Mathl. Comput. Modelling Vol. ‘20, No. 1, pp.

107-122, 1994
Pergamon Copyright@1994 Elsevier Science Ltd
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Dynamics of Tumor Interaction

with the Host Immune System
N. BELLOMO
Department of Mathematics, Politecnico, Torino, Italy
G. FORNI
Consiglio Nazionale delle Ricerche
Center of Immunogenetics and Histocompatibility, Torino, Italy

(Received January 1994; accepted February 1994)

Abstract-This paper deals with the mathematical modelling of the dynamics of tumor progres-
sion despite an active immune defense system. A general theory is proposed based on the modelling
of cellular interactions in a framework similar to the one of nonlinear statistical mechanics. Some
specific models are described with reference to well-defined physical systems and to their experimen-
tal analysis. Suitable experiments are related to the numerical simulation of the model in order to
validate the proposed theory.

Keywords-Tumor growth, Immune system, Kinetic interactions, Cellular interactions.

1. INTRODUCTION
This paper deals with the mathematical modelling of the dynamics of a system constituted by
a tumor which grows in vivo and interacts with the host immune system. The host system has
the potential capability of producing some significant anti-tumor reactions, since it can recognize
tumor-associated membrane antigens or mutated peptides presented by histocompatibility com-
plex [l]. These reactions, indeed, may either impair or enhance the growth progression, resulting
in cachexia or eventual death [2].
Mathematical models of tumor growth are traditionally developed in the framework of con-
tinuum mechanics, (see amongst others [3-7]), which model the system with classical diffusion-
convection equations. On the other hand, although continuous models can provide important
contributions to the prediction of the behaviour of such a complex system, it is recognized,
(see [S,9]), that the interactions between tumor cells and host environment occur at the cellular
level. Therefore, it seems natural to model the cellular interactions with the methods of kinetic
theory and to develop suitable evolution equations for statistical variables related to the distri-
bution over physical states which characterize the various interacting populations: tumor, host,
immune system cells. The moments of the aforementioned statistical variables can provide, as
usual in statistical mechanics, the evolution of macroscopic observables. In other words, the evo-
lution of macroscopic observables is derived by evolution equations developed at a microscopic
(cellular) level.

Partially supported by grants from MURST, Minister for University and Technological Research, CNR, National
Research Council, Italy, project MMPMI of the “Gruppo Nazionale per la Fisica Matematica,” and by AIRC,
Italian Association for Cancer Research. The authors are indebted to A. Belleni Moraute for several useful remarks
on an early edition of this paper.

Typeset by AM-T&X

MCM
20:1-H 107
 108 N. BELLOMO AND G.FORNI

This methodological approach, which is typical of the kinetic theory of gases [lo], is followed
in this paper, which provides a new modelling methodology proposed as an alternative to the
traditional one. One may hope that a suitable development of this new approach can contribute
to a further understanding of the extremely complex system with which we are dealing.
A general theory developed, as already mentioned, in a framework closed to that of non-
equilibrium statistical mechanics. The theory is then used to derive some detailed models, re-
ferred to the specific host-tumor system and to some specific experiments. The cell populations
characteristic of this system are identified, the interactions between them are modelled and,
finally, an evolution equation is derived for variables suitable to define the probability distribu-
tion over the cellular state of each population.
The various cells of the populations interact by means of binary encounters which may or
may not change the state of the participating pair and may or may not result in either their
proliferation or their death.
The theory is developed in a sufficiently general framework to be hopefully able to generate
further models referred to host-tumor immune relationships and perhaps to other immunological
problems. In other words, one of the final aims of this paper is to provide a general, Boltzmann-
type, kinetic theory for nonequilibrium immunological situations. The specific objective is to
obtain both a general theory and models suitable to predict the evolution of the tumor, immune
and host system characterized by interactions in natural conditions or when the manipulation
of the immune reactivity leads to prevention of tumor growth or the inhibition of established
tumors.
The paper is organized in five sections:

- Introduction.
- Description of the mathematical theory.
- Modelling of some specific physical systems.
- Simulations and comparisons with the experimental results.
- Discussion on the need of a physico-mathematical theory applicable to immunologic sys-
tems.

The mathematical framework followed, in the formulation of the mathematical theory, is the
one of the classical kinetic theory, (see [lO,ll]), and of the mathematical molecular theory in
biological sciences [12,13] with special attention to models based on the methods of nonequilibrium
statistical mechanics, (see [14-161).

