
In this paper, we study a time-delayed free boundary of tumor growth with Gibbs-Thomson relation in the presence of inhibitors. The model consists of two reaction diffusion equations and an ordinary differential equation. The reaction diffusion equations describe the nutrient and inhibitor diffusion within tumors and take into account the Gibbs-Thomson relation at the outer boundary of the tumor. The tumor radius evolution is described by the ordinary differential equation. It is assumed that the regulatory apoptosis process takes longer than the natural apoptosis and proliferation processes. We first show the existence and uniqueness of the solution to the model. Next, we further demonstrate the existence of the stationary solutions and the asymptotic behavior of the stationary solutions when the blood vessel density is a constant. Finally, we further demonstrate the existence of the stationary solutions and the asymptotic behavior of the stationary solutions when the blood vessel density is bounded. The result implies that, under certain conditions, the tumor will probably become dormant or will finally disappear. The conclusions are illustrated by numerical computations.
Citation: Huiyan Peng, Xuemei Wei. Qualitative analysis of a time-delayed free boundary problem for tumor growth with Gibbs-Thomson relation in the presence of inhibitors[J]. AIMS Mathematics, 2023, 8(9): 22354-22370. doi: 10.3934/math.20231140
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In this paper, we study a time-delayed free boundary of tumor growth with Gibbs-Thomson relation in the presence of inhibitors. The model consists of two reaction diffusion equations and an ordinary differential equation. The reaction diffusion equations describe the nutrient and inhibitor diffusion within tumors and take into account the Gibbs-Thomson relation at the outer boundary of the tumor. The tumor radius evolution is described by the ordinary differential equation. It is assumed that the regulatory apoptosis process takes longer than the natural apoptosis and proliferation processes. We first show the existence and uniqueness of the solution to the model. Next, we further demonstrate the existence of the stationary solutions and the asymptotic behavior of the stationary solutions when the blood vessel density is a constant. Finally, we further demonstrate the existence of the stationary solutions and the asymptotic behavior of the stationary solutions when the blood vessel density is bounded. The result implies that, under certain conditions, the tumor will probably become dormant or will finally disappear. The conclusions are illustrated by numerical computations.
The growth of the tumor is a very complicated phenomenon. In the last fifty years, a number of mathematical models have been proposed and studied from various angles to explain the growing process of tumors. In [1,2], Greenspan proposed and analyzed the non-vascularized solid tumor growth model under free boundary conditions. In 1995, Byrne and Chaplain proposed the following free boundary problem modeling tumor growth [3]:
c∂σ∂t=1r2∂∂r(r2∂σ∂r)+Γ(σB−σ)−λσ,0<r<R(t),t>0, |
∂σ∂r(0,t)=0,σ(R(t),t)=σR(t),t>0, |
dRdt=1R2∫R(t)0S(σ)r2dr,t>0, |
σ(R(t),t)=σR(t),σ(r,0)=σ0(r),0≤r≤R(0), |
R(0)=R0, |
which is called the Byrne-Chaplain tumor model, where σ is nutrient concentration, R(t) is the radius of the tumor and S(σ) denotes the cell proliferation rate within the tumor. Based on this model, many researchers have analyzed it from different perspectives and reached some conclusions about the well-posedness of the stationary solution, the existence and uniqueness of the solution and asymptotic behavior of global solution, which can be seen in the literature [4,5,6,7,8,9] and so on.
Moreover, numerous experiments show that tumor cell proliferation does not occur instantly and that it requires mitosis, a process that takes some time. Following this idea, Byrne established the following time-delayed avascular tumor growth model [10]:
0=1r2∂∂r(r2∂σ∂r)−Γσ,0<r<R(t),t>0, |
∂σ∂r=0,σ(R(t),t)=ˉσ,t>0, |
dR(t)dt=η(R(t),R(t−τ)),t>0, |
R(t)=φ(t),−τ≤t≤0, |
where σ is nutrient concentration, R(t) represents the radius of the tumor at time t, τ is a positive constant representing the time delay and the nonlinear smooth function η has a monotonic increase in the second variable. Cui and Xu studied the asymptotic behavior of mathematical model solutions for tumor growth with cell proliferation time delays in [11]. Xu and Feng [12] studied a mathematical model for tumor growth with a time delay in proliferation under the indirect influence of an inhibitor. Many researchers have taken an interest in the model and have published numerous research results about the well-posedness of the stationary solution, the existence and uniqueness of the solution and asymptotic behavior of global solution with the time-delays in [13,14,15,16].
