Journal of Pathology

J Pathol May 2023; 260: 1–4 PERSPECTIVE

Published online 28 March 2023 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/path.6070

Re-interpreting tumour behaviour and the tumour

microenvironment as normal responses to tissue disorganisation
Paul AW Edwards*
Department of Pathology, University of Cambridge, Cambridge, UK

*Correspondence to: PAW Edwards, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
E-mail: pawe1@cam.ac.uk

Abstract
Much of tumour cell biology and the tumour microenvironment may be normal wound-healing responses as a
consequence of the disruption of tissue structure. This is why tumours resemble wounds, and many features of the
tumour microenvironment, such as the epithelial–mesenchymal transition, cancer-associated fibroblasts, and
inflammatory infiltrates, may largely be normal responses to abnormal tissue structure, not an exploitation of
wound-healing biology.
© 2023 The Author. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Brit-
ain and Ireland.

Keywords: tumour microenvironment; wound healing; epithelial–mesenchymal transition; cancer-associated fibroblast; tumour-infiltrating
lymphocytes; malignancy; cancer

Received 23 November 2022; Revised 23 January 2023; Accepted 17 February 2023

No conflicts of interest were declared.

Introduction outside (Figure 1). Disruption of the sheet results in

Much of contemporary cancer research is focused on
the cell biology of tumour cells and their surrounding
stroma – on phenomena such as the ‘epithelial–
mesenchymal transition’ (EMT), ‘cancer-associated fibro-
blasts’ (CAFs), and ‘tumour-infiltrating lymphocytes’
(TILs) [1–3], which together form the ‘tumour microenvi-
ronment’. I suggest that much of this biology may be
understood as the inevitable and normal consequence of
the disruption – i.e. wounding – of the epithelium or other
tissue from which the tumour developed, and is not a
‘deliberate’ exploitation of these behaviours for the
tumour’s benefit as previously suggested [4].
This may be an example of a recurring problem in
cancer research, of finding interesting phenomena in
tumours without realising that they are normal phenom-
ena (see Box 1).
Cancer tissue is wounded tissue
alarm signals to trigger repair and regeneration: these
signals probably include collapse of the trans-epithelial
electrical potential [8,11], receptors at one epithelial face
being exposed to ligands secreted from the other face
(e.g. the HER/EGFR/ERBB family on the basolateral
face and NRG1/heregulin on the apical face) [9], and
changes in cell shape and tension [11]. The adjacent
stroma probably also responds: to signals from the dis-
tressed epithelium, or to exposure to epithelial cells
without a separating basement membrane [12]. The
stroma will, in turn, signal back to the epithelial cells
(Figure 1) [11].
Malignant epithelial tumours are chaotic mixtures of
disrupted epithelium and stroma (Figure 1). The epithe-
lium is no longer an intact sheet, and may or may not
be separated from the surrounding stroma by a basement
membrane [10], so the tumour and adjacent non-tumour
cells should be frantically trying to restore correct struc-
ture and will mount a wound-healing response. Much of
what we see in a tumour may be this response.

Cancer can be viewed as a failure of the 3D structure of

tissues – the failure of normal tissue development, “Tumours [are] wounds that do not heal”
homeostasis, and/or the ability to repair damage through
regeneration and wound healing. This is easiest to under- Many authors have described the similarities between
stand for epithelial tumours: normal epithelial cells are cancer and wound healing, down to details such as
part of a sheet, with an inside and outside, and a salt dif- gene-expression profiles [4,12,13], but, to my knowl-
ference and electrical potential between the inside and edge, where they have interpreted the similarity, they
© 2023 The Author. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited.
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2 PAW Edwards

Box 1 Mistaking normal cell properties for tumour-specific properties.

The difficulty of separating tumour behaviour from normal behaviour has a long history in cancer research. Over 100 years ago, Peyton Rous [5]
(of Rous sarcoma virus) warned of this: “essential … in cancer work to discriminate between characters unique with tumour and those which it pos-
sesses in common with normal tissue.” He was criticising Ehrlich, who had found that tumours grafted from one mouse to another were rejected, but
who had not done the control of grafting normal tissue, which, in the outbred mice he used, would also have been rejected. Ehrlich had in fact discov-
ered the rejection of grafts between non-identical animals (allografts). More recent examples include the discovery of candidate ‘leukaemia-specific
antigens’, which turned out to be normal stem-cell markers [6]; and the finding that surface antigens on epithelial cancers were heterogeneously
expressed, which was at first interpreted as revealing tumour heterogeneity but which proved to be typical of normal epithelia [7].
This reflects a general principle that tumours do not invent new biology: they have lost or altered control of pre-existing mechanisms. Also, behaviours
seen in tumours, such as fibrosis, are more likely to be ‘normal’ responses than tumour-specific host defences [4].

