Modelling Early Tumor Growth with Diffusion Equation

Asha Saidi Kalula (asha@aims.ac.za)

African Institute for Mathematical Sciences (AIMS)

Supervised by: Professor Jacek Banasiak

University of KwaZulu-Natal, South Africa

22 May 2009
Submitted in partial fulfillment of a postgraduate diploma at AIMS
Abstract
This essay is aimed at forming a lecture series on the modelling of early tumor growth using diffusion
equations. We present basic models for tumor growth and discuss the linear stability of their steady
states. The models discussed predict the size of the proliferating layer, the size of the tumor, and the
effects of the immune system response, on tumor growth.

Declaration

I, the undersigned, hereby declare that the work contained in this essay is my original work, and that
any work done by others or by myself previously has been acknowledged and referenced accordingly.

Asha Saidi Kalula, 22 May 2009

i
Contents

Abstract i

1 Introduction 1
1.1 What is Tumor? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Characteristics of Cancer Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.3 Forms of Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.4 Stages of Tumor Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2 Mathematical Models for Early Tumor Growth 3

2.1 Phenomenological Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.1.1 Exponential Growth Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.1.2 Logistic Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1.3 Gompertz Equation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.2 Heterogeneous Tumor Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.3 Modelling Avascular Stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

3 Vascular and Immune System Response 17

3.1 Modelling Vascular Stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.2 Immune System Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

4 Conclusion 23

References 25

ii
1. Introduction
Cancer is a complex disease which develops in three distinct stages, avascular, vascular and metastasis.
Each of these stages has affected considerable attention in research. In this essay we give an overview
of a tumor, how the cancer cells differ from the normal cells, the formation of a tumor, forms of
cancer, stages of tumor growth and we go on to detail of some basic models which can be used in our
understanding of cancer’s development. We will search for the steady states and linear stability of each
stage. Furthermore, we will discuss the response of the immune system to cancer.

1.1 What is Tumor?

A tumor is an abnormal growth of body tissue. In general, tumors appear to occur when there is a
problem with the division of cells in the body. Typically, the division of a cell in the body is strictly
controlled. New cells are created to replace older ones or to perform new functions. Cells that are
damaged or no longer needed, die to make room for healthy replacements. If the balance of cell division
and death is disturbed, a tumor may form, [F05].

1.2 Characteristics of Cancer Cells

Cancer cells have the features which differentiate them from normal cells. The following are the char-
acteristics of cancer cells as opposed to normal cells, [F05]:

• Escape from control of birth and opoptosis processes.

• Escape from control of maturation and differentiation processes.

• An ability to overcome the resulting immune response.

• Ability to make their own blood vessel.

• Poor control of genetic processes.

• Escape from control of migration processes.

• Ability to spread through blood vessel.

• Reduced cellular adhesion.

A tumor starts as a mild disorder of cell behaviour that slowly develops through well characterised stages
into full cancer, through the process known as tumor progress. Tumor progress may be caused by the
following, [F05]:

• Chemical carcinogens which may cause simple local changes in the Deoxyribonucleic acid (DNA)
sequence.

• Ionising radiation which may cause chromosome breaks and translocations.

1
 Section 1.3. Forms of Cancer Page 2

• Viruses which may introduce foreign DNA into the cell, beginning to provide genetic variation for
natural selection to work on.

Only a small number of genes known as oncogenes are involved in the development of cancer. An
oncogen is a gene that causes the transformation of normal cells into cancerous tumor cells. These
oncogenes are normally involved in the control of proliferation and differentiation. Proliferation is an
increase in the number of cells as a result of cell growth and cell division, [F05].

1.3 Forms of Cancer

There are many forms of cancer among which are the following, [F05]:

• Cancer of the epithelial cells which form the linings of the body, the skin and the surface of the
gut which are known as carcinomas and which constitute 90% of all cancers.
• Cancer of the haematopoietic (blood cell production) systems called leukaemias.
• Cancer of the immune system known as lymphomas.

Tumor cells do not multiply much faster than normal cells, but carry on multiplying in circumstances
where the normal cells would cease due to lack of growth factor. This is possible for tumor cells since
they can produce their own growth factors or their receptors may have altered in such a way that growth
is possible even when no growth factors is present, [F05].

1.4 Stages of Tumor Growth

A growth of a tumor passes through three distinct stages.

Avascular stage
This is the stage when the tumor does not have its own blood supply but depends on the adjacent
normal tissue for nutrients. At this stage, the tumor is too small to be seen in vivo and normally can
not grow beyond a certain size which is suggested to be 2 millimetres in diameter, [F05].This is because
the growth is diffusion limited and nutrients cannot be delivered to the tumor in order for it to grow
above that size. In other words for the tumor to grow there must be a surplus of nutrient available for
tumor cells.
Vascular stage
A real tumor enters the vascular stage by stimulating blood vessel formation, or angiogenesis, in order
to grow. This is done by secreting a substance known as a tumor angiogenesis factor. Angiogenesis is
the process in which tumors develop their own blood vessels.
Metastasis stage
At this stage, the tumor has already acquired their own blood supply and the tumor cell can spread via
circulatory systems and form secondary tumors elsewhere in the body. After this stage, a person has
multiple tumors in different parts of the body, which are very difficulty to detect and even more difficult
to treat, [RT07].
2. Mathematical Models for Early Tumor Growth
Modelling early tumor growth gives an insight into how a tumor develops with time. The modelling of
a tumor depends on the stages one considers.

2.1 Phenomenological Models

These are the models based on observations which give useful results but the method does not reflect
the complicated biology of cancer. Phenomenological models are descriptive but not explanatory since
they not explain how cells divide, nor how they interact. In this section we analyse three models: the
exponential growth law, the logistic equation and the Gompertz equation. We focus on the steady states
and linear stability of them.

2.1.1 Exponential Growth Law

The Malthusian or exponential growth law is sometimes used as a model for tumor growth. In this case
it is assumed that the rate of growth satisfies
dN
= rN, (2.1)
dt
with
N (t = 0) = N0 ,
where r is the net rate at which the cells proliferate, N (t) is the number of cells within a solid tumor
at time t. The model assumes that all nutrients and vital growth factors are available.

