupled to a reaction diffusion equation for the nutrient and a Brinkman type equation for the velocity. The system is equipped with homogeneous Neumann boundary conditions for the tumor variable, the chemical potential and the nutrient as well as a "no-friction" boundary condition for the velocity. The control acts as a medication by cytotoxic drugs and enters the phase field equation. The cost functional…
In this contribution, the non-local, integro-partial differential system of equations proposed by Hillen et al. (Bull. Math. Biol. 75, 2013, no.1, 161-184) to account for the the tumor growth paradox (or the observation that some incomplete cancer treatments may enhance tumor growth) is reviewed. It is shown that when cancer cells' diffusion effects and Neumann boundary conditions are taken into consideration, the same paradoxical tumor growth emerges.
In this paper, we study a free boundary problem modeling solid tumor growth with vasculature which supplies nutrients to the tumor; this is characterized in the Robin boundary condition. It was recently established [Discrete Cont. Dyn. Syst. 39 (2019) 2473-2510] that for this model, there exists a threshold value $μ^\ast$ such that the unique radially symmetric stationary solution is linearly stable under non-radial perturbations for $0<μ<μ^\ast$ and linearly unstable for $μ>μ^\ast$. In this paper we further study the nonlinear stability of the radially symmetric stationary solution, which int…
In this paper, we consider a model with tumor microenvironment involving nutrient density, extracellular matrix and matrix-degrading enzymes, which satisfy a coupled system of PDEs with a free boundary. For this coupled parabolic-hyperbolic free boundary problem, we prove that there is a unique radially symmetric solution globally in time. The stationary problem involves an ODE system which is transformed into a singular integro-differential equation. We establish a well-posed theorem for such general types of equations by the shooting method; the theorem is then applied to our problem for the…
We study a free boundary problem modeling multi-layer tumor growth with a small time delay $τ$, representing the time needed for the cell to complete the replication process. The model consists of two elliptic equations which describe the concentration of nutrient and the tumor tissue pressure, respectively, an ordinary differential equation describing the cell location characterizing the time delay and a partial differential equation for the free boundary. In this paper we establish the well-posedness of the problem, namely, first we prove that there exists a unique flat stationary solution $…
In this paper, a distributed optimal control problem is studied for a diffuse interface model of tumor growth which was proposed in [A. Hawkins-Daruud, K.G. van der Zee, J.T. Oden, Numerical simulation of a thermodynamically consistent four-species tumor growth model, Int. J. Numer. Math. Biomed. Engng. 28 (2011), 3-24]. The model consists of a Cahn-Hilliard equation for the tumor cell fraction coupled to a reaction-diffusion equation for a variable representing the nutrient-rich extracellular water volume fraction. The distributed control monitors as a right-hand side the reaction-diffusion e…
We consider a particular phase field system which physical context is that of tumor growth dynamics. The model we deal with consists of a Cahn-Hilliard type equation governing the evolution of the phase variable which takes into account the tumor cells proliferation in the tissue coupled with a reaction-diffusion equation for the nutrient. This model has already been investigated from the viewpoint of well-posedness, long time behavior, and asymptotic analyses as some parameters go to zero. Starting from these results, we aim to face a related optimal control problem by employing suitable asym…
We study a model introduced by Perthame and Vauchelet that describes the growth of a tumor governed by Brinkman's Law, which takes into account friction between the tumor cells. We adopt the viscosity solution approach to establish an optimal uniform convergence result of the tumor density as well as the pressure in the incompressible limit. The system lacks standard maximum principle, and thus modification of the usual approach is necessary.
We study a tumor growth model in two space dimensions, where proliferation of the tumor cells leads to expansion of the tumor domain and migration of surrounding normal tissues into the exterior vacuum. The model features two moving interfaces separating the tumor, the normal tissue, and the exterior vacuum. We prove local-in-time existence and uniqueness of strong solutions for their evolution starting from a nearly radial initial configuration. It is assumed that the tumor has lower mobility than the normal tissue, which is in line with the well-known Saffman-Taylor condition in viscous fing…
In this paper a macroscopic model of tumor cord growth is developed, relying on the mathematical theory of deformable porous media. Tumor is modeled as a saturated mixture of proliferating cells, extracellular fluid and extracellular matrix, that occupies a spatial region close to a blood vessel whence cells get the nutrient needed for their vital functions. Growth of tumor cells takes place within a healthy host tissue, which is in turn modeled as a saturated mixture of non-proliferating cells. Interactions between these two regions are accounted for as an essential mechanism for the growth o…
We investigate the dynamics of a nonlinear model for tumor growth within a cellular medium. In this setting the "tumor" is viewed as a multiphase flow consisting of cancerous cells in either proliferating phase or quiescent phase and a collection of cells accounting for the "waste" and/or dead cells in the presence of a nutrient. Here, the tumor is thought of as a growing continuum $Ω$ with boundary $\partial Ω$ both of which evolve in time. The key characteristic of the present model is that the total density of cancerous cells is allowed to vary, which is often the case within cellular media…
In this paper we study the rigorous sharp interface limit of a diffuse interface model related to the dynamics of tumor growth, when a parameter $ε$, representing the interface thickness between the tumorous and non tumorous cells, tends to zero. More in particular, we analyze here a gradient-flow type model arising from a modification of the recently introduced model for tumor growth dynamics in [A. Hawkins-Daruud, K. G. van der Zee, J. T. Oden, Numerical simulation of a thermodynamically consistent four-species tumor growth model, Int. J. Numer. Math. Biomed. Engng. 28 (2011), 3--24.] (cf. a…
The present paper deals with a free boundary problem modeling the growth process of necrotic multi-layer tumors. We prove the existence of flat stationary solutions and determine the linearization of our model at such an equilibrium. Finally, we compute the solutions of the stationary linearized problem and comment on bifurcation.
