Liao et al.

Molecular Cancer (2019) 18:65

https://doi.org/10.1186/s12943-019-0961-y

REVIEW Open Access

Reactive oxygen species: a volatile driver of

field cancerization and metastasis
Zehuan Liao1,2, Damien Chua1 and Nguan Soon Tan1,3*

Abstract
Field cancerization and metastasis are the leading causes for cancer recurrence and mortality in cancer patients.
The formation of primary, secondary tumors or metastasis is greatly influenced by multifaceted tumor-stroma
interactions, in which stromal components of the tumor microenvironment (TME) can affect the behavior of the
cancer cells. Many studies have identified cytokines and growth factors as cell signaling molecules that aid cell to
cell communication. However, the functional contribution of reactive oxygen species (ROS), a family of volatile
chemicals, as communication molecules are less understood. Cancer cells and various tumor-associated stromal
cells produce and secrete a copious amount of ROS into the TME. Intracellular ROS modulate cell signaling
cascades that aid in the acquisition of several hallmarks of cancers. Extracellular ROS help to propagate, amplify, and
effectively create a mutagenic and oncogenic field which facilitate the formation of multifoci tumors and act as a
springboard for metastatic tumor cells. In this review, we summarize our current knowledge of ROS as atypical
paracrine signaling molecules for field cancerization and metastasis. Field cancerization and metastasis are often
discussed separately; we offer a model that placed these events with ROS as the focal instigating agent in a
broader “seed-soil” hypothesis.
Keywords: Reactive oxygen species, Field cancerization, Metastasis, Tumor microenvironment, Cancer-associated
fibroblasts, Tumor-associated macrophages

Introduction anti-tumor treatment methods. Emerging therapeutic mo-

Worldwide, one in seven deaths is due to cancer; cancer dalities such as chimeric antigen receptor T-cell (CAR-T)
causes more deaths than Acquired Immune Deficiency immunotherapy approach have proven to be very effect-
Syndrome, tuberculosis, and malaria combined. Recent ive, but only a select subset of cancers responds to the
statistics report estimates that there will be 18.1 million treatment [3]. Furthermore, more than 90% of cancer
new cancer cases and 9.6 million cancer deaths worldwide deaths are caused by the metastatic spread of tumor cells
in 2018 [1]. Current trends also suggest that cancer will from the primary to distant sites [4]. Yet, our understand-
remain as one of the leading causes of death and the most ing of this process is limited, and there are no specific
important barrier to increasing life expectancy globally. therapeutic approaches to suppress cancer metastasis.
Cancer-related deaths have not rocketed because of sig- Moreover, resistance to conventional chemotherapeutics
nificant advances in diagnosis. Improvements and a genu- and disease relapse remain persistent clinical challenges
ine postponement of death for various cancer patients are [4]. These observations imply an incomplete understand-
often due to better detection methods and not to better ing of the cellular and biotic heterogeneity in the tumor.
treatments [1, 2]. However, we have made less progress Cancer is a genetic disease resulted from both internal
with traditional therapeutic options such as chemother- factors (e.g., inherited mutations, immune conditions,
apy, radiotherapy, and surgery still dominates current hormones, etc.) and external factors (e.g., environment,
diet, tobacco, diet, infection, radiation, among others)
* Correspondence: [email protected] [2]. These factors can affect important genes such as
1
School of Biological Sciences, Nanyang Technological University Singapore, proto-oncogenes, tumor suppressor genes and deoxy-
60 Nanyang Drive, Singapore 637551, Singapore
3
Lee Kong Chian School of Medicine, Nanyang Technological University ribonucleic acid (DNA) repair genes via cellular interme-
Singapore, 11 Mandalay Road, Singapore 308232, Singapore diates such as reactive oxygen species (ROS) [5]. ROS
Full list of author information is available at the end of the article

