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The paradox of tumor-associated neutrophils:

Fueling tumor growth with cytotoxic substances

A. McGarry Houghton

To cite this article: A. McGarry Houghton (2010) The paradox of tumor-associated neutrophils:
Fueling tumor growth with cytotoxic substances, Cell Cycle, 9:9, 1732-1737, DOI: 10.4161/
cc.9.9.11297

To link to this article: https://doi.org/10.4161/cc.9.9.11297

Published online: 14 May 2010.

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 review

Cell Cycle 9:9, 1732-1737; May 1, 2010; © 2010 Landes Bioscience

The paradox of tumor-associated neutrophils

Fueling tumor growth with cytotoxic substances
A. McGarry Houghton
Division of Pulmonary, Allergy & Critical Care Medicine; Department of Medicine; University of Pittsburgh Cancer Institute; University of Pittsburgh School of Medicine;
Pittsburgh, PA USA

Key words: neutrophils, inflammation, cancer, proteinases, microenvironment

Abbreviations: PMN, polymorphonuclear leukocyte; ROS, reactive oxygen species; NE, neutrophil elastase; CG, cathepsin G;
PR3, proteinase-3; MMP, matrix metalloproteinase; A1AT, alpha1-antitrypsin; ECM, extracellular matrix;
TAN, tumor-associated neutrophil

Human cancers are comprised of numerous cell types including
neutrophils. Although often ignored, neutrophils are frequently
present at sites of tumorigenesis including the kidney, breast,
colon and lung. These cells possess substances such as reactive
oxygen species and proteinases that are capable of modifying
tumor growth and invasiveness. This review addresses recent
reports describing both pro-host and pro-tumor roles for
neutrophils and neutrophil-derived substances and will
examine the alterations in neutrophil behavior that explain
this apparent biological discrepancy. Unfortunately, with the
exception of investigator driven manipulation of neutrophil
function, these cells function overwhelmingly against the
host in the setting of cancer. Many cancers are capable of
recruiting neutrophils to sites of tumorigenesis where they
enhance tumor growth. Identification of the neutrophil-
derived substances that promote tumor growth may yield
novel therapeutic approaches to inhibit cancer progression.
Alternatively, strategies designed to generate highly activated
and cytotoxic neutrophils within the tumor microenvironment
may provide a means to unleash the tumoricidal potential of
the host’s innate immune response.
Introduction
The association between inflammation and cancer dates to clas-
sic observations made by the anatomist Galen, when, in the 2nd
century A.D., he postulated the Greek version of the famous
four symptoms of inflammation: rubor, calor, dolor and tumor.1
The more modern concept that tumors arise in areas of chronic
inflammation is not as modern as one would think, having been
discovered by Virchow in 1863.2 Although Virchow’s hypothesis
remains intact, it is only in the recent past that we have broken
new ground, where specific inflammatory cell types have been
Correspondence to: A. McGarry Houghton;
Email: houghtonm@dom.pitt.edu
Submitted: 01/21/10; Accepted: 01/25/10
Previously published online:
www.landesbioscience.com/journals/cc/article/11297
demonstrated to play vital roles in tumorigenesis beyond creating
a chronic inflammatory milieu in which neoplastic transforma-
tion can occur.3
A recent concept in tumor-associated inflammation is that
cancer cells themselves are able to manipulate the host’s immune
response by perpetuating inflammation and polarizing inflamma-
tory cell responses through the release of bioactive substances.4,5
The cellular composition of tumors is the result of a complex
biological process that involves intricate crosstalk mediated by
cytokines and chemokines, which influence cell behavior and
movement. It is noteworthy that only about half of the cells
contained within many tumor types are actually malignant. In
addition to the cancer cells themselves, tumors are comprised of
stromal cells, fibroblasts, endothelial cells, pericytes, CD4 + and
CD8 + lymphocytes, NK cells, macrophages and neutrophils,
among others.3 Even this description is quite limited, with many
of these cell types capable of displaying different phenotypes,
such as Th1 and Th2 CD4 + lymphocyte subsets, and M1/M2
macrophages.6
Of all cell types residing within the tumor microenviron-
ment, neutrophils have received the least amount of attention.
Although commonly encountered, only recently have these
short-lived professional phagocytes been considered more than
an inconsequential bystander. This is somewhat surprising given
that neutrophils possess substances known to alter tumor growth
when elaborated from other sources. However, cynics would
point to their short half-life and lack of “intellect,” rendering
them incapable of meaningfully impacting tumor cell behavior.
This review will dispel conventional wisdom regarding tumor-as-
sociated neutrophils (TAN), address recently described roles for
these cells within the tumor microenvironment, and re-address
the tumoricidal potential of neutrophils when manipulated into
highly activated states.
The Neutrophil
To understand the roles that polymorphonuclear leukocytes
(PMNs or neutrophils) may play within the tumor microenvi-
ronment, it is important to understand established physiologi-
cal and patho-physiological roles for these cells. Simply put,