Steady state analysis

A steady state or equilibrium solution (N ∗ ) is a point at which the population size ceases to vary. In
other words, it is a point at which the rate of change over time of the population size is equal to zero.
Hence, putting
rN = 0, (2.2)
we obtain N ∗ = 0.

Stability analysis

Linear stability analysis is used to analyse the behaviour of solutions originating close to steady state. A
steady state can be stable or unstable. Whether the steady state is stable or unstable can be determined
by linear stability analysis, [L88] .
Let
dN
= rN = f (N ). (2.3)
dt

3
 Section 2.1. Phenomenological Models Page 4

We consider a small perturbation away from the steady state N ∗ so that,

N (t) = N ∗ + εn(t), (2.4)
where ε is very small. Substituting (2.4) into (2.3) we have
d(N ∗ + εn(t))
= f (N ∗ + εn(t)).
dt
It follows that,
dN ∗ dn(t)
+ε = f (N ∗ + εn(t)). (2.5)
dt dt
dN ∗
Since N ∗ is a steady state (a constant) then, dt = 0 and equation (2.5) becomes
dn(t)
ε = f (N ∗ + εn(t)). (2.6)
dt
Using Taylor expansion of (2.6) we get
dn(t) (εn)2 f ′′ (N ∗ )
ε = f (N ∗ ) + εnf ′ (N ∗ ) + + h.o.t.
dt 2!
We see that f (N ∗ ) = 0, since N ∗ is a steady state. Since we are looking for linear stability we can
neglect the higher order terms. Thus we obtain,
dn(t)
ε = εnf ′ (N ∗ ),
dt
which is the same as,
dn(t)
= nf ′ (N ∗ ). (2.7)
dt
Integrating (2.7) we get, ln n = f ′ (N ∗ )t + c where c is a constant of integration.
Applying the initial condition n(0) = n0 we obtain,
′ (N ∗ )t
n(t) = n0 ef .
Hence, n(t) → 0 as t → ∞ if f ′ (N ∗ ) < 0 and n(t) → ∞ as t → ∞ if f ′ (N ∗ ) > 0. Therefore N ∗ is
stable if f ′ (N ∗ ) < 0 and unstable if f ′ (N ∗ ) > 0.
Now, the exponential growth equation we have
f (N ) = rN so f ′ (N ∗ ) = r (2.8)
and, since r > 0, it means that the steady state is unstable. This can be confirmed by solving
dN
= rN. (2.9)
dt
Using the initial condition we obtain
N (t) = N0 ert (2.10)
and, as t → ∞, N (t) → ∞. So the model predicts that the tumor will increase exponentially without
limit. The model provides an accurate description of the early stages of the tumor’s development since
at this stage a tumor will be small such that there is unlimited supply of nutrients. After short initial
time, the growth of tumor slows down as the available nutrients are not sufficient for the unlimited
growth. Thus we use another model.
 Section 2.1. Phenomenological Models Page 5

2.1.2 Logistic Growth

The logistic equation incorporates the fact that as the tumor increases in size there will be a competition
for nutrients, space and other vital growth factors which will lead to a reduced growth and, eventually
to saturation. This were not considered in the Malthusian model. However, the logistic growth does
not take into account that this availability of resources to the cell depends on the cells’ location in the
tumor. The logistic equation reads  
dN N
= rN 1 − , (2.11)
dt K
with
N (t = 0) = N0 ,
where K > 0 is the carrying capacity of the environment and N is the size of the tumor (number of
cells). N = K in this case is the maximal size the tumor can reach in this particular environment.

Steady State Analysis:

Taking  
dN N
= rN 1− = f (N ) = 0, (2.12)
dt K
yields
N∗ = 0 or N ∗ = K.

Linear Stability Analysis:

Since  
N
f (N ) = rN 1− , (2.13)
K
we have
2rN
f ′ (N ) = r − . (2.14)
K
At the steady state N ∗ = 0, f ′ (0) = r > 0 and at N ∗ = K, f ′ (K) = −r < 0. Hence N = K is
a stable steady state while N = 0 is unstable. So the tumor will grow to the carrying capacity as the
time goes on. We can confirm this by solving
 
dN N
= rN 1 − , (2.15)
dt K

with the initial condition N (0) = N0 . By separation of variables, we have

dN
N

= rdt. (2.16)
N 1− K

Using partial fractions, we obtain

 
1
1 1 K

= + , (2.17)

N 1− N N N
K 1−
K
 Section 2.1. Phenomenological Models Page 6

hence equation (2.16) becomes

 
1
1
Z Z
K
 + dN = rdt, (2.18)

N N
1−
K
that is
 
N
ln N − ln 1 − = rt + C (2.19)
K
and
 
rt N (t)
N (t) = Ae 1− , (2.20)
K
where C is the constant of integration and A = eC . Applying the initial condition, we obtain
KN0
A= . (2.21)
K − N0
Hence,
KN0 ert
N (t) = , (2.22)
K − N0 + N0 ert
which can be transformed to
KN0
N (t) = . (2.23)
Ke−rt − N0 e−rt + N0
Now it is clear that as
t → ∞, N (t) → K.
This model predicts that the tumor reaches a limiting size as time becomes large.

2.1.3 Gompertz Equation

In the logistic model the availability of resources were taken into account. However, apart from lack of
resources, the growth of tumor is affected by the fact that the cells on the outer surface of the tumor
have better access to nutrients for proliferation to continue, so they are more fit than the cells at the
interior of the tumor. Thus we would expect the growth rate of the tumor to decrease as the tumor
becomes larger. Gompertz growth model can be derived as follows,
dN
= aN − bN ln N,
dt
= N (a − b ln n)
= N (ln ea − ln N b )
 b
N
= −N ln a
eb
 
N
= −bN ln a
eb
with initial condition N (0) = N0 , where a is the growth rate of the tumor, b is a retardation constant
a
and K = e b is the carrying capacity. Here, a gives an exponential increase when the tumor size (N ) is
small and b, the decay constant, damps out the growth rate when N is large.
 Section 2.2. Heterogeneous Tumor Growth Page 7

Steady State Analysis:

At equilibrium  
N
0 = −bN ln , (2.24)
K
which implies that N = K is the only steady state.