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Liao et al. Molecular Cancer (2019) 18:65 Page 2 of 10

are major cellular intermediates. In most studies, ROS are intracellular ROS plays a different role in cancer cell sur-
used as an umbrella term to describe a heterogeneous vival. At precancerous and early stages of cancer, intracel-
group of cellular free radicals that contain oxygen (O2) lular ROS promote cancer initiation via inducing oxidative
derived from various intracellular processes and extracellu- and base pair substitution mutations in pro-oncogenes
lar sources. ROS are highly reactive to biomolecules, and such as Ras and tumor suppressor genes such as p53 [13].
they can trigger multiple biological events [6]. ROS Apart from inducing mutations, ROS can also modify site
plays a contradictory role in cancer biology. Elevated specific amino acids side chains which alter protein struc-
ROS levels contribute to tumorigenesis, cancer pro- ture and functions [7]. Among the amino acids, cysteine
gression and spreading via the promotion and main- (Cys) is more prone to oxidation by ROS due to the pres-
tenance of tumorigenic cell signaling which results in ence of thiol group. Cys appears to be the principal actor
tumor cell proliferation, survival, autophagy, and metasta- in redox signalling, functioning as a regulatory reversible
sis [7]. In Table 1, we provide a non-exhaustive list of the molecular switch. As cancer progresses, the accumulation
various common ROS and their roles in cancer. of excess intracellular ROS can trigger apoptosis, tumor
Recently, the involvement of ROS as atypical context- cells escape apoptosis by producing high levels of intracel-
dependent drivers of tumorigenesis is gaining attention [8]. lular antioxidants [13]. In the late stages of tumor evolu-
On one hand, excessive ROS results in anti-tumorigenic ef- tion, metastatic tumors developed mechanisms that
fects via promoting cell death, inducing cell cycle arrest and exploit ROS as a springboard for the dissemination of can-
senescence [9]. On the other hand, it is known that tumor cer cells. As a result, whether ROS play anti-tumor or
cells promote their survival through enhanced ROS ma- oncogenic roles may depend on the different stages of
nipulation mechanisms, such as increased antioxidant levels cancer development and progression.
or increased ROS production, to maintain the delicate bal- Many canonical pathways involved in tumor-promoting
ance in ROS level that supports their proliferation and sur- inflammation and cell proliferation have been shown to be
vival [9, 10]. For example, autophagy can be induced by activated by ROS. Transcription factor NF-κB plays an
ROS to remove damaged mitochondria that contribute to important role in cellular processes such as immune and
oxidative stress, restoring ROS to physiological level [11]. inflammatory response, cellular proliferation and differenti-
However, the deletions of autophagy-related genes such as ation [14]. The canonical NF-kB pathway can be activated
autophagy-related 5 (ATG5), autophagy-related 7 (ATG7) by oxidative stress and proinflammatory cytokines
and beclin-1 (BECN1) can lead to defective autophagy. [15]. The activation of the canonical NF-κB pathway is
These deletions can result in the deregulated degradation dependent on the phosphorylation of IκB-Kinase (IKK)
of damaged mitochondria, and hence, elevated ROS pro- β, the ubiquitination-mediated degradation of
duction as well as oxidative stress [11]. NF-κB inhibitor alpha (IκBα), the translocation of
Despite current knowledge in ROS signaling in cancer NF-κB into the nucleus, resulting in the transcriptional
biology, the dual nature of ROS is still a huge conundrum activation of target genes [16, 17]. Studies have shown
in therapeutics targeting ROS. The inhibition or elevation that ROS can trigger the activation of the NF-κB path-
of ROS levels can yield drastically different results [2, 12]. way via inducing the tyrosine phosphorylation of IκBα.
Recent discussions suggested dichotomizing the effects of IκBα, which is usually phosphorylated on serine-32
ROS in cancer cells into two categories: early versus late and -36 by IKK, undergoes ubiquitination and degrad-
stages. Depending on the stage of cancer progression, ation for activation of the NF-κB pathway [18, 19].
Table 1 ROS and Their Roles in Cancer
ROS Roles in Cancer References
Generic ROS Activation of oncogenic Ras, Bcr-Abl, c-Myc which hyperactivates cell [7, 11]
proliferation; induce Wnt/β-catenin pathway which increases metastatic
potential; regulation of epithelial-mesenchymal transition (EMT) via matrix metalloproteinases (MMPs);
regulation of nuclear factor kappa-light-chain-enhancer of activated
B cells (NF-κB) pathways; contribution to drug resistance such as
through high mutagenic rates
Hydrogen Peroxide (H2O2) Promotes phosphoinositide 3-kinases (PI3Ks)/RAC-alpha serine/ [35, 102, 103]
threonine-protein kinase (Akt) survival pathway; induces mitogen-
activated protein kinase (MAPK)/extracellular signal-related kinases
(ERK) pro-proliferative signaling pathway; oxidative modification of
phosphatase and tensin homolog (PTEN); oncogenic stabilization
of hypoxia-inducible factor (HIF)-1α; conversion to hydroxyl radical
Superoxide (O2•−) Conversion to H2O2, peroxynitrite; Stimulates AMPK activity to induce [102, 104]
metastasis; oncogenic stabilization of HIF-1α
Hydroxyl radical (•OH) Initiates lipid peroxidation; promotes DNA mutagenesis [105, 106]
Liao et al. Molecular Cancer (2019) 18:65 Page 3 of 10