1732 Cell Cycle Volume 9 Issue 9

 review
neutrophils exist to defend the host from invading microorganisms.
They also assist in wound healing. Neutrophils are the most
common leukocyte type found in the bloodstream, constantly
on the ready to respond to chemotactic stimuli and fight acute
infection. They have very short half-lives, on the order of just
a few hours, but survive much longer within inflammatory
environments.7
Neutrophils have been supplied with toxic substances to kill
invading pathogens. They have gone to great lengths to keep
these substances under lock and key, so as not to inadvertently
damage host tissues.8 During the myelomonocytic stages of bone
marrow development, PMN synthesize large quantities of serine-
proteinases [neutrophil elastase (NE), cathepsin G (CG), pro-
teinase-3 (PR3)]. PMN later synthesize metalloproteinases [neu-
trophil collagenase (MMP-8), gelatinase B (MMP-9)], which,
like serine proteinases, are stored within cytoplasmic granules
for later use.9 Neutrophils have apparently adapted this strategy
for the purpose of rapid dispersal of enzymes to the phagolyso-
some while sequestering them from vital parts of the cell. When
functioning properly, PMNs respond to chemotactic stimuli to
enter sites of acute infection where they engulf foreign patho-
gens. Antimicrobial peptides (e.g., defensins), reactive oxygen
species (ROS) and serine-proteinases are then rapidly shuttled
to phagolysosomes where they kill invading microorganisms.10
Small amounts of proteinases are also released into the extracel-
lular matrix in quantum micro-bursts to transiently overwhelm
their inhibitors to accomplish focused proteolysis.11,12
Only under dire circumstances, such as severe sepsis or frus-
trated phagocytosis, will neutrophils spill large quantities of these
substances into the extracellular space in the form of neutrophil
extracellular traps (NETs) or free oxygen radicals and protei-
nases.13 These highly activated neutrophil sub-types can be cyto-
toxic to neighboring cells. The resultant tissue damage can result
in mortality for the host, especially when it occurs in the form of
acute lung injury, which is largely caused by neutrophil-derived
proteinases.14 Evolution has tolerated these “side effects” of neu-
trophil activity, as intact neutrophil function is essential for sur-
vival of the host. Disorders of neutrophil function in humans are
characterized by recurrent invasive infections and early mortal-
ity.15 Similarly, genetic deletion of NE caused increased mortality
in infection models in mice, as NE is a potent broad-spectrum
antimicrobial enzyme.16,17
Unlike immune cells that display alternative phenotypes
(i.e., M1 vs. M2 macrophages),18 neutrophil activation states likely
follow a linear progression. There are certainly different degrees
of PMN activation, but neutrophils tend to use more of a given
substance, rather than to use different substances, to achieve dif-
ferential function. As an example, quiescent PMN do not release
NE, wound-associated and tumor-associated PMN release some
NE, and activated neutrophils fighting infections release signifi-
cant quantities of NE. In practical terms, there are four different
types of neutrophils: (1) naïve circulating PMN, (2) mildly acti-
vated PMN (wound-associated and tumor-associated), (3) acti-
vated PMN (acute infection) and (4) highly activated (frustrated
phagocytosis, sepsis, cytotoxic). Naïve circulating PMN, when
recruited to sites of tumorigenesis, do not release or “dump” large
www.landesbioscience.com Cell Cycle
REVIEW
quantities of oxygen radicals and proteinases11 at the tumor cell
surface, but they do elaborate modest concentrations of enzyme
to the host’s detriment. However, neutrophils can be induced
to function in a tumoricidal or cytotoxic fashion when highly
activated.19 It is likely that the description of both pro-host
and pro-tumor PMN is a function of differential neutrophil
activation.
Impact of Neutrophil Infiltrates in Human Cancers
Historically, neutrophils were considered a means of host defense
against cancers, albeit a largely ineffective one. PMN would pre-
sumably be recruited to sites of tumorigenesis by macrophages (as
is the case in acute infection) where they would attempt to kill
tumor cells using the same substances with which they kill bacte-
ria. This does not appear to be the case. Although few in number,
all of the clinical studies regarding tumor-associated neutrophils
have demonstrated that their presence is associated with poor
clinical outcomes, including decreased survival. The few stud-
ies that would challenge this notion were performed prior to the