More in particular, the following comments are addressed to the attention of the reader:

- The physical system we study in this paper is certainly characterized by a great inner
complexity. Therefore, a physico-mathematical theory which attempts to define the be-
haviour of such a system cannot lead to a trivial formalization. Nevertheless, an effort is
made, throughout this paper, to simplify several mathematical aspects in order to make
the model as manageable as possible.
- A detailed analysis of the interactions between the cells of the various interacting pop-
ulations is crucial to the definition of the mathematical model. These interactions are
developed, by the model, into suitable evolution equations which describe the time evolu-
tion of the physical state of each population.
- The modelling steps are organized having in mind conceivable experiments suitable to
validate each step of the modelization process. Some of these experiments are proposed.
- The approach developed in this paper is an alternative, still to be developed, to the
traditional modelling of the tumor growth based upon classical continuum mechanics.

The reader is referred, among others, to [8,12,17,18] for a general bibliography on tumor im-
munology; and to (6,7,19-261 for experimental research in the field.
 Tumor Interaction 109

2. THE MATHEMATICAL THEORY

As already mentioned, the aim of this section is to develop a kinetic or Boltzmann-like theory to
describe the nonequilibrium evolution of a population of several interacting populations referred
to the physical system, briefly described in the Introduction.
The mathematical modelling, as in the kinetic theory of gases, starts from the modelling, at the
microscopic level, of the interaction between cell pairs and then ends in deriving, by suitable
balance equations, an evolutionequation for the probabilitydistributionover the physical state
of the cells for each population. Macroscopic information is obtained from suitable moments
of this distribution.
In detail, the axioms which define the mathematical theory are, still remaining in a very general
framework, the following:

AXIOM 1. The physical system consists of cells belonging to n interacting populations, each
population denoted by the subscript i, with i = 1,. . . ,5, where i = 1 corresponds to the tumor
cells, i = 2 corresponds to the cells of the feeding host and i = 3,4,5 to the cells of the immune
system. In particular, the analysis refers to Polymorpho Nuclear Leukocytes for i = 3,
Lymphocytes for i = 4, and Macrophages for i = 5, respectively.

AXIOM 2. The physical state of each cell is described by the variable u, called activation state,
or simply activation), whose values span in the interval [0, 11. The detailed physical meaning of
the variable u must be specified for each population. In the case of the immune system, u can be
concentrated on a finite number of discrete values Uh, h = 1,. . . , m. The statistical of the state
of the whole system is defined, for each of the n populations, by the the number densities

Ni = Ni(&U) : P, Tl x LO,
114 R+ , (2.1)
where by Ni(t, u) du defines the number of cells (referred to a certain volume, where the rel-
evant aspects of the phenomenon are observed) of the i-population which, at the time t, are
characterized by an activation in the range [u, u + du]. In particular,

1
?li = Ni(t, u) du (2.2)
I0

defines the number of cells in the same volume of the i-population. Moreover, the state of the
whole system is defined by the whole set of number densities

N={N,... ,%I, Ni 2 0. (2.3)

AXIOM 3. Encounters between pairs can be divided into conservative encounters, which pre-
serve the total number of cells and are characterized by transition of state, and proliferative
encounters, which are characterized by increase or decrease of the number of individuals. Con-
servative encounters occur between cell pairs, from the same or different populations, and
have transition rates of the type

-4j(v,W;U) = ‘%j(v,W)d’ij(v,W;
U) 7 (2.4)

where:
l Aij(v, w; u) denotes the number of encounters per unit volume and unit time between cell
pairs of the (i,j)-populations with states v and w, respectively, and transition into the
state u.
l nij(v, w) IS the encounter rate, which denotes the rate of such encounters.
l $)zj(U, w; u) is the transition probability density, which denotes the density of the
probability distribution of such encounters and transition into the state u.
 110 N. BELLOMO
AND G. FORNI

Proliferative encounters occur between cell pairs of the same or different populations, and
generate a proliferation or a destruction rate in the i-population of the type

si=N~(t,u)i:J1s,(u,v)Nj(~,v)dv,
j=l 0
(2.5)

where s denotes a term which will be definedproliferation-destruction rate coefficient.

AXIOM 4. The number of encounters per unit time in the unit volume, between cells of the
(i,j)-p op uJa t’10ns with states (u, w) is proportional to the product Ni(t,u)iVj(t, w).