Exogenous addition of H2O2 induces the phosphoryl- stress occurs when excessive ROS accumulate in the cell
ation of IκBα at tyrosine-42 as well as other tyrosine due to an imbalance of oxidative and reductive activities,
residues, resulting in the degradation of IκBα and the resulting in cellular damage. The antioxidant defense sys-
activation of the NF-κB pathway [17, 20]. tems include superoxide dismutase (SOD), catalase, gluta-
Similarly, MAPK family which consists of ERK1/2, c-Jun thione peroxide (GPx), glutathione reductase, glutathione
N-terminal kinase (JNK), MAPK-11 and the MAPK1 path- S-transferase (GST), and glutathione, which are important
way are important intracellular signal transduction path- to maintain a balanced level of intracellular ROS [31]. The
ways involved in cellular processes such as cell survival, NF-κB pathway can influence the ROS levels by increasing
cell death, growth, and differentiation [21]. Studies have the expression of SOD, GPx and GST [18]. Mitochon-
demonstrated that ROS can activate the epidermal growth dria is an important source of intracellular ROS, such
factor receptors (EGFR) and platelet-derived growth factor as superoxide O2•− and H2O2 [26]. Intracellular H2O2 is
(PDGF) receptors without corresponding ligands. Thus, formed by SOD-catalyzed dismutation from O2•− gen-
the activation of EGFR and PDGF can activate Ras and erated within the mitochondrial matrix, intermembrane
subsequently lead to the activation the ERK pathway space, and outer membrane [26]. Increased ROS produc-
[18]. Such modifications to the receptors conferred tion in cancer cells can lead to elevated SOD expression
ligand-independent activation of the tyrosine kinase as well as the inactivation of H2O2 scavenging enzymes,
receptors and contribute to resistance against antibody- producing abnormally high levels of H2O2 [11].
based therapies such as anti-EGFR (e.g. cetuximab, necitu- Apart from mitochondria, NADPH oxidase (NOX), an
mumab) or anti-PDGF (e.g. Olaratumab). Furthermore, enzyme system, is a major source of extracellular ROS
ROS may also activate the MAPK pathway via oxidative which mainly serves as communication molecules [2]. As
modification of intracellular downstream kinases such integral membrane proteins, the expression of membrane-
as apoptosis signal-regulating kinase 1 (ASK-1), a mem- associated NOX releases O2•− into the extracellular space
ber of the mitogen-activated protein kinase kinase kin- [32]. Furthermore, these enzymes are also internalized to
ase (MAP3K) superfamily for JNK and MAPK-11 [22]. form redoxosomes, extending the intracellular reach of
Another important pathway in cancer is the PI3K/PTEN ROS [33]. Exosomes, containing functional NOX com-
pathway whereby several of the signaling mediators are plexes to generate ROS, can also be released from cells
redox sensitive and play important roles in field canceriza- such as macrophages into the extracellular space and