use of advanced immunohistochemical techniques, and therefore
examined simple H&E stained sections, an unreliable method to
distinguish between the different inflammatory cell types.
More recently, Jensen et al. demonstrated that intra-tumoral
neutrophils, defined as CD66b + cells, were an independent
predictor of mortality in renal cell carcinoma.20 In their study,
intra-tumoral neutrophils decreased the five-year recurrence free
survival rate from 87 to just 53%. Previous reports in different
tumor types have reached similar conclusions. Neutrophil infil-
trates within alveolar spaces in bronchoalveolar cell carcinoma
(BAC), a subtype of lung adenocarcinoma, was associated with
poor clinical outcome.21 Interestingly, tumor cells in BAC pro-
duced interleukin-8 (IL-8), a known chemoattractant for neu-
trophils. Thus it appears that cancers are capable of recruiting
PMN to the tumor microenvironment, a concept elaborated
upon below.
Several investigators have used an assay designed to recognize
immuno-reactive neutrophil elastase to demonstrate that its’ pres-
ence in breast cancer homogenates correlated with poor clinical
outcomes.22-24 Although highly specific for PMN, NE could theo-
retically be produced by a poorly differentiated cancer cell. Since
IHC was not performed, the source of NE in these studies cannot
be definitively determined. Additional studies have demonstrated
increased lung cancer susceptibility when NE activity overcomes
that of its endogenous inhibitor, alpha1 antitrypsin.25,26
In addition to intra-tumoral PMN, there is some evidence
that peripheral blood neutrophil content may predict clinical
outcome in some cancers. Increased peripheral blood neutrophil
counts have been associated with poor outcomes for colorectal
carcinoma,27 small-cell lung cancer28 and metastatic melanoma.29
Because many confounders influence blood neutrophil counts in
cancer patients (chemotherapy, infection, use of bone marrow
stimulants, etc.), correlation of these findings with the presence
of PMN at sites of tumorigenesis will be required to validate the
use of blood neutrophil counts as a surrogate for the tumor-asso-
ciated neutrophil content.
1733
 Tumor-Associated Neutrophils: Friend or Foe?
There appears to be a difference between how neutrophils typi-
cally function within the tumor microenvironment and how they
can be manipulated to function within the tumor microenviron-
ment. The clinical outcome data discussed above and pre-clinical
studies employing simple PMN depletion approaches point to the
deleterious nature of tumor-associated neutrophils.30,31 Notably,
Sparmann and Bar-Sagi were able to demonstrate that the pres-
ence of mutant K-ras drives the expression of neutrophil recruit-
ing CXC chemokines resulting in neutrophil accumulation at
sites of tumorigenesis.32 Furthermore, depletion of PMN in this
setting substantially reduced tumor growth. Similarly, our group
has demonstrated that K-ras mutant lung tumors in mice recruit
PMN to the tumor microenvironment via CXC chemokine
release.33 Thus it appears that the recruitment of PMN can be a
tumor-driven process, and doesn’t necessarily represent a means
of host defense.
In contrast, there are also reports of tumoricidal activity dis-
played by neutrophils using tumors engineered to overexpress
specific interleukins or chemokines.19,34,35 These approaches have
taken advantage of the fact that PMN possess toxic substances
capable of killing tumor cells, and have manipulated the neutro-
phil to release these substances in concentrations not typically
encountered within the tumor microenvironment. Thus TAN
usually function against the host but possess the potential to
become valuable assets if their behavior can be safely manipu-
lated and properly controlled.
The recent description of N1 and N2 tumor-associated neu-
trophils brilliantly illustrates this point. Fridlender and col-
leagues used syngeneic tumor xenografts and LSL-K-ras tumors
in mice to study the effects of SM16, a TGFβ receptor kinase
antagonist.36 As expected, depletion of PMN in control tumors
resulted in decreased tumor growth, establishing a pro-tumor role
for these resident TAN. However, treatment of mice with SM16
caused abundant neutrophil infiltration and actually decreased
tumor growth. These neutrophils were highly activated and were
able to kill tumor cells in in vitro assays. Depletion of these cyto-
toxic PMN resulted in increased tumor growth. The authors con-
cluded that typical TAN (N2) promote tumor growth, and that
the alteration in cytokine and chemokine milieu created by SM16
therapy produced a cytotoxic (N1) neutrophil capable of killing
tumor cells. An analysis of cytokine, chemokine and other bioac-
