Medical Hypotheses (2007) 68, 1333–1341

http://intl.elsevierhealth.com/journals/mehy

Tissue homeostasis and cancer

a,b,*
Alejandro Rodrı́guez-Molinero , Marı́a López-Diéguez a,
José R. Banegas a

a
Department of Preventive Medicine and Public Health, Universidad Autónoma de Madrid,
Arzobispo Morcillo 2, 28029, Madrid, Spain
b
Clinical Research Unit, Fundación Hospital Comarcal San Antonio Abad, Vilanova i la Geltrú, Barcelona,
Spain

Received 3 October 2006; accepted 10 October 2006

Summary Epithelial cells are known to release an important amount of cytokines capable to modulate immune
system functions. On the other hand, immune system cells can release cytokines, which play an important role in the
control of the growth of epithelial cells. In this paper, we stand the hypothesis that a mutual (reciprocal) growth
regulation exists between epithelial cells and immune system. We propose a model describing plausible cytokine
circuits that may regulate (inhibit) both epithelial growth and epithelial inflammation. In addition, we describe how
dysfunction of these circuits could lead to tumoral growth, excessive inflammation or both. A failure in the regulation
of epithelial growth by the immune system could give rise to a neoplasm, and a failure in the regulation of the immune
system by the epithelium could give rise to inflammatory or autoimmune diseases. This model may satisfactorily
explain the link between inflammation and cancer.
c 2006 Elsevier Ltd. All rights reserved.

Introduction is replaced by a multistratified flat epithelium of a

Many body tissues can be repaired. The repair
capacity of some tissues is truly remarkable, e.g.,
rat liver can wholly regenerate after losing two
thirds of its mass [1,2]. Not only are tissues able
to repair themselves, but in the case of organs,
new tissues can appear according to the needs of
adaptation to the milieu, e.g., in the uterine cervix
subjected to multiple aggressions, standard mucosa
* Corresponding author. Tel.: +34 913975443.
E-mail address: rodriguez.molinero@gmail.com (A. Rodrı́-
guez-Molinero).
completely normal nature [3].
The cells that reproduce to form these new tis-
sues, do so in response to signals emanating from
other cells. It is widely known that a great part of
healing is coordinated by macrophages and other
cells through the release of a variety of sub-
stances that regulate cell growth [4,5]. Further-
more, cells that grow in culture have the
capacity to respond to many signals. Such regula-
tion is not only paracrine, but also endocrine, as
shown by the existence of molecules such as
erythropoietin, growth regulators, synthesized in
different organs and distal to the tissue where
they exert their effect [6].