Linear Stability Analysis:

Since
 
N
f (N ) = −bN ln , (2.25)
K
 
′ N
f (N ) = −b ln − b, (2.26)
K

at N = K,
f ′ (K) = −b. (2.27)

Since b is positive, the steady state N = K is linearly stable, [L88].

Quantitative Analysis

N


Using the substitution u = ln K , we have

dN du
N = Keu and = Keu . (2.28)
dt dt
Substituting this to the Gompertz equation and integrating, we obtain

u = Ae−bt , (2.29)

and using the initial condition we find

N0
A = − ln . (2.30)
K
Hence  
N (t) = Kexp −Ae−bt and, as t → ∞, N (t) → K. (2.31)

This model provides more accurate fit to empirical growth curves for avascular tumors and vascular
tumors in their early stage than the logistic equation. That is the empirical data best fit in Gompertz
growth equation.

2.2 Heterogeneous Tumor Growth

In the models discussed in Section 2.1, we assumed that the tumor cells are identical. In this model
we consider the fact that they may be of different from each other. We divide them into three types:
the proliferating cells, the quiescent cells and the necrotic cells. We model this by considering three
 Section 2.2. Heterogeneous Tumor Growth Page 8

different components as shown in Figure 2.1. The cells can change their state depending on the local
environmental conditions, whereby proliferating cells can either become quiescent cells or necrotic as
well as quiescent cells can either become proliferating cells or necrotic. Cells adjacent to the blood vessel
have enough supply of nutrients and so proliferate freely. As the distance from the vessels increases,
the local nutrient concentration falls because it has been consumed as it diffuses away from the blood
vessel. Eventually the concentration reach a point that tumor cells has sufficient nutrients to survive but
are unable to proliferate and form a quiescent layer. At greater distances from the vessel the nutrient
concentration may become so low that quiescent cells are unable to stay alive and form a necrotic layer.
The model is derived from the schematic Figure 2.1, which illustrates how cells may change from one
state to another, how new cells are produced (proliferating) and how dead cells are degraded, [L03].
kP P

kP Q

P(t) Q(t)
Proliferating cells Quiescent cells

kQP

kQD
kP D

D(t)
Dead cells

Lambda(λ)

Figure 2.1: Schematic diagram of model of heterogeneous tumor growth

P (t) is the number of proliferating cells at time t, Q(t) the number of quiescent cells and D(t) number
of necrotic cells. The total number of tumor cells N (t), is the sum of all three types of cells, that it is
given by:
N (t) = P (t) + Q(t) + D(t). (2.32)
From the Figure 2.1 the function
 Section 2.2. Heterogeneous Tumor Growth Page 9

• kP P represent the rate at which proliferating cells produce new cells.

• kQD the rate at which the quiescent cells die.

• kP D the rate at which the proliferating cells die.

• kP Q the rate at which proliferating cells become quiescent.

• kQP the rate at which quiescent cells become proliferating.

and λ is the decay rate of the necrotic core. From the diagram, a mathematical model may be written
as, [L03],
dP
= (kP P − kP Q − kP D ) P + kQP Q, (2.33)
dt
dQ
= kP Q P − (kQP + kQD ) Q, (2.34)
dt
dD
= kP D P + kQD Q − λD, (2.35)
dt
with
P (0) = P0 , Q(0) = Q0 and D(0) = D0 ,
where kIJ (I, J = P, Q, D) are transition rates between the proliferating, quiescent and dead states.
For simplicity we assume that these rates depend on the number of cells within the tumor and number
of cells in each state. Following [L03] we take the transition rates to be as follows:

k̂P P k̂P Q P k̂QP Q k̂QD (P + Q)

kP P = , kP Q = , kQP = , kQD = and kP D = k̂P D ,
N̂ + N N̂ + N N̂ + N N̂ + N
(2.36)
however they can also take another form, λ assumed to be constant. Substituting (2.36) into (2.33) to
(2.35) the model becomes,
   
dP k̂P P − k̂P Q P − N̂ + N k̂P D P + k̂QP Q2
= , (2.37)
dt N̂ + N
dQ k̂P Q P 2 − k̂QP Q2 − k̂QD (P + Q) Q
= , (2.38)
dt N̂ + N
   
dD k̂P D N̂ + N + k̂QD (P + Q) Q − λD N̂ + N
= . (2.39)
dt N̂ + N
If the natural cell death is neglected, that is, if kP D = 0, the equilibrium solution is determined as
follows:

0 = k̂P P P − k̂P Q P 2 + k̂QP Q2 , (2.40)

2 2 2
0 = k̂P Q P − k̂QP Q − k̂QD P Q − k̂QD Q , (2.41)
 
0 = k̂QD P Q + k̂QD Q2 − λD N̂ + N . (2.42)

Adding equations (2.40), (2.41) and (2.42), we have

 
k̂P P P − λD N̂ + N = 0. (2.43)
 Section 2.2. Heterogeneous Tumor Growth Page 10

If either D or P = 0, then the other one must be zero as well. Substituting P = 0 to equation (2.40)
we obtain Q = 0. Otherwise
k̂P P P
D=  , (2.44)
λ N̂ + N

and substituting (2.44) into (2.42), we obtain

 
P k̂QD Q − k̂P P = −k̂QD Q2 , (2.45)

hence
k̂QD Q2
P = , (2.46)
k̂P P − k̂QD Q
and by substituting (2.46) into (2.40) we get
! !2
−k̂QD Q2 k̂QD Q2
k̂P P − k̂P Q + k̂QP Q2 = 0. (2.47)
k̂QD Q − k̂P P k̂QD Q − k̂P P

This can be expanded to obtain,

2 Q4
−k̂P P k̂QD Q2 k̂P Q k̂QD
− + k̂QP Q2 = 0.
k̂Q Q − k̂P P 2 Q2
k̂QD − 2k̂P P k̂QD Q + k̂P2 P

By taking the common denominator and simplifying we get,

2
−k̂P P k̂QD Q3 + k̂P2 P k̂QD Q2 − k̂P Q k̂QD
2
Q4 + k̂QP k̂QD
2
Q4 − 2k̂P P k̂QD k̂QP Q3 + k̂P2 P k̂QP Q2 = 0.