AXIOM 5. An external action vi(t), which may depend on t, can be defined in such a way that
it acts directly on the rate of growth of u related to Ni

du
- = pi(t).
dt (2.6)

AXIOM 6. Generation from the bone marrow will be equivalent to the death of unstimulated
cells. The artificial addition of cells from each population is simulated by suitable source terms
yi = yi(t, u).
REMARK 2.1. Assumption Axiom 4 implies a statistical independence of the distributions Ni and
Nj. This hypothesis is generally used in phenomenological kinetic theory and can be accepted
for bounded times.
REMARK 2.2. The terms 1c,have the structure of a probability density
1
$%j(%W'1L) = 1, v'i,j = l,...n, vv,w. (2.7)
s0

REMARK 2.3. The term theory is here used to denote the axiomatization which has been defined
above. Such a theory generates a abstract mathematical model, i.e., a set of evolution
equations for the densities Nib, which can be obtained, as we shall see, by suitable balance
equations. The abstract model will be particularized, in the next section, to the description of a
specific physical system.
REMARK 2.4. The specific model involves the identification of its characterizing terms 17,II,and s
and is, in particular, the model is identified by the square matrixes

= [rlijl 7
1771 [+I= [thjlY [Sl= [Sijl. (2.8)
The identification of these terms model requires the project of suitable experiments.
The theory follows some of the classic methods of the phenomenological kinetic theory of gases
[lO,ll] and the classic theory of population dynamics [27]. In particular, the evolution equation is
obtained by equating the total derivative of Ni to the gain and loss terms, Gi and Li, generated
by the interactions between cell pairs and their related change of state

g + vi(t)& Ni(t,u) = Gi[N](t,u) - L[N](t,u) + si[N](t,u), (2.9)

( >
where Gi denotes the rate of increase, per unit time, of the number density referred to the
i-element, with state u, due to the encounters with all other cells. Similarly, Li denotes the rate
of decrease, related to Ni.
Technical calculations, based on the axioms which have been stated above, provide the expres-
sions of the gain and loss terms. Respectively,

Gi=eJ’/’vij (
j=l O O
21,~ )Q’.(v,w;u)Ni(t,v)Nj(t,W)dvdw+yi(t,u),
23 (2.10)
 Tumor Interaction 111

and

Li = N,(t,zL)~/17j,(ZL,w)Nj(t,V)dV, (2.11)
j=l O

where ri(t, U) takes into account the source term.

So that the expression of the mathematical model is obtained by substituting equations
(2.5), (2.10) and (2.11) into (2.9). This yields

Ni(t,u) = Ti(t~u) + 2 J’
(g +ViCt)z) J'Qj(W, W)+ij(V, W; U)Ni(t,W)Nj(t,UJ)dWdW
O O j=l

(2.12)

Such a model can be written in compact vector form as follows:

LN + [A(N)] x N = b(N, N) + [S(N)] x N + y(t, u), (2.13)

where

Y = {Ti)iLl7 (2.14)

[A(N)] is an n x n matrix with elements

1
Qj = o qij (u, v)Nj (t, v) dv, (2.15)
I

b = {bi}z=i is a vector with n elements bi defined as follows:

(2.16)

[S(N)] is an n x n matrix with elements

1
Sij =
I 0
sij(u,v)Nj(t,v)dv. (2.17)

Equation (2.13) can also be rewritten, with obvious meaning of symbols, as follows

LN + [C(N)] x N = b(N, N) + y(t, u). (2.13’)

REMARK 2.5. The model which we have just seen can be regarded as a superposition of a kinetic
and a population dynamics model which retains some features of both classes.
We can now consider the general case of models where the immune system is characterized by
continuous distribution over the state u, whereas the tumor and host cells are characterized by
a state localized on discrete values of the variable U. The term cp only acts on the cells of the
immune system. In this case,

Ni = 2 Nib(t) b(U - ah), i = 1,2, (2.18)

h=l
 112 N. BELLOMO AND G. FORNI

where 6 is the classic Dirac delta function. The next section gives some detailed examples of
the model stated in equation (2.18). In particular, we may assume (as is reasonable) that the
first two populations have a discretized state and that the immune system is characterized by
a continuous distribution over the variable U. Substituting, for the first two populations, the
discrete model (2.18) yields, in the case cpi = 0, the following semicontinuous model

i = 1,2, h=l,...,m:

u~, uk)ti)ij(up, uk; Uh)Nzp(t)Njk(t)

j=l p=l k=l

+ &$%j(uh+k) - sij(uh,uk)) Njk(t) -t ‘-Yi(t, Uh), (2.19a)

j=l k=l
I

i = 3,4,5, h=I,...,m:

1
2 m

+xX (%j(‘%uk) - %jb,~k))&k@) + -Yi(t,U)- (2.19b)

j=l k=l

If (pi # 0, the continuous derivative of N can be used for the continuous system. On the other
hand, the derivative of N for the discrete system can be approximated by a suitable ratio of finite
differences.
Discretization is a natural direction to follow in order to obtain a model suitable for numerical
simulations. In fact, the number densities can be discretized over a set of collocation points

Ni(t,u) = 5 Nib S(u - Q), i=1,...,5, (2.20)

h=l

or by any other analogous interpolation; then, a fully discrete model can be obtained

i= l,...,m, h=l,...,m:

E&q = 222 ..(

77%~ Up, Uk)@‘ij(Upr uk; %)Nip(t)Njk(t)
j=l p=l k=l

uhr uk) - sij(uh,uk)) Njk(t) f ?ih(t). (2.21)

I
 Tumor Interaction 113

This section concludes with some final remarks.

REMARK 2.6. The discrete model (2.21) has to be regarded, not only as a first step towards
numerical treatment of the differential equation. In fact, one can obtain a simplified model by
choosing a small number of discrete values of the variable u related to specific values corresponding
to particular states. For instance, if all distributions Ni are localized on the value u = 1, then the
model further simplifies into the classic deterministic model of population dynamics. Examples
of this type will be given in the next section.
REMARK 2.7. The model was technically proposed for five populations. Dealing with a larger
number of populations, for instance, by increasing the number of populations in the immune
system, is simply a matter of addition of new terms.
REMARK 2.8. Although three forms of the mathematical model were proposed, one has to look at
them as technical particularizations of the same general theory, axiomatized in the assumptions
Axiom l-Axiom 6. They are mathematically represented in the model defined in equation (2.12).
In other words, equations (2.19) and (2.21) can be regarded as technical developments of the
model (2.3).
REMARK 2.9. The evolution equations can be further simplified, whenever it is possible to assume
(e.g., for limited time intervals) that the number of cells of the host environment is constant, i.e.,
Ns = N2c = const.
REMARK 2.10. We need to be aware of the fact that the theory which we have proposed in this
section is based on the assumption that the cells of each population behave as free particles. This
is correct when the size of the tumor is sufficiently small. On the other hand, when the size of
the tumor is not of the same order of the one of the cells, then the theory must be adapted to
the fact that the tumor cells occupy a finite, nonnegligible volume. The shape of a tumor can be
roughly approximated by a sphere.
The contents of Remarks 2.6 and 2.9 will be taken into account in the analysis developed in the
next section. A more general theory should model the interaction between tumor cells located
on the surface of the tumor and the cells of the outer populations. This analysis gives rise to
initial-boundary value problems. This topic is planned as a research perspective.

3. MATHEMATICAL MODELS
More specific models can now be studied. In particular, the physical system we want to model
is constituted, at the macroscopic level, of the following elements:
l a tumor which grows in uivo,
l the host environment,
l the immune system.
Both the tumor and immune system are produced and fed by the host environment. The
immune system is composed of three populations (Assumption Axiom 1).
Particularization of the general theory substantially involves the derivation of specific models
for the terms viJ, sZg, and &, which define n x n matrixes denoted, in what follows, by

to be properly identified, which will be called, respectively, encounter, competition and interaction
matrices. Moreover, the activation state related to each population must be properly modelled
by giving a detailed meaning to the variable u with reference to each population.
Two specific models will be proposed and suitable experiments conducted to obtain detailed
values. Considering that the aforementioned matrices defined have to be identified experimentally,
these models have to be simple enough to allow the organization of suitable experiments. The
first model refers to the evolution of a tumor in a system where the immune defense has been
 114 N. BELLOMO AND G. FORNI

substantially suppressed. The second one refers to a system with operative immune surveillance.
These models will be used to compare theory and experiments. These two models, are based
almost entirely on the theory developed in Section 2 and are related to the experiment reported
in Section 4.
This section is organized into four subsections, each of which refers to the topics which have
been outlined above.

3.1. Modelling of the Matrix [q]

As we have seen in Assumption Axiom 3, the terms ~j which characterize the matrix [q] define
the reaction rate between cell pairs of populations (i, j). These elements have the dimension of
a velocity. The following modellization scheme can be adopted

Vij(U,W)= Cij(U,W)crij, (3.1.1)

where cZj is a parameter which defines the encounter rates between cells of the (i, j)-populations,
aij = 1 defines the probability that the encounter significantly modifies to the system. In par-
ticular, it may be assumed that CQ can attain the values 1 and 0: cqj = 1 when the encounter
generates some significant modification to the system and CYij= 0, when no significant modifica-
tion occurs. Table 3.1 is a sample proposal for these terms, when the interaction probability is
assumed to be independent on the state of the two cells.