In [17], the nutrients are hypothesized to be the energy needed to maintain the tightness of a tumor by cell-to-cell adhesion at the tumor boundary; thus, the nutrient concentration at the tumor boundary is smaller than the externally supplied nutrient concentration, and this difference satisfies the Gibbs-Thomson relation. However, Roose, Chapman and Maini [18] further found that tumor growth satisfied the modified Gibbs-Thomson relation, and the modified Gibbs-Thomson relation will be introduced in the following:
[∂σ∂r(r,t)+α(σ−N(t))]|r=R(t)=0, |
where N(t) fulfill the subsequent relationship
N(t)=ˉσ(1−γR(t))H(R(t)), |
where N(t) is induced by Gibbs-Thomson relation. H(⋅) is a smooth function on (0,∞), such that H(x)=0 if x≤γ, H(x)=1 if x≥2γ and 0≤H′(x)≤2/γ for all x≥0. Continuing with this thinking, Wu analyzed the effect of the Gibbs-Thomson relation on tumor growth with the external nutrient supply [19]. Others have researched the Gibbs-Thomson relation and drawn some conclusions about stationary solutions and asymptotic behavior of the solution, which can be found in [20,21].
Furthermore, the tumor will have a time delay during its growth, and the boundaries of the tumor model will also satisfy Gibbs-Thomson relation. Xu, Bai and Zhang [22] studied a free boundary problem for the growth of tumor with the Gibbs-Thomson relation and time delays. Xu and Wu [23] analyzed the problem of time-delayed free boundary of tumor growth with angiogenesis and the Gibbs-Thomson relation. Gaussian white noise is regarded as an inhibitor in [24,25,26]. At present, there is relatively limited research that considers a time-delayed free boundary of tumor growth with the Gibbs-Thomson relation, simultaneously. Hence, in this paper, we mostly examine how the external nutrient and inhibitor concentrations affect a time-delayed tumor growth under conditions that satisfy the Gibbs-Thomson relation.
c1∂u∂t=Δu−u,0<r<R(t),t>0, | (1.1) |
∂u∂r+α1(t)(u−N1(t))=0,r=R(t),t>0, | (1.2) |
c2∂v∂t=Δv−v,0<r<R(t),t>0, | (1.3) |
∂v∂r+α2(t)(v−N2(t))=0,r=R(t),t>0, | (1.4) |
ddt(4πR3(t)3)=4π(∫R(t−τ)0μu(r,t−τ)r2dr−∫R(t)0νv(r,t)r2dr−∫R(t)0μ˜ur2dr),t>0, | (1.5) |
u0(r,t)=ψ1(r,t),0≤r≤R(t),−τ≤t≤0, | (1.6) |
v0(r,t)=ψ2(r,t),0≤r≤R(t),−τ≤t≤0, | (1.7) |
R(t)=φ(t),−τ≤t≤0, | (1.8) |
where u and v represent the concentration of nutrients and inhibitors, respectively; c1 and c2 are positive constants, and ci=Tdiffusion/Tgrowth(Tdiffusion≈1min,Tgrowth≈1day) represents the relationship between the tumor growth time scale and the nutrition and inhibitor diffusion time scales; r is the radial variable; τ is the time delay in cell proliferation; R(t) is an unknown variable related to time t; α1(t) and α2(t) represent the blood vessel density. As there is just one vascular system in the tumor, it is logical to suppose that α1(t)=α2(t)=:α(t); μ, ν and ˜u are positive constants; ψ1, ψ2 and φ are given nonnegative functions. The three terms in (1.5) to the right are explained as follows: The first term is the overall volume increase caused by cell multiplication in a unit of time; μu is the rate of cell proliferation per unit volume. The second term is the total volume reduction caused by cell killing by the inhibitor in a unit time interval; νv is the rate of cell killing by the inhibitor per unit volume. The last term is the total volume contraction caused by apoptosis or cell death due to senescence in a unit time interval. N1(t)=ˉu(1−γR(t))H(R(t)) and N2(t)=ˉv(1−γR(t))H(R(t)) represent the functions satisfied by the external nutrient concentrations and the external inhibitor concentrations, respectively. Since the inhibitor has great side effects during tumor treatment, we need to control the inhibitor concentration without loss of generality, assuming that νˉv<μˉu.