tion and metastasis [18]. ROS can act as signaling media- transported to distant sites [34]. An elevated intracellular
tors by triggering oxidative modification of specific target ROS inevitably results in a copious amount of extracellu-
molecules [23]. For example, PTEN can be modified by lar ROS in the TME, thus neighboring normal cells will
H2O2 via oxidation of the Cys thiol groups of phospha- experience oxidative stress (Fig. 1) [35]..
tases, resulting in its inactivation [7, 24]. ROS have critical roles in tumor pathology. A high level
Most studies on ROS in cancer were largely focused of intracellular ROS due to defects in ROS production or
on the primary tumor. The roles of ROS in field canceri- detoxification processes can transform a normal cell into a
zation and metastasis, which contribute to local and dis- malignant cell [2]. Indeed, cancer cells have elevated levels
tant recurrence cancers, respectively, has been gathering of intracellular ROS and extracellular ROS. Cancer cells
attention. In the review, we will discuss the role of ROS in have a high level of intracellular ROS due to reasons such
the tumor microenvironment (TME) in driving field can- as increased metabolic activity and mitochondrial energet-
cerization and metastasis. ics, alterations of the electron transport chain, expression
of HIF-1 due to hypoxic condition and chronic inflamma-
Origin of ROS tion [36]. Furthermore, cancer cells also have elevated ex-
ROS are produced by various biochemical and physio- pression of membrane-associated NOX [32]. Oncogenic
logical oxidative processes in the cell. Mitochondria and KRAS was reported to increase the activity of NOX en-
nicotinamide adenine dinucleotide phosphate (NADPH) zymes on the tumor cell membrane and hence, promote
oxidase are the two major producers of ROS [25, 26]. extracellular ROS generation [37]. While cancer cells may
ROS were once viewed merely as by-products of cell be more tolerant to oxidative stress via an elevated robust
metabolism, but subsequent research showed that they antioxidant defense, the consequence may be detrimen-
have many roles in normal physiology. ROS serve as an tal to the TME and the adjacent normal cells. For ex-
important signaling molecule participating in a variety of ample, cancer cells expressed membrane-associated
cellular signaling pathways such as growth factor path- catalase to degrade extracellular ROS as well as express
ways, inflammation, engagement of integrins and adhe- membrane-associated SOD to convert the more react-
sion to the extracellular matrix [27–30]. ive O2•− into reactive H2O2 [32, 33]. This might explain
Oxidative stress contributes to aging and many dis- for the accumulation of oncogenic H2O2 in the TME,
eases such as cancer, diabetes, and obesity. Oxidative particularly in metastatic epithelial tumors [8, 35, 38].
Liao et al. Molecular Cancer (2019) 18:65 Page 4 of 10