0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2006.10.033
1334
Many of the cells with a known capacity to syn-
thesize substances that regulate the growth of
other cells, belong to the immune system [6]. In-
deed, many immunosuppressive substances, such
as corticoids or methotrexate, can markedly alter
tissue repair and formation processes, including
embryogenesis.
Immune system disorders, such as immunodefi-
ciencies, have been widely related with cancer
[7,8]. Some noxae capable of producing tumors
(alcohol) are linked to dysfunction of the immune
system and to alterations to tissue repair or forma-
tion (cirrhosis) [9,10]. Indeed, many new or re-
paired tissues are considered precancerous
lesions, and growth regulatory substances have fre-
quently been implicated in oncogenesis.
Abundant evidence suggests that the tissue re-
pair and formation system plays a fundamental role
in the genesis and growth of neoplasms (gr. néos
new + gr. plasma formation). Recently, Helicobac-
ter pilori-related stomach cancer has been discov-
ered to derive from cells that migrate from bone
marrow to repair the damage caused [11]. Cells,
such as macrophages and their derivatives, impli-
cated in both immunity and repair, have been
found in reduced numbers in tumors, such as hepa-
tocarcinoma and skin cancers [12,13]. Moreover,
oncogenic noxae, such as tobacco, alcohol or radi-
ation, cause major alterations in these growth reg-
ulatory cells [14,15].
It is interesting to note that many antineoplastic
agents, such as methotrexate or corticoids, are
really immunosuppressors and thus interfere in
the process of tissue growth [16,17]. Others, such
as Tamoxifen, directly alter the balance between
inhibitory and stimulatory factors of tissue growth.
Until now, cancer has been regarded as anoma-
lous tissue that falls outside normal growth regu-
latory mechanisms. Yet, in the light of the
above, doubts as to the ‘‘autonomy’’ of such tis-
sue that ‘‘ignores’’ the orders of the system, ap-
pear to be well-founded. There seems to be
increasing soundness in the notion that cancer is
due to an anomaly in the regulation of tissue
growth rather than to resistance to normal growth
regulation [18,19].
The hypothesis
The immune system is tasked with defending the
body against invasion by exogenous agents, but it
also has a primordial role in the maintenance of tis-
sue homeostasis [20–22]. This means that the im-
mune system is in charge of maintaining cell
growth and death within suitable limits, to ensure
Rodrı́guez-Molinero et al.
preservation of the tissue structure that enables
organs to perform their function.
Invasion of the body frequently takes place due
to a defect in tissue continuity, and generally cul-
minates in damaging the affected tissue. This calls
for the immune system to synchronize two clearly
related processes, namely: defense against the
noxa; and repair of tissue damage [23]. When an
epithelial barrier is disrupted and exogenous sub-
stances pass into the internal milieu, this triggers
an inflammatory response mediated by the innate
immune system and the TCD4 + Th1 lymphocytes
of the adaptive immune system. In tandem with
the inflammatory response, growth factors are se-
creted which tend to repair the epithelial defect.
Once the tissue repair is complete, the inflamma-
tion is also resolved, with the tissue returning to
a state of homeostasis [23,24].
Yet when, in this state of homeostasis, the
integrity of the epithelial barrier is intact, the in-
nate immune system and TCD4 + Th1 lymphocytes
are not active because the integrity of the barrier
prevents invasion by exogenous substances and
there is thus no need for phagocytic and cytotoxic
function. In such a homeostatic situation, a humor-
al defense predominates, via secretion of antibod-
ies, such as IgA, which are secreted by the mucosa
and neither activate the complement nor stimulate
phagocytosis, but instead facilitate the elimination
of the injurious agent at the exterior of the organ-
ism. This humoral response is mediated by
TCD4 + Th2 lymphocytes, which secrete a series
of so-called anti-inflammatory cytokines, owing to
their capacity to antagonize interferon and macro-
phage actions [25,26], and down-regulate the
growth of TCD4 + Th1 lymphocytes [27,28].
When the epithelial barrier is present, besides a
physical defense in terms of this barrier and the
possibility of a humoral defense coordinated by
TCD4 + Th2 lymphocytes, the immune system per-
forms a task of immunosurveillance toward what-
ever may be seen as foreign or injurious, and
tolerance toward self or substances seen as innoc-
uous. Indeed, in this task of tolerance toward
innocuous substances, immature dendritic cells as
well as regulatory T lymphocytes (Treg) and Th2
lymphocytes themselves have been implicated,
inasmuch as all are capable of secreting anti-
inflammatory cytokines (Il-10, Il-4, TGF-beta,
etc.) that block the immune system’s response
against innocuous substances [29–33].
The epithelial barrier itself is considered by
some authors to form part of the innate immune