From [3,4] we know that Tidiffusion≈1(i=1,2) min and Tgrowth≈1 day, noticing (1.1) and (1.3), so that ci≪1(i=1,2). In this paper, we just take into account the limiting situation in where ci=0(i=1,2). The time-delayed free boundary mathematical model for tumor growth with angiogenesis and the Gibbs-Thomson relation studied in this paper are as follows:
Δu=u,0<r<R(t),t>0, | (1.9) |
∂u∂r+α(t)(u−ˉu(1−γR(t))H(R(t)))=0,r=R(t),t>0, | (1.10) |
Δv=v,0<r<R(t),t>0, | (1.11) |
∂v∂r+α(t)(v−ˉv(1−γR(t))H(R(t)))=0,r=R(t),t>0, | (1.12) |
ddt(4πR3(t)3)=4π(∫R(t−τ)0μu(r,t−τ)r2dr−∫R(t)0νv(r,t)r2dr−∫R(t)0μ˜ur2dr),t>0, | (1.13) |
u0(r,t)=ψ1(r,t),0≤r≤R(t),−τ≤t≤0, | (1.14) |
v0(r,t)=ψ2(r,t),0≤r≤R(t),−τ≤t≤0, | (1.15) |
R(t)=φ(t),−τ≤t≤0. | (1.16) |
The organization of this paper is as follows: In Section 2, we present some preliminary findings. The existence and uniqueness of the solution to the Problem (1.9)–(1.16) are proved in Section 3. Section 4 is devoted to studying steady-state solutions and their stability. In Section 5, we give some numerical computations and have some discussions. In the last section, we give a conclusion.
In this section, we present some preliminary results that will be used in our following analysis:
p(x)=xcothx−1x2,g(x)=xp(x)=cothx−1x, |
and
h(x)=x3p(x),D(x)=h(x)α+g(x),l(x)=αp(x)α+g(x). |
Lemma 2.1. (1) p′(x)<0 for all x>0, and limx→0+p(x)=13,limx→∞p(x)=0.
(2) h(x) and g(x) are strictly monotone increasing for x>0, and
g(0)=0,limx→∞g(x)=1,g′(0)=13. |
(3) For any α>0, D(x) is strictly monotonely increasing for x>0.
(4) For any α>0, l(x) is strictly monotonely decreasing for x>0.
Proof. For the proof of (1), (2) and (3), please see [6,7,23].
(5) Through a simple differential calculation, we have
l′(x)=αp′(x)(α+g(x))−αp(x)g′(x)(α+g(x))2=(α)2p′(x)−αp2(x)(α+g(x))2<0, |
where we have to take advantage of p(x)>0 and p′(x)<0. Therefore, l(x) is strictly monotonely decreasing for x>0. This completes the proof.
Lemma 2.2. [11] Consider the initial value problem of a delay differential equation
˙x(t)=G(x(t),x(t−τ)),t>0, | (2.1) |
x(t)=x0(t),−τ≤t≤0. | (2.2) |
Assuming that the function G is defined and continuously differentiable in R+×R+ and strictly monotone increasing in the second variable, we have the following results:
(1) If xs is a positive solution of the equation G(x,x)=0 such that G(x,x)>0 for x less than but near xs, G(x,x)<0 for x greater than but near xs. Let (c,d) be the (maximal) interval containing only the root xs of the equation G(x,x)=0. If x(t) is the solution of the problem of (2.1), (2.2) and x0(t)∈C[−τ,0], c<x0(t)<d for −τ≤t≤0, then
limt→∞x(t)=xs, |
(2) If G(x,x)<0 for all x>0, then
limt→∞x(t)=0. |
In the following, we will use the above properties to help us prove the main theorems.
In this section, we will discuss the existence and uniqueness of the solution to Problems (1.9)–(1.16).
Theorem 3.1. Assume φ(t) is continuous and nonnegative on [−τ,0]. Suppose α(t) is continuous and positive on [−τ,∞), then there exists a unique nonnegative solution to Problem (1.9)–(1.16) on interval [−τ,∞).