Fig. 1 Fate of ROS: NOX proteins are integral membrane proteins of cells and release superoxides (O2•−) as products directly into the extracellular
space. Functional NOX proteins can also be internalized into forming redoxosomes, producing superoxides (O2•−) within the redoxosomes.
Furthermore, from cells such as macrophages, exosomal NOX complexes can be released and being incorporated into surrounding cells via
endocytosis. Besides NOX, xanthine oxidase and nitric oxide synthase proteins (both not shown) can also generate extracellular and intracellular
superoxides (O2•−) respectively. Superoxides (O2•−) are relatively impermeable through the cell membrane. However, intracellular and extracellular
SOD proteins catalyze the dismutation of superoxides (O2•−) into H2O2 and O2. H2O2 molecules are relatively permeable through the aquaporins
of the cell membrane and hence, can travel easily from cell to cell, providing regional oxidative stress

Apart from cancer cells, various tumor-associated cell Similar to CAFs, newly transformed fibroblasts became
types also produce ROS and contribute to the oxidative activated and desensitized to TGF-β. Normal fibroblasts
microenvironment. Cancer-associated fibroblasts (CAFs) treated with prolonged exogenous H2O2 displayed a sig-
are one of the most abundant stromal cells in the TME nificant increase in p65-NF-κB phosphorylation, triggering
and influence the pathology of cancer in many ways NF-κB activity. The NF-κB activation attenuated TGF-β
[39–41]. As CAFs is a cellular state rather than a cell signaling and hence, ensures the continued expression of
type, CAFs are generally known as activated fibroblast in FAP in the newly transformed fibroblasts [35].
the TME with no precise molecular definition [42]. In addition to CAFs, ROS are also released by many
CAFs produce and are highly influenced by ROS [43]. tumor-associated immune cells in the TME [48]. Tumor-
CAFs have been shown to have an elevated level of associated macrophages (TAMs) in the TME mainly ori-
H2O2 as compared to normal fibroblasts. The high pro- ginate from blood-circulating monocytes that infiltrate
duction of intracellular and extracellular H2O2 by CAFs into the TME and differentiate into mature pro-tumor
was due to impaired transforming growth factor beta macrophages mediated by cytokines in the TME [49–51].
(TGF-β) signaling [44, 45]. This impaired signaling leads Interestingly, the role of TAMs is a double-edged sword.
to the suppression of the antioxidant enzyme GPx1 as As part of the immune system, macrophages are the first
well as the production of intracellular ROS by impaired host cells to enter the TME and can potentially kill the
mitochondrial function and extracellular ROS by in- cancer cells [52]. In vitro, activated macrophages showed
duced NOX [46]. In addition, Caveolin-1, a negative anti-tumor activity via calreticulin binding receptors for
regulator of NOX derived ROS, also increases the level cancer cell recognition [53]. Macrophages also display
of extracellular ROS production by CAFs [47]. Notably, phagocytotic activity toward some damaged tumor cells
normal fibroblasts treated with exogenous H2O2 or [54]. However, the TME is known to have elevated
CAF-conditioned medium transformed into an oxida- levels of macrophages. During cancer initiation, cancer
tive, CAF-like state [35]. These newly transformed fi- cells recruit macrophages via chemokines which amp-
broblasts displayed elevated fibroblast activation lify an inflammatory response. Macrophages also pro-
protein (FAP) and α-smooth muscle actin (αSMA) ex- duce redoxosomes, i.e. exosomes containing functional
pression levels, both of which are biomarkers of CAFs. NOX complexes into the TME, generating extracellular
Liao et al. Molecular Cancer (2019) 18:65 Page 5 of 10