Table 3.1. Coefficients cq3.

The terms cij, have to be evaluated experimentally. Of course, it is sufficient to take into
account only encounters which generate change in the state of the interacting population, i.e.,
when aij = 1. The experiment can be organized identifying the number of encounters of a known
number of cells in a fixed time interval.

3.2. Modelling of the Matrix [S]

The elements sij which characterize the matrix [S] define the proliferation or destruction rate
due to the encounter between cell pairs of the populations (i, j). The modelling can be organized
in the same way. In order to take into account only encounters which generate an effectively
significant proliferation, the following modelization scheme can be adopted

(3.2.1)

where /3ij = 1 or & = -1 when the encounter generates some significant proliferation or de-
struction, respectively, and pij = 0, when such a proliferation does not occur. Table 3.2 is again
a sample proposal for these terms, when the interaction probability is assumed to be independent
on the state of the two cells. The double sign f refers to the fact the interaction may generate
either proliferation or destruction according to the state of the cells. In particular, this may
depend on the state of activation of the cells of the immune system. For instance, if the immune
system is such that u E [O, i], th e immune system feeds the tumor. On the other hand, when
u E ($, l] , then the immune system is able to destroy the tumor cells.
The terms c&, have to be evaluated experimentally. The measurement can be set up identifying
the proliferation rate related to specific encounters.
 lhmor Interaction 115

Table 3.2. Coefficients flij.

3.3. Modelling of the Matrix [$,I

As already mentioned, the terms $~ij refers to conservative encounters with transition of state
without proliferation, and define the probability that a cell of the i-population with activation
state v ends up, after the encounter with a cell of the j-population with state w, in the state u.
Also, in this case, very simple models will be proposed in order to deal with models tractable
in a simple way. Suitable experiments may reasonably modify and improve the models which will
be proposed in what follows.
In particular, we propose to model the terms $.~ij in the following way

7))i.j= S(” - rnij) ) (3.3.1)

where mij is selected in several ways, such as

Ml: Dominance of the higher state, max{v, w} I rnij I 1, Vi, j. (3.3.2)

M2: Dominance of the lower state, 0 5 77lij 5 min{v, w}, Vi, j. (3.3.3)
M3: Dominance of population i (or j) over j(or i), mij = vi, Vu, w. (3.3.4)

The models which have been proposed above yields to different expressions of the terms bi
of the vector b which characterize the model defined in equation (2.13). Technical calculations
provide the following results corresponding to equations (3.3.2)-(3.3.4), respectively,

Ml: bi = eaijcij
j=l
{J’(.fi)(u).fj(u) - fi(u) [l - F(fj)] (IL)}, (3.3.5)

M2: bi = 2
j=l
Qijcij {fj(u) [l - J’(fi)] (u) - F(fj)(u)fi(u)} , (3.3.6)

M3: bi = 5 cti3cijfi(u), or bi = Caijcij_fj(u), (3.3.7)

j=l j=l

where
(3.3.8)

If u is modelled as a discrete variable which can attain only a finite number of values, then $ij
is a discrete random variable which may be indicated as follows:

(3.3.9)

where

ch
+=l. (3.3.10)
 116 N. BELLOMOAND G. FORNI

3.4. Modelling of the Tumor-Host System Interactions

This subsection deals with the derivation, in the framework of the theory developed in Section 2,
of a simplified model related to the experiments which will be presented in the next paragraph.
The model will be a relatively simple one, such that an immediate analytic solution can be
obtained and used for preliminary comparisons between theory and experiments. With this in
mind, we consider a system characterized by three populations corresponding to the tumor, host,
and immune system. The state of each population is assumed to be concentrated on u = 1.
Therefore, referring to a certain region where the interaction phenomenon occurs, the state
variable of the model can be defined by the number of cells of the tumor, host environment, and
immune system, respectively

N = N(t), M = M(t), P = P(t). (3.4.1)

A simple (perhaps oversimplified) model can be derived, in the framework of the population
model only (i.e., by neglecting the kinetic-type interaction with change of state, and using the
following assumptions.

ASSUMPTION 3.4.1. The number of host cells remains substantially constant during tumor
growth, i.e., M = MO = const.

ASSUMPTION 3.4.2. The effective interactions are

N ++ M, with proliferation of N.
N H P, with depletion of N.
P t-1 P, with proliferation of F’.
P ++ N, with depletion of P.