system, in view of its evident protective function
and active participation in many immune responses
through secretion of multiple cytokines. In certain
Tissue homeostasis and cancer
cases, such as the intestinal epithelium, cells may
even act as antigen-presenters [34,35].
With barrier integrity intact, entry of pathogenic
agents is prevented and the tolerance process is
implemented [36,37]. It is therefore likely that
the epithelial cells themselves directly contribute
to the anti-inflammatory environment of the epi-
thelia that are intact. This is at least what one
would tend to infer from observation of the capac-
ity of epithelial cells at numerous sites to secrete
anti-inflammatory interleukins (Il-13, TGF-beta or
Il-10) [38–40]. Such is the epithelium’s cytokine
secretion capacity that skin keratinocytes have,
in certain circumstances, come to be identified as
the greatest local source of Il-10 [41].
Hence, the epithelia have an important immuno-
logic function, through direct protection of and
participation in the triggering of inflammatory pro-
cesses, and possibly also in the tolerance mecha-
nism toward innocuous substances [27,36].
No less interesting is the fact that the immune
system itself can control epithelial growth, not
only, as explained above, by facilitating secretion
of growth factors if necessary, but also by possibly
preventing their excessive proliferation. This is de-
duced from the fact that the same anti-inflamma-
tory cytokines that secrete immune cells in a
state of homeostasis, generally also have an anti-
proliferative effect on epithelial cells [42]. This ef-
fect is especially noteworthy in the case of
Transforming Growth Factor beta (TGF-beta),
which is arguably the endogenous substance with
the greatest known antiproliferative potential for
many cells [42].
The above leads us to conclude that the epithe-
lium may influence inflammation and this in turn
may influence epithelial growth, and what is more
important and less well known, that the epithelium
may possibly inhibit inflammation, and that the im-
mune system may inhibit epithelial growth.
Hence, a negative feedback is established be-
tween the two systems, which makes biological
sense because, when the epithelium is present,
its cytokines collaborate in inhibiting any unneces-
sary inflammation. Furthermore, absence of
inflammation is evidence of the fact that there is
a protective epithelium acting as a barrier, and
that no further growth of such epithelium is
required.
To our knowledge, this double regulation has
never been defined as such, despite the fact that
each of its constituent elements and their func-
tions are independently known. The existence of
this negative feedback between the epithelium
and the immune system is postulated as a hypoth-
esis, since we have evidence to prove the existence
1335
of each of its elements. Accordingly, we propose a
plausible interaction model below, even though
there may be other means of interaction and feed-
back, and –conceivably– different forms of inter-
action in the various tissues.
A model of homeostasis
Immature dendritic cells performing tasks of immu-
nologic surveillance in healthy epithelia [43] have
the capacity to stimulate secretion of anti-inflam-
matory interleukins (Il 4 Il10) by Th2 lymphocytes
[44], favor the generation by the latter of Treg-lym-
phocytes as well as secretion of TGF-beta by them
[45–50]. In turn, cytokines that secrete Th2 lym-
phocytes also favor Treg-lymphocyte generation
[51] (Fig. 1).
In brief, immature dendritic cells favor the pres-
ence and activity of regulatory Th2 and Treg-lym-
phocytes, which secrete anti-inflammatory and
antiproliferative cytokines. It is known that TGF-
beta, which secretes Treg-lymphocytes, inhibits
the growth of epithelial cells [52] and that epithe-
lial cells, for their part, secrete Il-10 [41], which
acts by way of feedback on the dendritic cells,
maintaining them in an immature state [53–56].
Inflammation
When the epithelial barrier is breached, the den-
dritic cell is activated and stimulates the
TCD4 + Th1 lymphocytes to trigger inflammation
and subsequent growth of the epithelial barrier (re-
pair) [57,58]. Th2-lymphocyte growth is inhibited
by the cytokines secreted by the Th1 lymphocytes,
and Treg-lymphocyte stimulation ceases seeing as
the dendritic cells are not immature and Th2 lym-
phocytes are not in abundance.
When the epithelial barrier is repaired and the
inflammation disappears, Il-10 increases, the den-
dritic cells return to a state of immaturity, and epi-
thelial homeostasis is restored.
Oncogenesis
If dendritic cells steadily die or mature for a reason
unconnected with the disruption of the epithelial
barrier, stimulation of Th2 and Treg-lymphocytes
will cease and, with this, inhibition of epithelial
growth by TGF-beta will be reduced.
Since TGF-beta is a powerful epithelial growth
inhibitor, it will come as no surprise that it is our
contention that any decline in its concentration
can be translated as a rise in cell growth rate.
1336 Rodrı́guez-Molinero et al.