ROS and being incorporated into surrounding cells via [73]. This posits the presence of a regional carcinogenic
endocytosis [34]. signal at these foci of cellular abnormalities, and if given
TAMs and CAFs are often detected close to each other, enough time and exposure, the carcinogenic agent will
suggesting extensive communications and interactions be- cause irreversible changes to the cells leading to onco-
tween these two cell types [55]. The reciprocal relation- genic transformation and field cancerization. Indeed, field
ship between TAMs and CAFs in the TME increases cancerization results in multifocal primary tumors in
tumor malignancy, and ROS may be a key player in the proximity with a higher chance of recurrence even after
interaction [56, 57]. ROS in the TME can trigger altered resection of the malignant tumors [74]. Presently, field
activation of macrophages and immunosuppression cancerization basically refers to pre-malignant changes
[58]. TAMs also release ROS which plays an essential in multiple and large areas of the primary tumor, within
role in immune alterations such as inducing apoptosis both the epithelial cells and surrounding stromal cells
in lymphocytes [48, 59]. There was evidence indicating [75, 76]. Despite its clinical importance, only a few cy-
that the TME induces TAMs to activate immunosup- tokines such as TGF-β, macrophage inhibitory cytokine
pressive mechanisms via ROS production [60]. Macro- 1 and PDGF-A have been implicated as possible field
phages exposed to increasing concentration of tumor carcinogens [77–79].
fluid significantly increased intracellular ROS generation Field cancerization can be initiated and propagated in
[58]. Elevated intracellular ROS corresponds to altered many ways, including mutagen ROS [80]. The chronic
cellular redox homeostasis and oxidative stress [61]. exposure of high extracellular H2O2 promoted the trans-
Myeloid-derived suppressor cells (MDSCs) also pro- formation of normal epithelial cells and fibroblasts, indi-
mote cancer progression via ROS [62]. MDSCs are a cating the presence of a premalignant field defect by
heterogeneous population of cells which can suppress T oxidative stress in the TME [81–83]. H2O2 is an ideal
cell responses and expand during inflammation and can- field effect carcinogen due to its higher cellular plasma
cer [63]. These cells were first observed in patients with membrane permeability and longer half-life than other
cancer [64–66]. Apart from their immunological func- ROS counterparts [7, 35]. H2O2 aggravates cancer cell
tions, MDSCs were also reported to promote tumor aggressiveness, transform primary epithelial cells by oxi-
angiogenesis, tumor cell invasion, and metastasis [67]. dative modification of the membrane associated PTEN
MDSCs are a unique component of the immune system and Src proteins, decreasing PTEN and increasing Src
which regulates the immune responses in cancer pa- activities [8, 35, 43, 84]. Normal fibroblasts treated with
tients [63]. Indeed, up-regulation of ROS primarily by H2O2 transformed into an oxidative, CAF-like state. In
NOX is one of the major factors responsible for the im- turn, these newly converted CAF-like cells produced
munosuppressive activity of MDSCs [68]. Granulocytic higher H2O2 caused by an impaired TGF-β signaling
MDSCs, a subpopulation of MDSCs, were found to use [35]. These observations indicated that stromal cells,
ROS primarily as the mechanism of immunosuppression such as CAFs, engaged redox signaling circuitries and
by close cell-cell contact with T cells [69, 70]. mitogenic signalings to reinforce their reciprocal rela-
Although both TAMs and MDSCs were found to sup- tionship with the epithelial tumor, further supports that
press T cell responses via different ROS mediated mecha- extracellular oxidative stress might act as a field effect
nisms, TAMs were the more potent immune suppressor carcinogen [35, 43]. Thus, ROS are atypical carcinogenic
[60]. MDSCs suppressed T cells via contact-independent signals which promote stromal-mediated field canceriza-
H2O2 production and TAMs exerted their more potent tion [35].
immunosuppressive effects by the production of contact- Conceivably, a single mutant cell represents the smal-
dependent H2O2 [60, 69]. Certain subpopulations of lest origin capable of initiating field cancerization by
MDSCs were found to be able to differentiate into im- causing neighboring normal cells to transform and to
munosuppressive TAMs in the presence of tumor-derived amplify an oxidative field [80]. Disseminated cancer cells
factors or tumor-bearing hosts [69, 71, 72]. can also start a new cancerized field by producing extra-
Hence, for cancer cells (the “seed”) to grow, expand cellular ROS. Although stromal cells such as CAFs do
and acquire more mutations to become malignant, a not transform into tumor cells themselves, alterations of
supportive TME (the “soil”) is required. ROS plays an es- stromal cells can promote field cancerization. This is be-
sential role in creating the immunosuppressive “soil” cause these stromal cells provide selective pressure such
ground for field cancerization and metastasis. as oxidative stress in the field for particular newly mutated
cells or disseminated cancer cells over the existing normal
ROS in field cancerization cells [80]. This provides the “soil” for newly mutated cells
Field cancerization was first reported in 1953 by Slaughter to acquire more mutations and progress towards cancer
et al. and is often used to describe the development of ab- as well as newly migrated cancer cells to grow and survive
normal epithelia and stroma bordering a tumorigenic area in the new environment [80]. ROS in the new
Liao et al. Molecular Cancer (2019) 18:65 Page 6 of 10