Proof. Combined with (1.9) and (1.10), the solution is given explicitly in the form of
u(r,t)=αα+R(t)p(R(t))R(t)sinhrrsinhR(t)ˉu(1−γR(t))H(R(t))=αˉuα+g(R(t))R(t)sinhrrsinhR(t)(1−γR(t))H(R(t)). | (3.1) |
Similarly, the solution of (1.11) and (1.12) is given explicitly in the form of
v(r,t)=αα+R(t)p(R(t))R(t)sinhrrsinhR(t)ˉv(1−γR(t))H(R(t))=αˉvα+g(R(t))R(t)sinhrrsinhR(t)(1−γR(t))H(R(t)). | (3.2) |
Substituting (3.1) and (3.2) into (1.13), we deduce
dRdt=μˉuR(t)[αR3(t−τ)p(R(t−τ))(α+g(R(t−τ)))R3(t)(1−γR(t−τ))H(R(t−τ))−νˉvμˉuαp(R(t))α+g(R(t))(1−γR(t))H(R(t))−˜u3ˉu]. | (3.3) |
If we denote x(t)=R3(t), then we have
dxdt=3μˉux(t−τ)l(x13(t−τ))(1−γx13(t−τ))H(x13(t−τ))−[3νˉvl(x13(t))(1−γx13(t))H(x13(t))+μ˜u]x(t)=:G(x(t−τ))−F(x(t)). | (3.4) |
Then, the initial condition of x(t) has the following form:
x0(t)=[φ(t)]3,−τ≤t≤0. | (3.5) |
The ODE uniqueness of the solution of the initial value problem implies that the Problem (3.4), (3.5) has a unique solution x(t) exists on [0,∞). Further, we use the prolongement method on intervals [nτ,(n+1)τ],n∈N. Therefore, we obtain the solution of (3.4) exists on [−τ,∞). Next, we need to show that the solution is nonnegative. Where
G(x(t−τ))=3μˉux(t−τ)l(x13(t−τ))(1−γx13(t−τ))H(x13(t−τ)), |
F(x(t))=[3νˉvl(x13(t))(1−γx13(t))H(x13(t))+μ˜u]x(t). |
By a simple calculations, we derive
F′(x(t))=3νˉvl(x13(t))(1−γx13(t))H(x13(t))+μ˜u+x(t)[3νˉvl′(x13(t))13(x(t))−23(1−γx13(t))H(x13(t))+3νˉvl(x13(t))(γ3x43(t))H(x13(t))+3νˉvl(x13(t))(1−γx13(t))H′(x13(t))13(x−23(t))]. |
From Lemma 2.1, we know that F′(x(t))>0 for all x(t)>0. Because φ(t) is continuous on intervals [−τ,0], x(t) is continuous on intervals [−τ,0]. Then, we derive that there exists a unique solution of (3.4) on [0,∞) (see [27]). From the Lemma 2.1, we have G(x(t−τ))≥0 for all x(t−τ)>0. By Theorem 1.1 in [28], we obtain the solution to Problem (3.4) and (3.5) is nonnegative on [0,∞), which completes our proof.
In this section, we will discuss the steady state solution and their stability with the α(t) division constant and bounded.
By discussing the existence of stationary solution by classifying the parameters, we have the following result.
Theorem 4.1. Assume that x∗ is the unique solution to J(x)=0. Then there exists a unique positive constant 3f(x∗) such that the following results are vaild:
(ⅰ) If μˉu>νˉv+μ˜u, there exists two different stationary solutions (us1(r),vs1(r),Rs1) and (us2(r),vs2(r),Rs2) to Problem (1.9)–(1.16), where Rs1<Rs2.
(ⅱ) If μˉu=νˉv+μ˜u, there exists a unique stationary solution (us(r),vs(r),Rs) to Problems (1.9)–(1.16).
(ⅲ) If μˉu<νˉv+μ˜u, there are no stationary solutions to Problems (1.9)–(1.16).