The mathematical model which follows is

dN
- = aMoN - BNP,
(3.4.2)
CE
- = cP2 - dPN,
dt

where a, b , c, and d are positive constants. By introducing the dimensionless variables

(3.4.3)

system (3.4.1) can be written as

dx
- = xx - 1/xy,
dt
(3.4.4)
dy =
z py" - 6xy.
\
The physical meaning of the parameters X , u, and p is evident:
X refers to the ability of the host system to feed the tumor.
u refers the capacity of the immune system to contrast the tumor growth.
I_Lrefers to the capacity of the immune system to increase its own population.
The solution of the initial value problem, with initial conditions x = y = 1, can be obtained by
standard numerical integration for ordinary differential equations, (see [28, Chapter 21). If the
immune system is suppressed, i.e., y = 0, then the solution is

n: = 8. (3.4.5)
 Tumor Interaction 117

Figure 3.1. Qualitative behaviour of the tumor growth contrasted by the immune
system.

If the immune system is active, then it contrasts the growth of the tumor. The most efficient
contrast occurs for 6 = 0. In this case, the solution is analytic

Z = (1 - @)V’%At (3.4.6)

This solution clearly shows how the immune system can hamper the tumor growth. Such a
solution is meaningful if the size of the tumor is not too large, and the surface effects mentioned
in Remark 2.10 do not need to be taken into account.
Figure 3.1 shows the qualitative behaviour of the solution reported in equation (3.4.6) for fixed
values of p and Y/P and different values of A. In principle, the immune system can be successful
in destroying the tumor. Unfortunately, when the tumor becomes larger than a certain critical
size, which is indicated in the figure by a continuous line, then the metastases are detached and
spread over the body. The effective destruction can be achieved only by tumors characterized by
small values of A.
This simple model suggests classification of the aggressivity of the tumor by the parameter X
and the highest defense capability of the immune system by the parameters p and V/P. This
type of identification can be organized by suitable experiments, as shown in the next section.
It needs to be mentioned again that such a model is a simplification of the theory proposed in
Section 2 and shows how such a theory can generate the usual models of population dynamics.
On the other hand, if u can attain values different from one, then the effect of the interaction
matrix has to be taken into account. This needs the proper identification of the probabilities ?Ih
defined in equation (3.3.9).
Being aware that the models (3.4.5) and (3.4.6) contain somewhat limited information com-
pared with the one which is available by the theory of Section 2, still some very preliminary
comparisons between theory and experiments can be organized waiting for the identification of
the key terms q and $, which will require additional theoretical and experimental studies. These
comparisons will be performed in the next section.

4. EXPERIMENTS AND IDENTIFICATION

This section deals with the simulation of the model related to suitable experiments which are set
up in order to validate the proposed theory or, at least, the specific model model. In particular,
suitable experiments and suitable comparisons between the experimentally measured values and
the prediction of the model have been set up. It will be shown indeed, that a satisfactory
agreement is reached.
Let us first describe the main features of the experiments which has been set up. In detail,
the experiments have been addressed to compare the predictions of the model to the measured
 118 N. BELLOMO AND G. FOFLNI

values in uivo with reference to the following two specific physical situations:
(i) Tumor growth in a host environment where the immune system has been essentially sup-
pressed.
(ii) Tumor growth in a system, in which the immune surveillance is active.
Reference will be made, in both cases, to the two specific models derived in Section 3.

4.1. Description of the Experiment

The main characteristics of the experiment are the following:

l Mice: Normal 7-week-old female BALB/cnAnCr(BALB/c)(H-2d, Mid’) mice (Charls
River Lab., Calco, Italy) were treated in accordance to the European Community guide-
lines. When sublethal whole body irradiation was required, mice received 5 Gy from a
137C source providing a dose rate of 0.5 Gyjmin.
l Tumors: The experiment was set up with two kinds of tumors: a highly aggressive and
poorly immunogenic cell line established from the first in vivo transplant of a moderately
differentiated mammary adenocarcinoma that spontaneously arose in a 20-month-old mul-
tiparous BALB/c mouse (TA/A) and a poorly immunogenic methylcholantherene-induced
sarcoma of BALB/c mice (CE-2). Mice were challenged S.C. in the inguinal region with
0.2 ml of a single cell suspension containing 4 x lo4 trypan blue dye excluding cells, which
is about the minimal 100% tumor introducing dose for tumors.
The cages were coded, and the incidence and growth of tumors were evaluated twice weekly in
a fashion blind to the group in which they had been treated. Neoplastic masses were measured
with calipers in the two perpendicular diameters for 60 days. Mice tumor-free at the end of
this period were classed as survivors. No de novo tumor incidence was observed 30 days after
challenge.