tive molecule production showed differential expression between
N1 and N2 neutrophils.
Although mostly semantics, one could argue that N1 PMN
are simply more activated neutrophils than N2, and not really
alternatively activated, like M1/M2 macrophages. Additional
studies of tumor-associated PMN activation states are certain to
follow in the near future. The challenge to investigators will be
not only to recognize quiescent PMN (? N0), modestly activated
PMN (N2), and highly activated PMN (N1), but to determine
which end-effectors dictate tumor cell behavior. We predict that
the molecules used by N1 and N2 neutrophils will be the same
(ROS, NE, MMPs, etc.), but that N1 cells will simply elaborate
these molecules in greater concentrations.
1734 Cell Cycle Volume 9 Issue 9
The major caveat when considering the therapeutic potential
of highly activated and cytotoxic PMN (N1) is the consequence
to neighboring host tissues. Severe pneumonias and sepsis, both
characterized by the presence of highly activated PMN, are con-
ditions in which acute lung injuries (ALI) and acute respiratory
distress syndrome (ARDS) arise.37 The occurrence of these dis-
eases is not trivial, with mortality rates reaching approximately
40%.38 The SM16 treatment protocol employed by Fridlender
et al. was just one week in the LSL-K-ras model, and an assess-
ment of lung injury was not performed. Therefore, it remains
to be seen what the cost of N1 neutrophils will be to the host.
Nevertheless, the therapeutic potential of cytotoxic PMN should
not be ignored.
Neutrophil-Derived Molecules in Cancer Progression
Neutrophils predominantly use proteinases and ROS to exert
their influence. These molecules include the serine-proteinases
NE, CG and PR3; matrix metalloproteinases MMP-8 and
MMP-9; and reactive oxygen species. Neutrophils are also capa-
ble of synthesizing bioactive molecules such as cytokines and
chemokines, known to affect tumor growth when elaborated
from other sources. The impact of each of these molecules on
tumor growth is discussed in detail below, with the omissions of
CG and PR3, neither of which has been adequately studied in
cancer models.
Neutrophil elastase (NE). NE is a neutrophil-derived protei-
nase with broad substrate specificity, including the rather inert
matrix protein, elastin.37 The enzyme is quite neutrophil specific,
although certain subsets of activated monocytes also express
NE.39 Our group has recently shown that NE promotes lung
tumor growth in the Lox-Stop-Stop (LSL)-K-ras mouse model of
lung adenocarcinoma.40 LSL-K-ras/NE-/- mice displayed increased
survival and decreased lung tumor growth and proliferation rates
when compared to LSL-K-ras/NE+/+ mice. We initially suspected
that NE was functioning as a traditional matrix-degrading
enzyme and releasing bioactive molecules that were sequestered
within the extracellular matrix (ECM). However, after an exten-
sive search, we were unable to identify any differences in candi-
date growth factors between the two groups of mice.
Further study demonstrated that NE directly induced tumor
cell proliferation. NE produced differential effects on tumor cell
proliferation over a dose range, with modest concentrations of
enzyme producing cell proliferation, and excessive concentrations
producing cell death. Again, these observations highlight the
importance of neutrophil activation states on tumor behavior.
NE-induced tumor cell proliferation occurs via a complex
alteration of tumor cell signaling ultimately leading to phosphati-
dylinositol-3 kinase (PI3K) hyperactivity (Fig. 1). NE entered
tumor cell endosomes where it encountered potential substrates.
One of these substrates was insulin receptor substrate-1 (IRS-1),
a known binding partner of the p85 regulatory subunit of PI3K.41
Upon the degradation of IRS-1 by NE, the pool of bio-available
PI3K increased, and was free to interact with more potent growth
factors, such as the platelet-derived growth factor (PDGF) and
PDGF-receptor (PDGFR) complex. The activation of PI3K led
 Figure 1. Tumor endosomal NE induces cell proliferation. Tumor associated neutrophils secrete NE near the tumor cell surface where it enters into
tumor endosomes via clathrin pit and is located within early-endosomal antigen-1 (EEA-1)+ endosomes. NE degrades IRS-1, a homeostatic binding
partner of PI3K pathway activity via of its interaction with the p85 regulatory subunit of PI3K within lung cancer cells. The loss of IRS-1 increases the
pool of bio-available PI3K, which is recruited by more potent growth factors such as PDGF-PDGFR. The net result is PI3K pathway activation and subse-
quent tumor cell proliferation.