Figure 1. Epithelial tumours viewed as wounded epithelia. Epithelial tumours are disrupted epithelium, and will therefore mount at least
some of the responses that a normal epithelium would when disrupted. Left: intact epithelium is a continuous sheet with an electrical poten-
tial across it [8], salt differences (not shown), and ligands produced at one face (shown green on apical face) that cannot reach receptors on
the other face (shown yellow on basolateral face) [9]. Grey, basement membrane. Right: in malignant epithelial tumours, the epithelial sheet
is disrupted, and the basement membrane may or may not be breached [10]. This activates wound-healing responses in the epithelium, which
include signals (orange arrows) to stromal cells, represented to the right, in blue, by a macrophage, lymphocyte, and fibroblast; signals from
the alerted stroma back to the epithelium (blue arrows); electric currents; and interaction between ligands and receptors [9,11].

have suggested that tumours exploit wound-healing response to breach of the epithelial sheet, and other
programmes to achieve properties such as invasiveness, changes in structure or behaviour.
rather than the wound-healing programme being an
inevitable consequence of the disruption of the epithe-
lium. In particular, Dvorak, who in 1986 proposed that
The ‘epithelial–mesenchymal transition’ (EMT)
a cancer is “a wound that does not heal”, also “proposed
that tumours co-opted the wound-healing response to
induce the stroma they required” (my italics), and The ‘epithelial–mesenchymal transition’ is a set of
“tumours disguise themselves as wounds and call upon phenotypic changes in epithelial tumour cells towards
the host to ‘heal’ them” [4]. A recent review [14], for a more mesenchymal phenotype, such as loss of polar-
example, states “Cancer-associated fibroblasts (CAFs) ity and expression of the mesenchymal protein
vimentin [1]. It is part of normal wound healing but
… can adopt … [a phenotype] comparable to … fibro-
has, controversially, also been invoked as a mecha-
blasts in … wound-healing”, and apparently does not
nism – indeed a driver – of malignancy, invasion,
consider that these fibroblasts are indeed wound-healing
and metastasis [1,12].
fibroblasts because the tissue is mounting a wound-
We can re-interpret EMT as an inevitable conse-
healing response. quence of disrupting epithelium, not something that
These contrasting concepts are not, of course, mutu- tumour cells exploit to invade and metastasize [1,12].
ally exclusive: some wound-healing responses may be
consequences of disruption, while others may be
invoked by cancer mutations.
Motility, proteases, and angiogenesis

Applying the idea It is often assumed that invasion and metastasis require
enhanced motility [15], but normal epithelial cells at a
Perhaps, then, we could understand the behaviour of wound are highly motile [12] – skin keratinocytes at a
malignant tumour cells by reference to what normal cells wound edge can move around 50 μm/day [16], much
would be doing in similar circumstances – which we can faster than a typical tumour infiltrates tissue. The
call ‘wound healing’. In an epithelial tumour, the epithe- observed high motility of some tumour cells may be their
lial cells and stroma will be changing behaviour in normal response to disorganisation.
© 2023 The Author. The Journal of Pathology published by John Wiley & Sons Ltd J Pathol 2023; 260: 1–4
on behalf of The Pathological Society of Great Britain and Ireland. www.pathsoc.org www.thejournalofpathology.com