environment enact field cancerization by promoting oxi- anoikis and evade the immune surveillance until they arrive
dative stress, causing pre-malignant transformation of the at a secondary site where they extravasate and colonize dis-
surrounding cells as well as a series of immunosuppressive tal organs [88]. Although most cancer deaths are the result
responses [80]. These findings suggest that the epithelial of metastases, cancer research has mainly focused on the
and stromal cells bathed in an oxidative milieu, continu- primary tumor.
ously experienced oxidative stress that modulates their Metastasis begins with EMT, which is a transdifferentia-
functions (Fig. 2) [35, 61]. tion program whereby epithelial cancer cells lose cell-cell
Altogether, these results confirm the presence of adhesion and concomitantly acquire mesenchymal fea-
stromal-mediated field cancerization, whereby the influ- tures of migration and invasion [86]. Several pieces of evi-
ences of stromal oxidative stress can be propagated and dence have established a strong connection between EMT
amplified, and effectively create a mutagenic or onco- of epithelial cancer cells and ROS. TGF-β1 is
genic field promoting multifocal tumor formations [35]. well-established as one of the more prominent players of
This finding features the mesenchymal-mesenchymal and the induction of EMT [89]. TGF-β1 regulates
epithelial-mesenchymal communications in the propaga- urokinase-type plasminogen activator (uPA) and MMP9
tion of field effect and the creation of a TME niche [43]. to facilitate cell migration and invasion via the activation
of NF-κB through the Rac1-NOXs-ROS-dependent mech-
ROS in cancer metastasis anism [90]. Similarly, ROS also plays a crucial role in the
Metastasis is the spread of the primary tumor cells to dis- regulation of EMT via the non-canonical
tant organs, and this process is considered the main cause TGF-β1-TGF-β-activated kinase 1 (TAK1) pathway. The
of cancer morbidity and mortality [4]. Once metastasis oc- increase in integrin:Rac-induced ROS by TAK1 deficiency
curs, surgical excision of the primary tumor no longer guar- results in a cascade of signals leading to accelerated EMT.
antees disease-free survival, and the probability of cancer Consistently, the expression of TAK1 was reduced in inva-
relapse in distal organs increases significantly. Metastasis is sive squamous cell carcinoma (SCC), an observation absent
a complex, multi-step process beginning with cancer cells from benign SCCs [91]. In a recent study, Matsuno and
in the primary tumor undergoing EMT [85, 86]. This leads colleagues showed that ROS regulates EMT via the activa-
to an invasive tumor epithelial phenotype characterized by tion of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), in-
detachment from and degradation of the basement mem- creasing Notch signaling which ultimately increases EMT
brane [87]. Eventually, the invasive cancer cells gain access [92]. It is known that exogenous ROS by sources such as
to local vasculature and/or lymphatics, intravasate and ionizing radiation also results in the induction of TGF-β1
enter the systemic circulation. In the absence of basement [93]. Taken together, increasing evidence revealed a
membrane attachment, circulating cancer cells circumvent multifaceted role of ROS in EMT. The fact that ROS is

Fig. 2 ROS in the TME: ROS can directly or indirectly modulate the functions of many cell types in the TME. ROS are able to transform normal
epithelial cells and normal fibroblasts into malignant cells and CAFs respectively. ROS produced by cancer cells, TAMs and MDSCs can have an
immunosuppressive effect on T-cells and B-cells. ROS can accumulate in the extracellular matrix, causing neighboring normal cells to acquire
malignant phenotypes. Migration of the ROS-producing cells (cancer cells, CAFs, TAMs, MDSCs) to distant tissue or organ can start a new cancer
field, transforming neighboring normal cells into cancer supporting cells or new malignant cells. This expanding field provides the appropriate
“soil” for the survival and growth of newly-disseminated cancer cells or newly-transformed cells (the “seed”)
Liao et al. Molecular Cancer (2019) 18:65 Page 7 of 10