to increased pAkt production, which was observed both in vitro
and in vivo.
The most notable finding in this study was the entrance
of NE into tumor endosomes. This was the first descrip-
tion of a secreted proteinase gaining access to a cell beyond its
plasma membrane (the only exception being the engulfment
of apoptotic PMN by macrophages that places NE within
macrophage phagolysosomes). NE entered clathrin pits and was
taken into early endosomes. There was specificity to this mecha-
nism, as NE specifically did not enter caveolae. The ability of a
secreted proteinase to gain access to tumor endosomes generates
an entirely novel means by which proteinases may alter tumor
cell growth and expands the list of potential substrates for these
enzymes to include proteins previously considered restricted
access.
Neutrophil-derived NE may prove to be a viable therapeutic
target for non-small cell lung cancer (NSCLC). Synthetic inhibi-
tors of the enzyme were previously generated for the treatment
of chronic obstructive pulmonary disease (COPD) and emphy-
sema, although never thoroughly tested for a number of rea-
sons.42 We utilized one of these inhibitors (ONO-5046, ONO
Pharmaceutical) to inhibit lung tumor growth in LSL-K-ras mice
by three-fold. Additional studies are underway in our laboratory
to establish NE as a therapeutic target in NSCLC.
Matrix metalloproteinase-9 (MMP-9). Gelatinase B (MMP-
9) is a relatively ubiquitous enzyme expressed by many cell types
including neutrophils.43 It displays broad substrate specificity
including against basement membrane structures. Within neu-
trophils, MMP-9 is housed within secondary (specific) granules
alongside MMP-8. Numerous studies have established pro-tumor
roles for MMP-9 in tumorigenesis. MMP-9-/- mice have been
used to confirm deleterious roles for the enzyme in the Lewis
Lung Carcinoma (LLC) model of lung metastasis, HPV16 model
of skin carcinogenesis, and the RIP1-Tag2 model of pancreatic
islet carcinoma.44,45 It remains debatable whether or not cancer
cell-derived MMP-9 mediates basement membrane degradation
during vascular invasion and metastasis formation.46 However,
it is clear that inflammatory cell-derived MMP-9 drives tumor-
associated angiogenesis. Bone marrow transfer studies have been
used to demonstrate that inflammatory cell-derived MMP-9 pro-
teolytically releases vascular endothelial growth factor (VEGF)
sequestered within the ECM.47 Although numerous proteinases
are capable of releasing VEGF, MMP-9 is especially efficient in
this regard.48 This VEGF is bioactive and available for use by
neighboring tumor cells, which in turn augments tumor-associ-
ated angiogenesis and ultimately tumor growth.
The exact source of inflammatory cell-derived MMP-9
remains debatable, and likely varies by tumor type. Mast cells,
macrophages and neutrophils all possess MMP-9 and can be
found infiltrating cancers. Nozawa and colleagues used a com-
bination of bone marrow transplantation in MMP-9-/- mice fol-
lowed by antibody-mediated PMN depletion to diminish tumor
growth and angiogenesis in RIP1-Tag2 tumors.47 Although
this strongly implicates neutrophil-derived MMP-9 in tumor-
associated angiogenesis, it should be noted that the Gr-1 anti-
body utilized here recognizes both Ly6C (monocyte) and Ly6G
(granulocyte) antigens and therefore depletes both monocytes
and neutrophils. Nevertheless, the early infiltration of neutro-
phils and neutrophil-derived MMP-9 is essential for blood vessel
formation and tumor growth.