4.2. Comparisons between Theory and Experiments

The comparisons between theory and experiments will be organized using the simplified models
reported in equations (3.4.5) and (3.4.6). It is plain that, due to the simplifications applied to the
theory of Section 2 to obtain the aforementioned models, we will not talk about model validation,
but simply of the first steps towards such a problem. In particular, this comparisons only refers to
the population dynamics. On the other hand, the validation of the full model requires additional
experiments which are in progress at present.
The experimental and theoretical results are reported in Figures 4.1 and 4.2, which show the
growth of the diameter of a quasi-spherical tumor in the case of the CE-2 and TS/A, respectively,
referring to irradiated and nonirradiated mice. The dashed and continuous lines refers to the
theory for irradiated and nonirradiated mice, respectively, for both tumors. The experimental
results are indicated, by triangular dots in the first case and large dots in the second one. Both
figures show how the interaction with the immune system consistently delays growth. The size
of the tumor is represented assuming an approximately spherical shape.
The same figures show that, at least in the conditions of this experiment, the agreement between
theory and experiments is very satisfactory. The agreement is better for nonirradiated mice. In
fact, if the size of the tumor remains small, then the theory is consistent. When the size of the
tumor becomes large, then the theory must be modified in order to take the effect of the surface
phenomena into account.
More in detail, the results of such a comparison can be listed as follows:
l The size of the challenge, at t = 0 is of 0.442 mm for the CE-2 tumor and of 0.612 mm for
the TS-A tumor. The diameters are expressed in mm, the time in days.
 Tumor Interaction 119
20

0 CE - 2
1 A

i- /

Figure 4.1. Progressive growth of the mean tumor diameter q5 versus days d after
challenge for untreated and sublethally irradiated BALB/c mice, CE-2 tumor.

0 10 23 t 30
Figure 4.2. Progressive growth of the mean tumor diameter Cpversus days d after
challenge for untreated and sublethally irradiated BALB/c mice, TS/A tumor.

l The action of the immune system is essentially the same for both tumors and is charsc-
terized by the values
1_1=0,025, !=1.40.
I-L
l The term A which characterizes the growth of the tumor in the absence of interaction
with the immune system is X = 0.160 in the case of the less aggressive CE-2 tumor and
A = 0.175 in the case of the more aggressive TS-A tumor.
l The experiment only focuses on the competition between tumor cells and immune system.
The change of state is not observable.
Considering that the problem of developing experiments suitable to a further validation of the
theory is still open, some ideas on the set up of experiments are given here. With this in mind,
we recall that sublethal total body irradiation is a rough and radical way to temporarily inhibit
almost all the immune mechanisms. In fact, the high bone marrow susceptibility to irradiation
temporarily blocks the maturation of lymphocytes, granulocytes, leukocytes, and macrophages.
In the absence of bone marrow supply, their peripheric levels number gradually drops to zero.
In BALB/c mice, a marked immunodeficiency is already evident 5 days after irradiation and
lasts for another 15 days. Indeed, sublethal irradiation may affect many other body functions.
However, the enhanced growth observed with both CE-2 and TS/A tumors in sublethally ir-
radiated mice is probably the direct consequence of the temporary absence of all cell-mediated
immune mechanisms. Previous experiments have shown that tumor growth is modulated by the
cell mechanisms of natural immunity. Reconstitution of sublethally irradiated mice with lym-
phocytes, polymorphonuclear leukocytes, or macrophages restore host natural reactivities and
results in impaired tumor growth, (see [2,23]).
 120 N. BELLOMO
AND G. FORNI

Experiments are currently in progress to explore in which way the selective removal of lym-
phocyte subpopulations and polymorphonuclear granulocytes affects CE-2 and TS/A growth.
On the other hand, experiments will evaluate in which way the positive modulation of immune
reactivity through lymphokines or prevaccination with mitomycin-C treated tumor cells with
impair CE-2 and TS/A growth. These experiments can provide more analytic data to validate
the general theory and the model.