Collecting the like terms we get,

     
Q4 k̂QP k̂QD
2 2
− k̂P Q k̂QD 2
+ Q3 −k̂P P k̂QD − 2k̂P P k̂QD k̂QP + Q2 k̂P2 P k̂QP + k̂P2 P k̂QD = 0.
(2.48)

We can factor out Q2 from the equation 2.48 to have,

h      i
Q2 Q2 k̂QP k̂QD
2 2
− k̂P Q k̂QD 2
+ Q −k̂P P k̂QD − 2k̂P P k̂QD k̂QP + k̂P2 P k̂QP + k̂P2 P k̂QD = 0.
(2.49)

From equation (2.49) we have,

Q2 = 0 or
     
2
Q2 k̂QP k̂QD 2
− k̂P Q k̂QD 2
+ Q −k̂P P k̂QD − 2k̂P P k̂QD k̂QP + k̂P2 P k̂QP + k̂P2 P k̂QD = 0. (2.50)

Solving equation (2.50) and simplifying we get,

q
2
k̂P P k̂QD + 2k̂P P k̂QP ± k̂P P k̂QD + 4k̂QP + 4k̂QD k̂P Q
Q=   .
2k̂QD k̂QP − k̂P Q
 Section 2.2. Heterogeneous Tumor Growth Page 11

k̂P P
For a solution to be physically realistic P , Q and D must be positive, hence Q < .
k̂QD

We are going to determine the linear stability of the trivial equilibrium point and leave out the non
trivial equilibrium point because it is more complicated to be done analytically. Let the equation (2.37)
be f (P, Q, D), equation (2.38) be g(P, Q, D) and equation (2.39) as h(P, Q, D). The derivatives of
these function are
    
N̂ + P + Q + D k̂P P − 2P k̂P Q − k̂P P P − k̂P Q P 2 + k̂QP Q2
fP =   ,
N̂ + P + Q + D
   
2 N̂ + P + Q + D Qk̂QP − k̂P P P − k̂P Q P 2 + k̂QP Q2
fQ =  2 ,
N̂ + P + Q + D
fD = 0,
    
N̂ + P + Q + D 2P k̂P Q − k̂QD Q − k̂P Q P 2 − k̂QP Q2 − k̂QD P Q − k̂QD Q2
gP =  2 ,
N̂ + P + Q + D

    
N̂ + P + Q + D −2k̂QP Q − k̂QD P − 2k̂QD Q − k̂P Q P 2 − k̂QP Q2 − k̂QD P Q − k̂QD Q2
gQ =  2 ,
N̂ + P + Q + D
gD = 0,
     
N̂ + P + Q + D k̂QD Q − λD − k̂QD P Q + k̂QD Q2 − λD N̂ + P + Q + D
hP =  2 ,
N̂ + P + Q + D
     
k̂QD P + 2k̂QD Q − λD N̂ + P + Q + D − k̂QD P Q + k̂QD Q2 − λD N̂ + P + Q + D
hQ =  2 ,
N̂ + P + Q + D
      
N̂ + P + Q + D −λ N̂ + P + Q + D + 2D − k̂QD P Q + k̂QD Q2 − λD N̂ + P + Q + D
hD =  2 .
N̂ + P + Q + D

The Jacobian matrix at (0, 0, 0) is given by,

   k̂ 
fP fQ fD PP
0 0
N̂
J =  gP gQ gD  =  0 0 0 .
 
hP hQ hD 0 0 −λ

Replacing λ with α we have,

 
 k̂P P
 N̂ − λ 0 0 

0  = 0.
 

 0 −λ
 0 0 −α − λ
 Section 2.3. Modelling Avascular Stage Page 12

k̂P P
This gives, λ = 0, −α or N̂
. Since one of the eigenvalues is positive, then the equilibrium point
is unstable.

2.3 Modelling Avascular Stage

In the previous section we considered the case when the size of the tumor depends only on time: that is
N = N (t), which leads to the use of ordinary differential equations. In this section, the growth of the
tumor is assumed to depend on the concentration of the nutrients which varies in space as it diffuses.
To describe this phenomena we use partial differential equations.
At this stage the tumor does not have its own blood vessel but depends on the adjacent normal tissue. As
the tumor grows supply of nutrients through diffusion from the adjacent tissue are no longer sufficient.
The insufficiency nutrients for the tumor cause the cells in the centre to die as the nutrient concentration
at the centre decreases since it has been consumed as it diffuses away from the blood vessel. This leads
to the formation of a necrotic core. At some stage tumor cannot grow any further and it reaches a
diffusion-limited steady state. By modelling the nutrient concentration in this steady state, the condition
under which a necrotic core is formed can be investigated. Assuming that the problem is spherically
symmetric, let c(r) be the concentration of the limiting nutrient (assumed to be oxygen) at radius r.
Let r1 be the radius of the necrotic core and r2 the radius of tumor. Assuming r2 to be given, we want
to investigate how big the necrotic core will be. Hence let c satisfy the steady state diffusion equation,
[F05]
0 = −k + D∇2 c, (2.51)
which means that as the nutrients ( oxygen ) diffuse they are consumed by the cells at a rate k and k is
negative because the amount of nutrient concentration is reduced. The problem is spherically symmetric
and depends only on the radius so  
2 1 d 2 dc
▽ c= 2 r , (2.52)
r dr dr
and the equation (2.51) becomes
 
1 d 2 dc
0 = −k + D 2 r , for r1 < r < r2 , (2.53)
r dr dr

where D is a constant diffusion coefficient. Since the oxygen is only taken by the living cells,
 