Re-interpreting tumour behaviour
Epithelial wound healing also includes secretion of
matrix metalloproteases to break down clot, and initiates
angiogenesis [11,12].
Dense stroma and cancer-associated
fibroblasts (CAFs)
Fibrosis, i.e. scarring, the laying down of collagen-rich
tissue by fibroblasts, occurs at the breach of an epithe-
lium (think of scars forming where skin is cut). The
dense, collagen-rich stroma seen in many tumours,
called ‘desmoplasia’, resembles chronic fibrosis [4,17],
so could simply be the response to broken epithelium.
The various fibroblast-like cells found in tumour stroma,
‘cancer-associated fibroblasts’, are similar to cells
observed in wounds [2].
Lymphocyte and macrophage infiltration
There is much interest in inflammatory cells in
tumours, notably ‘tumour-infiltrating lymphocytes’
(TILs), because of their possible role in an immune
response to the tumour [3]. But any breach in an epithe-
lium threatens infection, so some of the inflammatory
cells (neutrophils, macrophages, or lymphocytes) could
be summoned to defend against infection, rather than
the tumour. Indeed, some TILs are primed to viruses that
infect epithelia [18].
Differences and variability
Changes seen in tumours will not, of course, exactly
match those in a wound caused by mechanical damage.
For example, tumours do not usually cause
haemorrhage, which contributes to damage signalling
via complement and platelet activation [11]. And matrix
structures such as basement membranes may or may not
be disrupted [10].
The tumour microenvironment will also vary between
tumours because of variations in their growth pattern,
anoxia, and necrosis, etc. (as well as any differences in
mutations that affect wound healing). For example, lob-
ular breast cancer cells invade in single file, while many
other breast cancers are solid masses of cells.
Why is this a useful argument?
This line of argument may be useful because it may pro-
vide a framework for understanding tumour behaviour.
For example, cancer-associated fibroblasts are probably
best understood by comparison with fibroblasts in
wounds, as already suggested [2]. We might better
understand the role of EMT in invasion if we knew
© 2023 The Author. The Journal of Pathology published by John Wiley & Sons Ltd
on behalf of The Pathological Society of Great Britain and Ireland. www.pathsoc.org
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3
whether there were differences between EMT in wound
healing and in cancers.
This argument should also help us to understand how
mutations lead to cancer, by separating out the compo-
nents of tumour behaviour that are truly abnormal, and
hence the product of mutation. This would also inform
therapy, which might otherwise target components of nor-
mal wound healing without much benefit to the patient.
It also generates new questions and redirects old ones.
A recurring question about the similarity between
tumours and wounds has been why wound-associated
changes are transient in wounds but persist in tumours
(although reversing malignancy can reverse the changes
[19]). This becomes the wrong question if changes are
caused by disorganisation, which persists.
This argument also focuses attention on what drives
disorganisation, and, more precisely, how mutations dis-
rupt organisation. Is unlimited survival and proliferation
alone enough to bulldoze through normal homeostasis
and disrupt tissue architecture, or does malignancy also
require alteration of signals that control 3D organisation?
An important question is whether cancer driver muta-
tions directly modify the wound-healing response, for
example by enhancing EMT or sending signals to the
stroma. This seems likely. A component of EMT is
down-regulation of E-cadherin/CDH1, and inactivation
of CDH1 is a driver mutation, for example in lobular
breast cancer. Oncogenic signalling pathways including
the Wnt, TGF-β, and Notch pathways apparently
directly affect EMT, even in normal tissues [20]. Acti-
vating KRAS can modify the ability of epithelial cells
to correct tissue damage [21]. But whether driver muta-
tions directly modify stromal responses is more difficult
to pin down, because we must distinguish between direct
effects and the indirect effects of breaking the rules of
tissue organisation. Nevertheless, it seems that onco-
genic mutations can cause inflammatory signalling
[22]. For example, activating KRAS in pancreatic epithe-
lium can reprogramme neighbouring fibroblasts [23],
and activated RAS genes can induce senescence, which
results in signalling to neighbouring cells [24].
Dvorak’s [4] original concept, that tumours exploit
wound healing, could still prove to be insightful. Could
turning on wound-healing responses permit cells to pro-
liferate and move into inappropriate environments?
Could, for example, the constitutive activation of
Erbb2/Her2 seen in some carcinomas be mimicking the
proliferative wound signal, access of apical Nrg1 ligand
to basolateral Erbb2 [9]?
Conclusion
In conclusion, we need to know how much of malignant
tumour cell biology is simply programmed in as a nor-
mal wound-healing response, consequent on disruption
of normal tissue architecture. And we need to understand
how cancers become disorganised, in fact how they
become malignant.
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4 PAW Edwards

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© 2023 The Author. The Journal of Pathology published by John Wiley & Sons Ltd J Pathol 2023; 260: 1–4
on behalf of The Pathological Society of Great Britain and Ireland. www.pathsoc.org www.thejournalofpathology.com