Proof. The stationary solution of the Problem (1.9)–(1.16), denoted by (us(r),vs(r),Rs), must satisfy the following equation:
1r2∂∂r(r2∂us(r)∂r)=us(r),0<r<Rs, | (4.1) |
∂us(r)∂r+α(us(r)−ˉu(1−γRs)H(Rs))=0,r=Rs, | (4.2) |
1r2∂∂r(r2∂vs(r)∂r)=vs(r),0<r<Rs, | (4.3) |
∂vs(r)∂r+α(vs(r)−ˉv(1−γRs)H(Rs))=0,r=Rs, | (4.4) |
∫Rs0μus(r)r2dr−∫Rs0νvs(r)r2dr−∫Rs0μ˜ur2dr=0. | (4.5) |
Combined with (4.1) and (4.2), the solution is given explicitly in the form of
us(r)=αˉuα+g(Rs)RssinhrrsinhRs(1−γRs)H(Rs). | (4.6) |
Similarly, the solution of (4.3) and (4.4) is given explicitly in the form of
vs(r)=αˉvα+g(Rs)RssinhrrsinhRs(1−γRs)H(Rs). | (4.7) |
Thus, we obtain that the Rs satisfies
[p(Rs)−νˉvμˉup(Rs)]αα+g(Rs)(1−γRs)H(Rs)=˜u3ˉu. | (4.8) |
Let
f(x)=(1−νˉvμˉu)l(x)(1−γx)H(x). |
After a direct differential computation, we derive
f′(x)=(1−νˉvμˉu)H(x)α[α+g(x)]2x2J(x)+(1−νˉvμˉu)l(x)(1−γx)H′(x), |
where
J(x)=α[(x2−γx)p′(x)+γp(x)]+(2γx−x2)p2(x). |
Next, we will discuss the classification according to the value range of x. If x≥2γ, then H(x)=1⇒H′(x)=0. By a direct differential computation, we obtain
f′(x)=(1−νˉvμˉu)α[α+g(x)]2x2J(x). |
On the one hand, 0≤H′(x)≤2γ for all x≥0. On the other hand, J(x) is strictly monotonely increasing for all x>γ (The proof of monotonicity of J(x) can be found on [23]) and limx→2γJ(x)=αγ[2γp′(2γ)+p(2γ)]=αγ[xp(x)]′|x=2γ=αγg′(x)|x=2γ>0. Therefore, if γ<x≤2γ, we have f′(x)>0 In the same way, we have limx→γ+J(x)=αγp(γ)+γ2p2(γ)>0. Thanks to Range{g(x)}∈(0,1) and g(x) is strictly monotonely increasing for all x>0, which implies that there exists a constant M0>0 such that M0p(M0)=g(M0)>12. Setting M1=max{M0+1,3γ,2γ(α+1)}, we have
[αγ+(2γ−M1)M1p(M1)]p(M1)<(αγ+12(2γ−M1))p(M1)≤(αγ+12(2γ−2γ(α+1)))p(M1)=0, |
then J(M1)=α[(M21−γM1)]p′(M1)+[αγ+(2γ−M1)M1p(M1)]p(M1)<0. When x>γ, we have J′(x)<0. The mean value theorem implies that we have a unique constant x∗∈(γ,M1) such that J(x∗)=0; when x>x∗, we have J(x)<0; when x∈(γ,x∗), we have J(x)>0.
Thus
f′(x)=(1−νˉvμˉu)α[α+xp(x)]2J(x)+(1−νˉvμˉu)l(x)(1−γx)H′(x), |
f′(x)>0 for x∈(γ,x∗); f′(x)=0 for x=x∗; f′(x)<0 for x>x∗. Then f(x∗)=maxx∈[γ,M1]f(x)∈(0,13). According to the analysis, we have the following conclusions:
(ⅰ) If μˉu>νˉv+μ˜u, we can get that there exist two different stationary solutions (us1(r),vs1(r),Rs1) and (us2(r),vs2(r),Rs2) to Problems (1.9)–(1.16), where Rs1<Rs2.
(ⅱ) If μˉu=νˉv+μ˜u, we can get that there exists a unique stationary solution (us(r),vs(r),Rs) to Problems (1.9)–(1.16).
(ⅲ) If μˉu<νˉv+μ˜u, we know that there are no stationary solutions to Problems (1.9)–(1.16).
This completes the proof.
After discussing the existence of stationary solutions, we then study the asymptotic behavior of stationary solutions.
For convenience, let |φ|=max−τ≤t≤0φ(t) and minφ=min−τ≤t≤0φ(t). Together with Theorem 4.1 and the case where α(t) is a constant, it implies the following result.
Theorem 4.2. For any nonnegative initial value function φ that is continuous, when −τ≤t, there is a nonnegative solution to Problems (3.3) and (1.16), and the dynamics of those solutions are as follows:
(Ⅰ) If μˉu>νˉv+μ˜u, when |φ|<Rs1, we can obtain limt→∞R(t)=0, when minφ>Rs1, we have limt→∞R(t)=Rs2.
(Ⅱ) If μˉu=νˉv+μ˜u, when |φ|<Rs, then limt→∞R(t)=0, when minφ>Rs, we have limt→∞R(t)=Rs.