1 d 2 dc
0=D 2 r , for r < r1 . (2.54)
r dr dr

Let c2 be the concentration of the normal tissue and c1 be the concentration at or below which cells
die. Let us first consider small tumors, so that there is no necrotic core; that is r1 = 0. The boundary
conditions are c(0) bounded and c(r2 ) = c2 . Solving the equation (2.53), we obtain

1k 2 A
c(r) = r + + B. (2.55)
6D r
Using the boundary conditions to find the values of the constants of integration (A and B), we have
A = 0, and
kr 2
B = c2 − 2 . (2.56)
6D
 Section 2.3. Modelling Avascular Stage Page 13

Hence,
k
r22 − r 2 + c2 .


c(r) = − (2.57)
6D
This is valid as long as c(0) ≥ c1 , because for a necrotic core to be formed we must have c(r1 ) ≤ c1 .
Since we are looking at the situation where there is no necrotic core, r1 = 0 so c(0) ≥ c1 . From (2.57),

k
r22 − r12 + c2 ,


c(r1 ) = −
6D
substituting r1 = 0 and using the condition c(0) ≥ c1 , we have

6D
r22 ≤ (c2 − c1 ) .
k
We define
6D
(c2 − c1 ) = rc2
k
to be the critical value of r below which tumor will not have necrotic core. Therefore in such case
6D
r22 ≤ rc2 = (c2 − c1 ) . (2.58)
k
Let’s now assume that r2 > rc , so that r1 > 0, which means that there is a necrotic core. We want to
find how large r1 is for a given size of the tumor. Using the result (2.55), in the necrotic core c must
be constant (ĉ) because there are no living cells and hence there is no consumption of nutrients, thus
ĉ ≤ c1 by definition. Since c1 is the concentration at or below which cells die, then we have ĉ = c1 as
the maximum concentration in which a necrotic core will be formed. The boundary conditions for the
region of living cells are
dc
c(r1 ) = c1 , c(r2 ) = c2 and J(r1 ) = 0 where J = −D . (2.59)
dr
J is the
(radial) flux of nutrient which is proportional to the gradient of the concentration of nutrient
dc dc
J ∝ dr implies that J = −D dr , where D > 0 is known as the diffusion coefficient, and the negative
sign because a diffusion of nutrients is from a high concentration to a low concentration region (by
dc
Fick’s
 law of diffusion). By continuity of the derivative of dc the
 concentration dr at r = r1 , we have
dc 
dr r=r1 = 0 from the left since c = c1 = constant and thus dr r=r1 = 0 from the right. The continuity

dc
of dr follows from the continuity of the concentration and conservation of mass. Consider the flux in
interval I(r = r(t), r(t+ △ t) = r+ △ r), so the front moves by △ r in a small time △ t (with average
velocity v̄ = △r
△t ). At the beginning the mass contained in the interval I is c(r̄) △ r (for small △ r we
assume c to be constant over I). After △ t we have c1 △ r in I. This change could only occurred
by flux through r and (r+ △ r). Thus (c1 − c(r̄)) △ r = (J(r) − J(r+ △ r)) △ t. If △ t → 0, then
△r
△t → v̄ and c(r̄) → c1 by the continuity of concentration and hence J continuous.

From equation (2.55), using the boundary condition, we obtain

k 2 A k 2 A kr1 A
c1 = r + + B, c2 = r + +B and 0= − 2. (2.60)
6D 1 r1 6D 2 r2 3D r1
 Section 2.3. Modelling Avascular Stage Page 14

Subtracting c1 from c2 and substituting the value of A from the third equation, we have

kr13 1
 
k 2 2 1
c2 − c1 = r − r1 + − ,
6D 2 3D r2 r1
  
k 2 2

3 1 1
= r2 − r1 − 2r1 − ,
6D r1 r2
kr22 r1 2
  
r1
= 1+2 1− ,
6D r2 r2
 
k r1
= 1+2 (r2 − r1 )2 . (2.61)
6D r2

It can be proved that if r2 → ∞, then from (2.61), the necrotic core also grows with rr21 → 1 and the
difference between the radius of the tumor and necrotic core becomes constant, that is r2 − r1 → h, a
constant, where
D
h2 = 2 (c2 − c1 ) . (2.62)
k
Hence h gives the thickness of the shell of proliferation cells which does not depend on the size of tumor
itself but depends on the excess nutrient concentration above the threshold that is, how fast the nutrient
is consumed and how fast it diffuses. By knowing the size of this shell, the treatment of the tumor can
be done so as to kill the tumor cells in this area using therapy or removing them by an operation.

Moving Boundary Problem

In the model discussed in Section 2.3, we were investigating how big the necrotic core would be if the
size of the tumor was known. Now we want to investigate the tumor growth by including the principle
of conservation of mass (which states that: the rate of change of the amount of material in a region is
equal to the rate of flow across the boundary plus any that is created within the region) and kinetics.
Now we have r1 = r1 (t) and r2 = r2 (t) since the radius varies with time. The necrotic core occupies
0 ≤ r < r1 (t) and the living cells r1 (t) < r < r2 (t). Making a quasi-steady-state assumption that
the oxygen’s diffusion time-scale is much shorter than the tumor growth time-scale, equation (2.51) is
still valid. For the necrotic core to form we must have r2 > rc . The value of c can be obtained from
equation (2.57) if r2 < rc , and equations (2.55) and (2.60) if r2 > rc .
Considering the case where r2 > rc , we include the effect of the proliferation of live cells and degradation
of dead ones since, as time goes on the live cells divide and the dead cell break down and are taken
as waste products. We assume that all cells outside the necrotic core are proliferating. This is a
simplification as for low concentrations of nutrients the cells can be still alive but unable to proliferate.
The assumption on proliferation is that cell volume is produced by living cells at a rate P which generally
depends on concentration c. The assumption on degradation is that the cell’s volume is lost at a rate
L as necrotic cells are broken down and their waste product removed, [F05].
Let ρ(r, t) be the density of the tumor and v(r, t) the velocity field in the tumor at radius r and time t.
Then the conservation of mass gives
∂ρ
= −ρL − ∇ · J = −ρL − ∇(ρ · v) in 0 < r < r1 (t) and (2.63)
∂t
∂ρ
= ρP − ∇ · J = ρP − ∇(ρ · v) in r1 (t) < r < r2 (t), (2.64)
∂t
 Section 2.3. Modelling Avascular Stage Page 15