Figure 1 Homeostasis. If the epithelial barrier is intact, there is an abundance of IL-10 secreted by the epithelial
cells, which maintains the dendritic cell in an immature state. The immature dendritic cell, in turn, stimulates
TCD4 + Th2 lymphocytes to secrete Th2 interleukins (IL-4, IL-10), and regulatory lymphocytes to secrete TGF-beta. The
TGF-beta produced by these cells inhibits the growth of the epithelial cells, which provide feedback and so contribute
to the immature state of the dendritic cells by secreting IL-10.

Growing epithelial cells can secrete Il-10 seeking
negative feedback by dendritic cells, but if there
are no dendritic cells or if these are in a mature
phase, TGF-beta will not increase in order to cur-
tail local growth. This succession of events may
generate or facilitate the appearance of a
neoplasm.
Evaluation of the hypothesis
Given that TCD8 + and natural killer lymphocytes
are capable of destroying tumor cells, and perform
better when appropriately stimulated by cytokines
that release TCD4 + Th1 lymphocytes, it was
thought until now that inflammatory state and
Th1 response were the immune system’s best
means of combating tumor mass. We, on the other
hand, think – and have indeed said as much – that
tumor growth should be studied in terms of exces-
sive growth rather than in terms of tissue invasion.
This means that attention should be paid to which
cytokines synthesized by the immune system facil-
itate cell reproduction and which cytokines inhibit
it. From this point of view, it is clear that the
immune system coordinated by Th2 and Treg-lym-
phocytes and dendritic cells or immature macro-
phages, has an enhanced capacity to curtail
epithelial growth, which ultimately is what consti-
tutes 95% of all neoplasms. Indeed, most neo-
plasms are infiltrated or surrounded by a greater-
than-expected number of cells belonging to these
types, a phenomenon that until now has seemed
paradoxical [59–63]. Hence, if our hypothesis were
accurate, inflammation could facilitate rather than
impede tumor growth; indeed, this fact has been
repeatedly demonstrated in the literature, though
only recently has attention been paid to its impor-
tance [23,64–67]. We feel that we have put
forward a plausible mechanism whereby inflamma-
tion facilitates tumor growth.
We have proposed that TGF-beta is the cytokine
via which the immune system slows epithelial
growth, and that the defect in this cytokine must
be assumed to be implicated in oncogenesis
[68,69]. In this regard, it has been shown that for
the TGF-beta receptor KO mice, have a greater
incidence of epithelial neoplasms [70,71], and it
is known that in many neoplasms the intracellular
TGF-response pathway is altered and is resistant
to its inhibitory activity, but if our hypothesis is
correct, then, even without alterations in the
transduction pathway, the mere reduction in
TGF-beta in the tumor mass could be a cause of
growth [72]. It has recently been reported, at least
in the case of colon and endometrial cancers, that
Tissue homeostasis and cancer
a reduction in TGF-beta is more frequently seen in
tumors than are alterations in their transduction
pathway [69,73–76].
Treg-lymphocytes are anti-inflammatory and hin-
der the antitumoral action of TCD8 + and natural
killer lymphocytes, with the result that the pres-
ence of these cells has always been regarded as
facilitating tumor growth [77,78]. This is inconsis-
tent with the repeatedly proved observation that,
rather than impeding tumor genesis and growth,
inflammation actually facilitates it. From our point
of view, the presence of Treg-lymphocytes in the
tumor mass is positive, because they are the great-
est source of TGF-beta in the entire immune sys-
tem and are thus able to inhibit the growth of
epithelial cells. This prediction is supported by
some studies, which, seeking to prove the con-
trary, have instead concluded that infiltration by
tumor regulatory cells does not worsen and, in-
deed, may improve disease prognosis [79,80]. It
has even been observed that Treg-lymphocytes
may produce tumor remissions [81–83].
However, the presence of Treg-lymphocytes in
neoplasms might not suffice to inhibit their growth
if there no dendritic cells that stimulate them to
secrete antiproliferative cytokines. Thus, accord-
ing to our model, an absence of dendritic cells or
a defect in their function, could give rise to a neo-
plasm. In support of this hypothesis, we have the
very telling evidence that dendritic cells are found
to be reduced in number or damaged in almost all
types of tumors [12,13,15]. Surprisingly, moreover,
the presence of these cells is inversely correlated
with disease stage [84–87], in that the more den-
dritic cells, the less advanced the disease.
According to our hypothesis, the cells of healthy
epithelials secrete anti-inflammatory cytokines,
such as Il-10. Among other things, this maintains
the dendritic cells in an immature state
[84,88,89], which ultimately favors TGF-beta
secretion by regulatory lymphocytes. Hence, in
the event of there being a lack of dendritic cells,
there would be Il-10 secretion by the epithelium
but it would not achieve an adequate TGF-beta re-
sponse. Most tumors are made up of epithelial cells
that grow uncontrollably and, as our model pre-
dicts, secrete substantial amounts of interleukin
10 [56,90–93], though, as has been seen, the
TGF-beta response is defective. There is thus the
possibility that tumor cells may well be sending
out the appropriate signal and it is the immune sys-
tem that is inadequately inhibiting growth.
In brief, many tumors secrete Il-10 but lack TGF-
beta. Their dendritic cells are reduced in number
or damaged, and infiltration by Treg-lymphocytes,
unlike inflammation, does not accelerate their
1337
growth. As seen above, these facts, poorly under-
stood until now, could be explained by a paracrine
growth-control system such as that outlined here.
Tumors could therefore be caused by a defect in
the regulation of epithelial growth, whether be-