(Ⅲ) If μˉu<νˉv+μ˜u, then limt→∞R(t)=0.
Proof. Let
Q(x,y)=x[αα+g(y)y3p(y)x3(1−γy)H(y)−νˉvμˉuαp(x)α+g(x)(1−γx)H(x)−13˜uˉu]μˉu, | (4.9) |
then we have
∂Q∂y=μˉuαx2[γyl(y)H(y)+H′(y)y3l(y)(1−γy)+(y3l(y))′(1−γy)H(y)]. | (4.10) |
By the Lemma 2.1, we can get ∂Q∂y>0. Thus, we know that Q is a function of monotonically increasing values about the variable y. According to (4.9), we get
Q(x,x)=x[αα+g(x)x3p(x)x3(1−γx)H(x)−νˉvμˉuαp(x)α+g(x)(1−γx)H(x)−13˜uˉu]μˉu=μˉux[f(x)−13˜uˉu]. | (4.11) |
Therefore, we can obtain that
(a) If μˉu>νˉv+μ˜u, we can easily get Q(x,x)<0 for all x<Rs1, Q(x,x)>0 for all Rs1<x<Rs2 and Q(x,x)<0 for all x>Rs2.
(b) If μˉu=νˉv+μ˜u, we can easily get Q(x,x)<0 for all x≠Rs.
(c) If μˉu<νˉv+μ˜u, we can easily get Q(x,x)<0 for all x>0.
Combined with (a)-(c) and Lemma 2.2, we know that the Theorem 4.2 is true. The proof is complete.
There exist two constants m, M (0≤m<M) so that m≤α(t)≤M.
According to (3.3), we have
dRdt≤μˉuR(t)[MR3(t−τ)p(R(t−τ))(M+g(R(t−τ)))R3(t)(1−γR(t−τ))H(R(t−τ))−νˉvμˉuMp(R(t))M+g(R(t))(1−γR(t))H(R(t))−˜u3ˉu]. | (4.12) |
Furthermore, we consider the following initial value problem
d˜Rdt=μˉu˜R(t)[M˜R3(t−τ)p(˜R(t−τ))(M+g(˜R(t−τ)))˜R3(t)(1−γ˜R(t−τ))H(˜R(t−τ))−νˉvμˉuMp(˜R(t))M+g(˜R(t))(1−γ˜R(t))H(˜R(t))−˜u3ˉu],t>0, | (4.13) |
˜R0(t)=φ(t),−τ≤t≤0. | (4.14) |
Define
G1(x,y)=μˉux[My3p(y)(M+g(y)))x3(1−γy)H(y)−νˉvμˉuMp(x)M+g(x)(1−γx)H(x)−˜u3ˉu],t>0. |
In the same way that α(t) is a constant, there exists a unique constant X∗ satisfies the following equation:
J1(x)=α[(x2−γx)p′(x)+γp(x)]+(2γx−x2)p2(x). |
Let f1(x)=(1−νˉvμˉu)l(x)(1−γx)H(x), then the following analysis and results is similar that α(t) is a constant.
Lemma 4.3. Assume that X∗ be the unique solution to J1(x)=0. Then there exists a unique positive constant 3f1(X∗) such that the following results hold true:
(ⅰ) If μˉu>νˉv+μ˜u, there exist two different stationary solutions (uMs1(r),vMs1(r),RMs1) and (uMs2(r),vMs2(r),RMs2) to Problem (1.9)–(1.16), where RMs1<RMs2.
(ⅱ) If μˉu=νˉv+μ˜u, there exists a unique stationary solutions (uMs(r),vMs(r),RMs) to Problem (1.9)–(1.16).
(ⅲ) If μˉu<νˉv+μ˜u, there are no stationary solutions to Problems (1.9)–(1.16).
Lemma 4.4. For any nonnegative initial value function φ that is continuous, when −τ≤t, there is a nonnegative solution to Problems (4.13) and (4.14), and the dynamics of those solutions are as follows:
(Ⅰ) If μˉu>νˉv+μ˜u, when |φ|<RMs1, we can obtain limt→∞RM(t)=0, when minφ>RMs1, we have limt→∞RM(t)=RMs2.
(Ⅱ) If μˉu=νˉv+μ˜u, when |φ|<RMs, then limt→∞RM(t)=0, when minφ>RMs, we have limt→∞RM(t)=RMs.