where J is the mass flux in the tumor which is due to advection. This flux is given by the product of
tumor density and the velocity field. It is negative because it moves accros the boundary r1 (t). This
is a kinetic free boundary problem. Both r1 and r2 are unknown, but we know their relationship from
Section 2.3. Let’s assume that the density in the tumor is constant. The conservation of mass equations
becomes,
1 ∂
0 = −ρL − ρ 2 (r 2 v), (2.65)
r ∂r
which implies
1 ∂
∇ · v = 2 (r 2 v) = −L in 0 < r < r1 (t), (2.66)
r ∂r
and
1 ∂
∇ · v = 2 (r 2 v) = P in r1 (t) < r < r2 (t), (2.67)
r ∂r
where v is the radial velocity. Solving for v, we have
−Lr f (t)
v= + 2 in 0 < r < r1 (t). (2.68)
3 r
Applying the continuity of the velocity field at r = r1 (t), in 0 < r < r1 (t), we obtain f (t) = 0 and
1
v = − Lr. (2.69)
3
And in r1 (t) < r < r2 (t), we have
P r g(t)
v= + 2 . (2.70)
3 r
Applying continuity of the velocity field at r = r1 (t), we obtain the value of g(t) by substituting
v = − 31 Lr in (2.70) as
1
g(t) = − (P + L) r13 , (2.71)
3
and hence,
1 1 r3
v = P r − (P + L) 12 in r1 (t) < r < r2 (t). (2.72)
3 3 r
Using the fact that the outermost cells in the tumor are moving at the velocity of expansion of the
tumor drdt (t) = v(r2 (t)), we have
2

dr2 1 1 r3
= P r2 − (P + L) 12 (2.73)
dt 3 3 r2
which can be transformed to
"    3 #
dr2 1 P +L r1
= P r2 1 − . (2.74)
dt 3 P r2
 3 P +L
Hence r2 will increase until rr21 becomes equal to where dr2
dt = 0. We make approximation
P
r2 = r1 + h, where h is constant. At the equilibrium we have
 3
r2 P +L
= , (2.75)
r2 − h P
 1
L −3

h
1− = 1+ . (2.76)
r2 P
 Section 2.3. Modelling Avascular Stage Page 16

L
assuming P is small, we approximate the right hand side of (2.76) using Maclaurin series to obtain
 − 1
L 3 L
1+ ≈1− . (2.77)
P 3P

Substituting (2.77) into (2.76), we have

h L
1− ≈1− . (2.78)
r2 3P
3hP
Therefore, r2 ≈ L is the approximated upper bound of the tumor.
3. Vascular and Immune System Response
3.1 Modelling Vascular Stage

This is the stage where the tumor has its own blood supply. As we have seen in the avascular stage
the tumors growth depends on the availability of nutrients through diffusion from adjacent normal
tissue. To grow beyond the diffusion limited-stage tumor must have blood supply. It achieves this by
secreting a tumor angiogenesis factor (TAF) which diffuses across the tissue between a tumor and blood
vessel, activates new blood vessel formation and attracts this vessel towards the tumor. Let c be the
concentration of tumor angiogenesis in the region between the tumor and the target blood vessel. The
conservation equation for the concentration is given by:

rate of change of TAF = diffusion of TAF − loss of TAF due to cell − decay of TAF ,
(3.1)
which can be mathematically written as
∂c
= Dc ∇2 c − f (c)g(n) − h(c), (3.2)
∂t
where

• h(c) is the rate of decay of TAF, given by h(c) = dc.

• Dc is the TAF diffusion coefficient.

• f (c)g(n) the rate of intake by the cells, this rate depends on the cell density and availability of
TAF. That is, the greater the density of the cells, the more TAF will be removed by cells. Also,
no matter how much TAF is available, a cell can only consume a certain amount of it. Hence
f (c) has to be an increasing function which tends to a maximum value of TAF concentration the
cells can consume.

• n is the cell density which make up the new blood vessel.

The equation for this cells is

∂n
= F (n)G(c) − H(n) − ∇ · J, (3.3)
∂t
where H(n) is the rate loss in the absence of TAF, F (n)G(c) is the cell rate of production when
stimulated by TAF at concentration c and J is the cell flux. The function F (n) takes into account the
fact that production of cells will reach saturation point, we take it to be a logistic growth.
The flux J of the cells consists of two parts, random motion as they diffuse, and chemotactic motion
of the cells as they will be attracted towards the tumor by TAF. Thus,

J = Jdiffusion + Jchemotaxis , (3.4)

where
Jdiffusion = −Dn ∇n, (3.5)
and Jchemotaxis is proportional to the product of the gradient of the chemical concentration and density
of the cell, given by
Jchemotaxis = nχ(c)∇c, (3.6)

17
 Section 3.2. Immune System Response Page 18

where ∇c is the gradient of the chemical concentration, χ(c) > 0 is the constant of proportionality
known as chemotactive coefficient and it is positive because cells flow up the chemical gradient. Hence

J = −Dn ∇n + nχ(c)∇c. (3.7)

The forms for various functions are as follows:

 
Vm c n n
f (c) = , h(c) = dc H(n) = kp n, g(n) = , F (n) = rn 1 − , (3.8)
km + c n0 n0
and 
0 c ≤ c∗ ,
G(c) = c − c∗ (3.9)
 c > c∗ ,
cb
where c∗ ≤ cb , G(c) takes account that there is a threshold concentration level (c∗ ) of TAF below which
proliferation does not occur. The model becomes
 
∂c 2 Vm c n
= Dc ∇c − − dc, (3.10)
∂t km + c n0
 
∂n n
= rn 1 − G(c) − kp n + Dn ∇2 n − χ(c)∇ · (n∇c) . (3.11)
∂t n0
The above model is too complicated for analytical means. However, simulation has been performed
using biologically realistic parameter values to show that cells in a distant blood vessel grow and migrate
towards the tumor as would be expected, [J96].