5. SOME REMARKS ON THE MATHEMATICAL THEORY

The interplay between mathematics and biology can enumerate several successful collabora-
tions. Complex biological systems can be modelled by adapting classic equations of mathematical
physics to the analysis of biological systems. Examples can be found in the book by Segel [13]
or in that by Lin and Segel [29], in the survey paper by Keener and Tyson [30] on the modelling
of wave phenomena in the heart and in the book by Cronin [31] on the analysis of nerve impulse
propagation by the celebrated Hodgkin and Huxley model.
On the other hand, some successful results are not sufficient to generate a mathematical the-
ory for biological systems. This may be one of the reasons which suggested the statement of
unreasonable effectiveness of mathematics in the natural sciences to the famous mathematician
Eugene Wigner, in his paper [33].
In fact, biology is an highly sophisticated science ruled by mechanisms at cellular and molecular
scales which are extremely difficult to be interpreted and modelled. In general, one should attempt
to develop a general mathematical theory rather than specific models and it is not unreasonable
to state that a new mathematics is needed.
The effort of the authors of this paper is addressed in the direction which is outlined above.
In fact, the paper proposes (rather than a specific model) a class of models which should hope-
fully describe the time-evolution of several populations in interaction-competition. The common
features of such a model are the following:
l Several populations interact with competition, proliferation, and cooperation behaviours.
l The interaction occurs between pairs of (cells) individuals of the same or different popu-
lations.
l The state within each population is defined by a suitable probability distribution. The
mathematical theory provides, on the basis of the pair interactions, the evolution equations
of such a distribution.
l The modelling of the interaction laws between pairs of individuals of the various popula-
tions must be directly based upon suitable experiments organized at a cellular level.
l The validity of the mathematical theory should be tested by means of suitable comparisons
between the results provided by the mathematical theory and the one given by experiments
on the whole system. That is a system of several populations interacting in a living
organism.
The various aspects of the general theory and the interplay of the common features which have
been listed above are represented in the block diagram of Figure 5.1.
Some remarks may further clarify some of the concepts which have been stated above.
REMARK 5.1. The general theory is not limited to a specific system. In fact, such a theory can,
at least in principle, be related to the mathematical description of several systems. One needs a
proper selection of the state variable, i.e., a proper definition of the populations which constitute
the system, and a suitable modelling of the interaction processes at the cellular level.
REMARK 5.2. The interaction between theory and experiments is developed at two different
levels. Experiments at a microscopic scale (cellular level) and experiments at a macroscopic scale
(the size of each population: in our case, the size of the tumor).
REMARK 5.3. It is important to provide a careful modelling of the external actions cp which
can modify the evolution of a certain population by a direct action. In particular, it appears
 Tumor Interaction 121

Phenomenological Observation and Measure

of the Physical System

Modelling of the Pair Interactions

Modelling of the Proliferation Processes

Derivation of the Mathematical Model

Figure 5.1. Modelling and model analysis.

important to select, on the basis of the previsions of the model, the actions which (if applied) can
effectively prevent the growth of the size of a certain population (in our case, the tumor) over a
certain critical size.

REMARK 5.4. The theory was here developed dealing with tumor cells, environment and immune
system as populations of isolated individuals. A necessary development consists in dealing with
a modelling such that the tumor is dealt with as a continuous system and the environment
and immune system behave as populations of individuals. This approach will require a detailed
modelling of the interactions on the boundary of the tumor.

Let us finally conclude this section by a few brief comments on the mathematical aspects of the
problems related to the qualitative and quantitative analysis of the model. In particular, one can
observe that the model consists of a nonlinear system of integro-differential equations. The related
mathematical problem is an initial value problem in the case cp = 0 and an initial-boundary value
problem in the case cp # 0.
The quantitative solution of this problem does not seem a particularly difficult task. In fact,
classic methods of applied mathematics, see [28], can be used to obtain quantitative results. In
general, one discretizes the distributions Ni in order to reduce the problem into a system of
ordinary differential equations. The procedure is essentially the one already dealt with in order
to obtain equations (2.21). Then, the system of ordinary differential equations can be numerically
integrated by explicit of implicit methods.
On the other hand, the qualitative analysis, i.e., existence and qualitative properties of the so-
lutions may, in some cases, involve serious difficulties. In principle, one uses methods of nonlinear
functional analysis in a line similar to the one followed in [11,33], where a qualitative analysis is
developed for a class of equations which have some analogy to the one proposed in this paper.
On the other hand, the main difficulty comes from the presence of the proliferative encounters
and by the quadratic growths ruled by the matrix [s]. Although qualitative analysis is not an
objective of this paper, it seems important to point out that a detailed analysis of the stability
and instability properties may bring relevant information on the predictions of the model.
122 N. BELLOMO AND G. FORNI

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