www.landesbioscience.com Cell Cycle 1735

 Matrix metalloproteinase-8 (MMP-8). Neutrophil collage-
nase (Collagenase-2 or MMP-8) is a potent type I collagenase
predominantly produced by PMN.43 It was the first MMP dem-
onstrated to function in a pro-host capacity within the tumor
microenvironment, a concept now extended to other MMPs,
including MMP-12.49 The use of bone marrow transfer experi-
ments allowed investigators to demonstrate that neutrophil-
derived MMP-8 reduced the number of skin cancers developed
in response to 7,12 dimethylbenzanthracene (DBMA) and tet-
radecanoylphorbol acetate (TPA).50 In this study, MMP-8 was
required both for the initial influx of neutrophils into sites of
tumorigenesis and for proper resolution of neutrophil inflam-
mation. The authors concluded that the genetic instability cre-
ated by persistent inflammation in the absence of MMP-8 led to
increased tumor growth. The means by which MMP-8 partici-
pates in the resolution of inflammation remains unclear. MMP8
cleaves the neutrophil chemokine CXCL-5 generating a more
potent chemoattractant, which does explain the observed differ-
ences in acute PMN influx. It was suspected that MMP-8 likely
degraded other neutrophil chemokines to eliminate chemotac-
tic gradients during resolution. However, subsequent studies
have demonstrated that KC and MIP-2, the major neutrophil
chemoattractants in mice, are not substrates for MMP-8.51 Thus
the exact contribution of neutrophil-derived MMP-8 within the
tumor microenvironment remains obscure.
Tumor-derived MMP-8 has subsequently been shown to
retard tumor growth. B16 melanoma cells engineered to express
MMP-8 display reduced metastasis formation when compared to
WT cells.52 Mechanistically, MMP-8-expressing tumor cells show
increased adherence to matrix structures, which may interfere with
their invasive potential. Studies of MMP-8 in human breast can-
cer have confirmed the pro-host nature of tumor-derived MMP-
8. However, given the proposed mechanism by which MMP-8
inhibits tumor growth and invasiveness, it is unlikely that these
functions are relevant to neutrophil-derived MMP-8.
Reactive oxygen species (ROS). Neutrophils are an abundant
source of reactive nitrogen and oxygen species. These agents are
essential for host defense against microorganisms, a fact high-
lighted by the clinical syndrome of chronic granulomatous disease
(CGD). CGD is characterized by recurrent invasive infections and
early mortality, which results from a genetic mutation in NADPH
oxidase, rendering these PMN incapable of generating ROS.15
ROS play two major roles within the tumor microenviron-
ment: genotoxicity and cytotoxicity. Consistent with the con-
cept that differential states of PMN activation dictate tumor
behavior, it would appear that modest concentrations of ROS
are genotoxic (pro-tumor) and high concentrations are cyto-
toxic (pro-host). The genotoxic capacity of neutrophil-derived
ROS have been demonstrated using mutatect tumors.53 Using
mutations in the Hprt locus as a measure of genotoxicity,
Wilkinson and colleagues were able to demonstrate that these
mutations correlated with the level of neutrophil infiltration.54
Furthermore, manipulation of IL-8 expression, which regulates