3.2 Immune System Response

The immune system is a network of cells, tissues, and organs that work together to defend the body
against attacks by foreign bodies. The immune system must recognise foreign bodies to respond. Let’s
assume that the tumor cells have undergone some changes on the way to malignancy and hence are able
to be recognised by the immune system as foreign. In most cases, the immune system destroys foreign
bodies in two ways, one is a humoral response which is done by soluble proteins, known as antibodies,
in the bodily fluid. The second is a cytotoxic response whereby the killer cells respond to the cancer
cells.
For definiteness, let’s consider the cytotoxic response. Let X(r, t) be the concentration of the tumor
cells at position r and time t, and let E(r, t) be the concentration of the effector cells constituting the
cytotoxic response. In the absence of immune response, the tumor grows according to the equation
 
∂X X
= rX 1 − + D∇2 X. (3.12)
∂τ K

The effector cells work by combining with the tumor cells and destroy them by lysis (refers to the death
of a cell by the breaking of the cellular membrane), that is,
k
1 k
2
E+X −→ C −→ E + P, (3.13)

where C is a complex of effector and tumor cells, and P is the product of lysis. Using the law of mass
action, which states that the rate of a reaction is proportional to the product of the concentration of
 Section 3.2. Immune System Response Page 19

the reactants, neglecting the spatial variation of the cell of the immune system, the equations of the
effector and the complex are given by
dE
= −k1 EX + k2 C, (3.14)
dτ
dC
= k1 EX − k2 C. (3.15)
dτ
Since the lysis is expected to occur much faster than the processes in the volume element considered,
we make the quasi-steady state hypothesis

k1 EX − k2 C = 0. (3.16)

By adding equations (3.14) and (3.15), we have

d(E + C)
= 0, which implies that E + C = E0 . (3.17)
dτ
By substituting the value of C into equation (3.16), we obtain
k2 E0
E= . (3.18)
k1 X + k2
Hence the rate at which X is destroyed by immune cells is given by
k1 k2 E0 X
− k1 EX = − . (3.19)
k2 + k1 X
Thus, the equation for X, including the immune response, is given by
 
∂X X k1 k2 E0 X
= rX 1 − − + D∇2 X. (3.20)
∂τ K k2 + k1 X
Let  
X k1 k2 E0 X
f (X) = rX 1 − − , (3.21)
K k2 + k1 X
so we have
∂X
= f (X) + D∇2 X. (3.22)
∂τ
The function f satisfies f (0) = 0. Furthermore
 
X k1 k2 E0 X
f (X) = rX 1 − − ,
K k2 + k1 X
   
X k1 k2 E0 X
= X r 1− − ,
K k2 + k1 X
 
(rK − rX) (k2 + k1 X) − k1 k2 E0
= X ,
K (k2 + k1 X)
  
X Kk2 1
= −X X2 + (k2 − Kk1 ) + (k1 E0 − r) . (3.23)
k1 rk1 K(k2 + k1 X
The roots of function f (X) are X = 0, or
X Kk2
X2 + (k2 − Kk1 ) + (k1 E0 − r) = 0, (3.24)
k1 rk1
 Section 3.2. Immune System Response Page 20

considering the sum and product of roots of (3.24), we have

1
X1 + X2 = − (k2 − Kk1 ) , (3.25)
k1
Kk2
X1 X2 = (k1 E0 − r) . (3.26)
rk1
If r > k1 E0 , then X1 X2 < 0, hence either X1 < 0 and X2 > 0 or X1 > 0 and X2 < 0. Therefore,
we have a single positive root, say X = X ∗ . If r < k1 E0 , we have either X1 and X2 > 0 or both
negative. For all X > 0 and r < k1 E0 , the sign of f (X) from the equation (3.23) depends on the sign
of (k2 − Kk1 ), that is if k2 > Kk1 , f (X) < 0 whereas, k2 < Kk1 , f (X) > 0.
Assume r > k1 E0 . We want to find if the equation (3.22) has a travelling wave solution. Consider a
travelling wave solution of the form

X(r, τ ) = φ(z), z = r − cτ. (3.27)

Such a wave moves at a constant speed c from left to right. So we have

∂X dφ ∂z
= · = −φ′ c,
∂τ dz ∂τ
∂X dφ ∂z
= · = φ′ , (3.28)
∂r dz ∂r
∂2X
= φ′′ .
∂r 2

By substituting equation (3.28) into equation (3.22), we have

− φ′ c = f (φ) + Dφ′′ (3.29)

which is a second order ODE, which can be written as a system of first order ODE as

φ′ = v, (3.30)
f (φ) vc
v′ = − − . (3.31)
D D
This system has the steady state v = 0 and f (φ) = 0. Considering f (φ) = 0, we have φ = 0 or φ = X ∗ ,
the steady states are (0, 0) and (X ∗ , 0). We determine the linear stability of these points. Setting

φ′ = v = h(φ, v), (3.32)

f (φ) vc
v′ = − − = g(φ, v), (3.33)
D D
we find the Jacobian " #
0 1
′ . (3.34)
− f D(φ) −c
D