(Ⅲ) If μˉu<νˉv+μ˜u, then limt→∞RM(t)=0.
Combined proof of Theorem 4.2, Lemma 4.3 and Lemma 4.4, we can proof of Theorem 4.5.
When α(t) has an upper bounded, we combined the Theorem 4.2 with the comparative principle of the ODE, we have the result shown bellow.
Theorem 4.5. For any nonnegative initial value function φ that is continuous, when −τ≤t, there is a nonnegative solution to Problems (4.13) and (4.14). Moreover, if α(t) has a upper bound, the dynamics of those solutions are as follows:
(Ⅰ) If μˉu>νˉv+μ˜u, when |φ|<RMs1, we can obtain limt→∞R(t)=0 and when minφ>RMs1, we have limsupt→∞R(t)≤RMs2.
(Ⅱ) If μˉu=νˉv+μ˜u, when |φ|<RMs, then limt→∞R(t)=0 and when minφ>RMs, we have limsupt→∞R(t)≤RMs.
(Ⅲ) If μˉu<νˉv+μ˜u, then limt→∞R(t)=0.
Proof. According to (4.12) and the comparison principle [11], we only need to prove that ∂G1∂y>0. In fact,
∂G1∂y=μˉux2[(y3l1(y))′(1−γy)H(y)+yγl1(y)H(y)+H′(y)y3l1(y)(1−γy)], | (4.15) |
where l1(y)=MM+g(y). From Lemma 2.1, it is obvious that ∂G1∂y>0. Meanwhile, the comparison principle [11] indicates that
R(t)≤RM(t). | (4.16) |
By Lemma 4.3, noticing R(t)≥0 and taking upper limits for both R(t) and RM(t) as t→∞, one can get Theorem 4.5. This completes the proof.
Similarly, we consider the following initial value problem
dˉRdt=μˉuˉR(t)[mˉR3(t−τ)p(ˉR(t−τ))(m+g(ˉR(t−τ)))ˉR3(t)(1−γˉR(t−τ))H(ˉR(t−τ))−νˉvμˉump(ˉR(t))m+g(ˉR(t))(1−γˉR(t))H(ˉR(t))−˜u3ˉu],t>0, | (4.17) |
ˉR0(t)=φ(t),−τ≤t≤0. | (4.18) |
Define
G2(x,y)=μˉux[my3p(y)(m+g(y)))x3(1−γy)H(y)−νˉvμˉump(x)m+g(x)(1−γx)H(x)−˜u3ˉu],t>0, |
In the same way that α(t) is a constant, there exists a unique constant X∗ satisfies the following equation:
J2(x)=α[(x2−γx)p′(x)+γp(x)]+(2γx−x2)p2(x). |
Let f2(x)=(1−νˉvμˉu)l2(x)(1−γx)H(x), then the following analysis and results is similar that α(t) is a constant.
Similarly, we have
Lemma 4.6. Assume that X∗ be the unique solution to J2(x)=0. Then there exists a unique positive constant 3f2(X∗) such that the following results are valid:
(ⅰ) If μˉu>νˉv+μ˜u, there exist two different stationary solutions (ums1(r),vms1(r),Rms1) and (ums2(r),vms2(r),Rms2) to Problem (1.9)–(1.16), where Rms1<Rms2.
(ⅱ) If μˉu=νˉv+μ˜u, there exists a unique stationary solutions (ums(r),vms(r),Rms) to Problem (1.9)–(1.16).
(ⅲ) If μˉu<νˉv+μ˜u, there are no stationary solutions to Problems (1.9)–(1.16).
Lemma 4.7. For any nonnegative initial value function φ that is continuous, when −τ≤t, there is a nonnegative solution to Problems (4.17) and (4.18), and the dynamics of those solutions are as follows:
(Ⅰ) If μˉu>νˉv+μ˜u, when |φ|<Rms1, we can obtain limt→∞Rm(t)=0, when minφ>Rms1, we have limt→∞Rm(t)=Rms2.
(Ⅱ) If μˉu=νˉv+μ˜u, when |φ|<Rms, then limt→∞Rm(t)=0, when minφ>Rms, we have limt→∞Rm(t)=Rms.
(Ⅲ) If μˉu<νˉv+μ˜u, then limt→∞Rm(t)=0.
Combined proof of Theorem 4.2, Lemma 4.6 and Lemma 4.7, we can proof of Theorem 4.8.