cause of damage to the immune cells tasked with
such regulation, or because these cells are im-
mersed in a chronic inflammatory state, which pre-
vents them from performing their function. Were
this to be the case, the noxae that cause cancer
would have to do so via one of these two mecha-
nisms. The truth is that numerous cancer-related
noxae, such as asbestos for instance, are known
to cause chronic inflammation. Others have been
associated with damage to the immune system,
such as alcohol which causes ‘‘immunosuppres-
sion’’, tobacco which damages the alveolar macro-
phage, or radiation which reduces the number of
dendritic skin cells, also known as Langerhans cells
[94].
Hence, some carcinogenic substances damage
the cells proposed by us as controllers of epithelial
growth. Given that there are a number of such cells
and that they can be regenerated, sporadic expo-
sure to one of these substances would not be ex-
pected to produce uncontrolled growth. Chronic
exposure, on the other hand, might reduce the
population of local regulatory cells to the point
where there is excessive secondary epithelial
growth, and if such exposure continues, this may
then degenerate into neoplasia. This is in line with
the fact that, before neoplasms appear, exposure
to carcinogenic noxae must generally be chronic,
and there is therefore nothing undue in the fact
that these should be preceded by disorderly cell
growth, such as that caused by alcohol in the liver,
i.e., cirrhosis.
At the same time, if uncontrolled growth is
caused by damage to the regulatory cells, or by
chronic inflammatory state, drugs that have shown
some efficacy in the treatment of neoplasms,
would have to act by preventing inflammation, or
replacing the population of immune cells tasked
with curtailing growth. Insofar as the former is con-
cerned, it is evident that the vast majority of che-
motherapeutic drugs used in cancer are powerful
anti-inflammatories or immunosuppressors, start-
ing with corticoids, which in addition maintain
dendritic cells in a state of immaturity [95]. Even
analgesic and anti-inflammatory non-steroids,
which block prostaglandin-mediated maturation
of dendritic cells [96] but are not directly antipro-
liferative, have shown themselves to be useful in
the prevention of several neoplasms [97]. With
respect to the possibility of repopulating damaged
immune cells [98–100], it is noteworthy that
1338
recently there have been reports of complete
remissions of disseminated cancers through the
use of high doses of G-CSF, which, among other
things, is a cytokine that mobilizes T helper 2-
inducing dendritic cells [101].
Consequences of the hypothesis and
discussion
We propose the inadequacy of the immune system
tasked with inhibiting tissue growth, as a possible
facilitating cause underlying the appearance of
neoplasia. In contrast, we have purposely not clar-
ified whether the dysfunction of the regulatory sys-
tem is also sufficient cause to generate a
neoplasm. Personally, we think that system dys-
function is enough to cause cancer, and that the
anomalies manifested by neoplastic cells are no
more than changes secondary to growth alteration.
However – and we are not seeking to clarify this
point in this paper – anyone who, unlike us, be-
lieves in primary alterations of neoplastic cells, is
equally capable of perceiving immune dysregula-
tion as an adjuvant growth mechanism.
If the double negative interaction between the
epithelium and immune system as proposed by us
is confirmed, this would generate new ways of
understanding diseases due to excess epithelial
growth, as well as many diseases with excess im-
mune response.
Aside from cancer, other diseases are accompa-
nied by excess or disorderly cell growth, such as
psoriasis, cirrhosis, polyposis etc. We trust that
our hypothesis will be equally applicable when it
comes to clarifying the physiopathology of these
entities. We likewise feel that, due to excessive im-
mune response, some diseases, like inflammatory
intestinal diseases for instance, may stem from a
disorder of the same system as outlined here.
A hypothesis is a relationship among facts in-
tended to achieve a better understanding of a
problem. The facts set out here within a logical, or-
derly, explanatory system, are based on the role
that certain cytokines are known to play, not so
much in the behavior of neoplasms but rather in
growth and inflammation. In view of the fact that
the physiopathology of cancer is not known, re-
search into the matter has to some extent been
conducted ‘‘by feel’’, which renders it difficult to
interpret findings appropriately and has made for
an abundant bibliography replete with contradic-
tory results. The strength of our hypothesis lies in
the string of functions performed by immune
system cytokines, and not in cancer references,
since we are all too aware that, in many cases, it
Rodrı́guez-Molinero et al.
is possible to find equally valid bibliography with
contradictory results. If the reason for generating
a hypothesis is to gain a better understanding of a
reality, then in our opinion, the hypothesis pre-
sented is valid in terms of its ability to explain a
wide variety of facts. Indeed, our hypothesis seeks
to explain the state of tissue homeostasis, and its
scope is more limited when it comes to cancer as
a possible system dysfunction.
Conclusions
The immune system has the necessary mechanisms
and elements to regulate epithelial growth and its
plausible that it may do so. Furthermore, the epi-
thelium has elements to inhibit the action of the
immune system, and it may possibly do so.
A failure in the regulation of epithelial growth by
the immune system could give rise to a neoplasm. A
failure in the regulation of the immune system by
the epithelium could give rise to inflammatory or
autoimmune diseases.
Acknowledgements
We should like to thank Sandra López Guinea for
her invaluable feedback and constant support to
the ideas developed in this hypothesis.
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