To find the eigenvalues, we solve

λc f ′ (φ)
λ2 + + = 0, (3.35)
D D
getting q
c 2 4f ′ (φ)
− Dc


+ D − D
λ1 = , (3.36)
2
 Section 3.2. Immune System Response Page 21

and q
c 2 4f ′ (φ)
− Dc −


D − D
λ2 = , (3.37)
2
where
2rφ k12 k2 E0 φ − k2 k1 E0 (k2 + k1 φ)
f ′ (φ) = r − + . (3.38)
K (k2 + k1 φ)2
At the steady state (0, 0),
f ′ (0) = r − k1 E0 , (3.39)
and, since r > k1 E0 , f ′ (0) > 0. To determine linear stability we consider two cases: when eigenvalues
are real and when they are complex.
Case 1: For real eigenvalues.
From equations (3.36) and (3.37) we have,
 c 2 4f ′ (φ)  c 2 4f ′ (0)
− >0 so − >0 (3.40)
D D D D
and hence r
 c 2 4f ′ (0) c
− < . (3.41)
D D D
Thus λ1 < 0 and λ2 < 0 for c > 0 . Therefore (0, 0) is a stable node.
Case 2: For complex eigenvalues we have,
 c 2 4f ′ (φ)
− < 0, (3.42)
D D
and we only need to consider the real part of the eigenvalues. From equations (3.36) and (3.37) we
have Re(λ1 ) and Re(λ2 ) < 0 for c > 0, hence it is a stable spiral.
c 2
( ′
> 4fD(φ) ,


stable node if D
So at (0, 0)we have c 2 ′ . (3.43)
< 4fD(φ)


stable spiral if D

At (X ∗ , 0), using equation (3.38), we have

2rX ∗ k12 k2 E0 X ∗ − k2 k1 E0 (k2 + k1 X ∗ )

f ′ (X ∗ ) = r − + ,
K (k2 + k1 X ∗ )2
Kr (k2 + k1 X ∗ )2 − 2rX ∗ (k2 + k1 X ∗ )2 − Kk2 k1 E0 (k2 + k1 X ∗ ) + Kk12 k2 E0 X ∗
= ,
K (k2 + k1 X ∗ )2
Kr (k2 + k1 X ∗ )2 − 2rX ∗ (k2 + k1 X ∗ )2 − Kk22 k1 E0
= . (3.44)
K (k2 + k1 X ∗ )2

This gives f ′ (X ∗ ) < 0 for X ∗ > K ∗ K ∗ 2 ∗ 2

2 , or X < 2 and r (k2 + k1 X ) (K − 2X ) < Kk2 k1 E0 , and
f ′ (X ∗ ) > 0 otherwise. We consider f (X ∗ ) < 0, from equations (3.36) and (3.37) we have real
eigenvalues λ1 > 0 and λ2 < 0 for all c since f ′ (X ∗ ) < 0 and hence
r
 c 2 4f ′ (φ) c
− > . (3.45)
D D D
 Section 3.2. Immune System Response Page 22

Therefore
q the steady state (X ∗ , 0) is a saddle point for all c. From equation (3.43), if c ≥ cmin =
2D f D(φ) , the point (0, 0) is a stable node and if c2 < 4Df ′ (φ) it is a stable spiral. Figure 3.1 illustrates
′

the phase plane trajectories. By heuristic reasoning, the phase plane trajectories in Figure 3.1 have a
trajectory from (X ∗ , 0) to (0, 0). This trajectory qlies entirely in the quadrant φ ≥ 0 and φ′ ≤ 0 with
0 ≤ φ ≤ X ∗ for all wave speeds c ≥ cmin = 2D f D(φ) provided that (0, 0) is a stable node. Hence
′

there is a heteroclinic connection which implies existance of the travelling wave.

φ′

0 φ
X∗

Figure 3.1: Phase plane trajectories

Figure 3.2 is a sketch of a travelling wave solution.

φ(z)

X’

z
0

Figure 3.2: Travelling wave front

′
For c < 2D f D(φ) , (0, 0) is a stable spiral and (X ∗ , 0) is a saddle point, we also have travelling wave
solution but this solution is not physically realistic since for some values of z, φ will have negative values
because the wave spirals around (0, 0).
Therefore from the phase plane trajectories, we can see that strong immune response can drive the
tumor to extinction while weak immune system will allow it to grow indefinitely.
4. Conclusion
The models presented in this essay vary in complexity and provide different information on tumor growth.
The first three models tell us how the number of tumor cells vary with time, and predict that a tumor
will grow exponentially in its very early stage. Apart from that, logistic and Gompertz predict that as a
tumor grows it will tend to the carrying capacity of the environment.
In avascular stage, the tumor’s growth is governed by the nutrient-diffusion limit and thus tumor cells
at the centre start to die and create a necrotic core. At this stage, the model has been able to predict
the size of the necrotic core, the size of the shell of proliferating cells and the size of the tumor.
A tumor has the ability to develop its own blood vessel, and hence to overcome the nutrient diffusion
limit stage and become vascularized. It has been shown that the cells in distant blood vessel proliferate
and migrate towards the tumor. Using this result an anti-angiogenesis treatment has been used to break
this network so as to starve the tumor and hence reduce its growth.
Finally, the model for an immune system suggests that if the immune system is stronger, the effector
cells will be able to kill the tumor cells, whereas the weaker ones will not.

23
Acknowledgements
I give all the glory to God, for the grace and strength He gave me throughout the course. Thank you
Lord.
I would like to express my gratitude to my supervisor Professor Jacek Banasiak, my tutors Hermane and
Aziz, for their assistance, guidance and contribution throughout this essay.
My gratitude also goes to the AIMS administration Professor Neil Turok, the founder, Professor Fritz
Hahne, the director and others for giving me opportunity to study here. Thanks for your support.
Special regards to Jan, Frances, Igsaan, Emmanuel, lecturers, tutors and the rest of AIMS staff.
I cannot end this acknowledgement without appreciating EX-AIMS students from Tanzania for their
advice. A lot of thanks also goes to all AIMS students whose company made AIMS an interesting place
to be.
Finally I would like to thank my family for their love, care and encouragement. May God bless you all.

24
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[J96] Chaplain M. A. J, Avascular growth, angiogenesis and vascular growth in solid tumors: The
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[L88] Edelstein-Keshet L, Mathematical models in biology, SIAM’s Classics in Applied Mathematics

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[L03] Preziosi L (ed.), Cancer modelling and simulation, Chapman and Hall/CRC Mathematical Bi-
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25