Similarly, when α(t) has an lower bounded, we combined the Theorem 4.2 with the comparative principle of the ODE, we have the result shown bellow.
Theorem 4.8. For any nonnegative initial value function φ that is continuous, when −τ≤t, there is a nonnegative solution to Problems (4.17) and (4.18). Moreover, if α(t) α(t) has a lower bound, the dynamics of those solutions are as follows:
(Ⅰ) If μˉu>νˉv+μ˜u, when |φ|<Rms1, we can obtain limt→∞R(t)=0 and when minφ>Rms1, we have liminft→∞R(t)≥Rms2.
(Ⅱ) If μˉu=νˉv+μ˜u, when |φ|<Rms, then limt→∞R(t)=0 and when minφ>Rms, we have liminft→∞R(t)≥Rms.
(Ⅲ) If μˉu<νˉv+μ˜u, then limt→∞R(t)=0.
Proof. According to (4.12) and the comparison principle [11], we only need to prove that ∂G2∂y>0. In fact,
∂G2∂y=μˉux2[(y3l2(y))′(1−γy)H(y)+yγl2(y)H(y)+H′(y)y3l2(y)(1−γy)], | (4.19) |
where l2(y)=mm+g(y). From Lemma 2.1, it is obvious that ∂G2∂y>0. Meanwhile, the comparison principle [11] indicates that
R(t)≥Rm(t). | (4.20) |
By Lemma 4.7, noticing R(t)≥0 and taking lower limits for both R(t) and Rm(t) as t→∞, then the Theorem 4.8 is true. The proof is complete.
Therefore, the number of steady-state solutions varies in different value ranges. When the steady-state solution exists, it has a corresponding homeostasis.
In this section, by using Matlab, we will present some numerical results to validate our theoretical results, see Figures 1–3. First, we give the values γ=2,α=5,8 and α=8,γ=2.5,3 for the two groups of parameters for the function f(x), then we can obtain Figure 1. It is obvious that the function f(x) is increasing in α and decreasing in γ.
Figures 2 and 3 show that in some special cases, the steady-state solutions are larger than 2γ. In this case, H(x)=1, hence,
f(x)=(1−νˉvμˉu)l(x)(1−γx). | (5.1) |
If the parameters in (3.4) are taken as
ˉu=5,ˉv=5,˜u=10,μ=1,ν=1,α=8,γ=2,τ=3,x0=100,1600, | (5.2) |
then we can solve the equation f(3√x)=˜u3ˉu, we get Figure 2.
The dynamics of the solution to (3.4) allow us to obtain Figure 3.
In this paper, we study how the external nutrient and inhibitor concentrations affect a time-delayed tumor growth under the Gibbs-Thomson relation.
This Problem (1.9)–(1.16) has a unique nonegative solution (Theorem 3.1).
(a) When α(t) is a constant, we further demonstrate the existence of the stationary solutions (Theorem 4.1) and the asymptotic behavior of the stationary solutions (Theorem 4.2);
(b) When α(t) is bounded, we also demonstrate the asymptotic behavior of the stationary solutions and their existence (Theorem 4.5 and Theorem 4.8).
From the biological point of view, the results show that
(ⅰ) if μˉu>νˉv+μ˜u, there exists two different stationary solutions, for small initial function satisfying max−τ≤t≤0φ(t)<Rs1, the tumor will disappear; for large function satisfying min−τ≤t≤0φ(t)<Rs1, the tumor will not disappear and will tend to the unique steady-state;
(ⅱ) if μˉu=νˉv+μ˜u, there exists a unique stationary solution, for small initial function satisfying max−τ≤t≤0φ(t)<Rs, the tumor will disappear; for large function satisfying min−τ≤t≤0φ(t)<Rs, the tumor will not disappear and will tend to the unique steady-state;
(ⅲ) if μˉu<νˉv+μ˜u, there is no stationary solution, the tumor will disappear.
The result implies that, under certain conditions, the tumor will probably become dormant or will finally disappear. The conclusions are illustrated by numerical computations. We hope these results may be useful for future tumor research.
The authors declare they have not used Artificial Intelligence (AI) tools in the creation of this article.
This work was supported by the Characteristic Innovation Projects of Colleges and Universities in Guangdong Province, China (No. 2016KTSCX028), the High-Level Talents Project of Guangdong Province, China (No. 2014011).
All authors declare no conflicts of interest in this paper.
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