tumor-associated PMN content, was sufficient to alter the level
of genotoxicity observed.
1736 Cell Cycle Volume 9 Issue 9
As one would expect, high quantities of PMN-derived ROS
are tumoricidal, but at the expense of cytotoxicity to host tissues.
ROS kill tumor cells via increased oxidative stress and increased
signal transduction down pro-apoptotic pathways. The most
injurious of the ROS is likely hypochlorous acid (HOCl). PMN-
derived HOCl primarily kill tumor cells via lysis, or directly
damaging cell membranes.55 The induction of apoptosis may also
be involved in ROS-mediated cytotoxicity.56
Neutrophil-derived cytokines. Neutrophils are also capable
of impacting their microenvironment by the de novo synthe-
sis and secretion of bioactive molecules, such as cytokines and
chemokines. Therefore, TAN are likely capable of altering the
cellular composition of the tumor microenvironment, and may
even participate in polarizing the phenotypes of other immune
cells. PMN have been shown to express several cytokines includ-
ing TNFα, IL-1β, IL-12, and members of both the CC and CXC
family of chemokines.57 Specifically, PMN synthesize IL-8 and its
murine counterparts (CXCL-1, -2), CXCL-10 (IP-10), CXCL-11,
and hepatocyte growth factor (HGF), among others. The most
notable of these is IL-8, a prototype CXC chemokine that binds
CXCR-2 receptors located on endothelial cells and PMN.58 As
such, IL-8 promotes both angiogenesis and neutrophil recruit-
ment. It is easy to speculate that PMN-derived IL-8 production
within the tumor microenvironment would generate a positive
feedback loop to ensure continual re-population of TAN, how-
ever, this has not been proven. Furthermore, the production of
the ELR- CXC chemokines (i.e., CXCL-10) by PMN could drive
a Th1 response,59 ultimately suppressing tumor growth.
There are two definitive reports of tumor cell induced
expression of PMN-derived bioactive molecules. Neutrophil-
derived HGF has been correlated with increased tumor growth
in lung cancers.60 Additionally, breast cancer cells induce PMN
to produce oncostatin M, which requires both the release of
GM-CSF, and direct cell-cell interaction between tumor cell
and PMN.61 Oncostatin M then interacts with tumor cells to
induce the expression of VEGF, thereby fueling tumor-associ-
ated angiogenesis.
Conclusions
Neutrophils possess substances capable of altering tumor cell
behavior and are present in sufficient numbers at sites of tum-
origenesis to do so. The major theme regarding TAN function is
that their impact on tumor growth is a product of their activation
state. The commonly encountered TAN is moderately activated
and promotes tumor growth and invasiveness via release of ROS
and proteinases. The mechanisms involved here go well beyond
simple remodeling of ECM, and continue to be uncovered. In
contrast, when neutrophils are highly activated, they release these
same substances in concentrations toxic to tumor cells. Going
forward, the challenge to investigators will be to develop reliable
means to either inhibit these PMN-derived molecules altogether,
or to devise a safe means to generate cytotoxic neutrophils within
the tumor microenvironment, while limiting damage to host
tissues.

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