involved in several pathways that directly link to many development of redox-therapies that target the
critical EMT-inducing pathways underscores its im- metastasis.
portance and the crucial role of ROS in EMT.
Circulating cancer cells acquire anoikis resistance, Conclusion and perspectives
where it loses its dependence on integrin-mediated While field cancerization and metastasis are often discussed
extracellular matrix contact for survival and growth [38]. separately, these two phenomena may be analogously repre-
Many studies have shown that ROS is indeed one of the sented by a growing tree that eventually sprouts branches
key players in anoikis sensitivity. The metastasis-associated and develops a wide canopy. At its roots, a cancerized field
gene, angiopoietin-like 4 (ANGPTL4) has been shown to fuels the acquisition of mutations or transcriptome changes,
be a key player. Via an outside-in signaling mechanism, i.e., the “trunk” to promote growth. This co-evolution of
ANGPTL4 protein engages with integrin to stimulate the tumor-stroma drives tumor cell clonal selection. Hence,
production of ROS, which subsequently activates PI3K/Akt some branches and offshoots begin to appear, i.e., intratu-
and ERK to confer anoikis resistance to tumor cells [38]. In mor heterogeneity. ROS helps to propagate, amplify, and ef-
a recent study, anoikis resistance in gastric cancer cells was fectively create a mutagenic and oncogenic field will
attributed to an increase in NOX4-induced ROS generation facilitate the formation of multifoci tumors and act as a
[94]. The increase in ROS levels by NOX4 upregulates springboard for metastatic tumor cells. However, not all
EGFR, which is a growth factor involved in cell survival new profile change and mutations confer a selective advan-
and anoikis inhibition [95]. Similarly, another study also re- tage, and therefore some branches do not fully develop.
vealed that EGFR is directly associated with increased cell Over time, tumor cells with the appropriate profile of meta-
survival in the absence of extracellular matrix [96]. Indeed, static “driver” genes within the cancerized field become ag-
intracellular ROS plays an integral role such as in the regu- gressive and gain the capacity to invade, intravasate, evade
lation of growth factors to bring about anoikis resistance of the immune system and metastasize. The seed-soil concept
cancer cells which is an important step in metastasis. by Paget becomes relevant in determining the survival of
In the final stage of successful metastasis, circulating this disseminated tumor cells [97]. Again, ROS produced by
cancer cells will extravasate and colonize the new sec- exosomes could assist to interrogate and corrupt the distant
ondary tumor site due to its predisposed microenviron- soil for more effective colonization of the disseminated
ment [97]. It has been revealed that interactions from cancer cells. It is attempting to speculate that metastatic
primary tumor sites are able to set up a pre-metastatic dormancy, where a disseminated tumor cell remains in a
niche in the secondary tumor site, and this determines quiescent state at a remote organ while waiting for appropri-
the survival of disseminated tumor cell at the new site. ate environmental conditions to begin proliferation again,
The secondary TME also determines the outcome of the may be partly attributed to poorly-prepared soil. Upon en-
disseminated cancer cell, whether it thrives or remain graftment within a suitable secondary site, the metastasized
dormant [98]. Increasing evidence has shown that ROS tumor cell may once again enact field cancerization to cor-
play a role in creating a ‘soil’ in distal organs, setting up rupt its new microenvironment. ROS play important roles
a supportive tumor environment for disseminated cancer during field cancerization and metastasis, but many events
cells. One of such ways is through the cellular disposal remained relatively understudied. The scarcity of mouse
of miR-23b via exosomes. miR-23b is a microRNA that models to monitor the production of volatile ROS by the
is negatively involved in tumorigenesis through the regu- tumor and to identify the cells affected by ROS in vivo re-
lation ROS [99]. The study also suggested that the trans- mains a bottleneck to our understanding.
fer of exosome containing miR-23b from bone marrow
Abbreviations
mesenchymal stem cells, a common secondary tumor Akt: RAC-alpha serine/threonine-protein kinase; ANGPTL4: Angiopoietin-like 4;
site in breast cancer, might enable a metastatic niche ASK-1: Apoptosis signal-regulating kinase 1; ATG5: Autophagy-related 5;
that promoted breast cancer cell dormancy, an observa- ATG7: Autophagy-related 7; BECN1: Beclin-1; CAF: Cancer-associated
fibroblast; CAR-T: Chimeric antigen receptor T-cell; Cys: Cysteine;
tion that was contingent with breast cancer recurrence DNA: Deoxyribonucleic acid; EGFR: Epidermal growth factor receptors;
[100]. The accumulation of MDSCs from haemopoietic EMT: Epithelial-mesenchymal transition; ERK: Extracellular signal-related ki-
cells in the microenvironment of metastatic niches nases; FAP: Fibroblast activation protein; GPx: Glutathione peroxide;
GST: Glutathione S-transferase; HIF: Hypoxia-inducible factor; IKK: IκB-Kinase;
causes the increase in production of ROS that sup- IκBα: NF-κB inhibitor alpha; JNK: c-Jun N-terminal kinase; MAP3K: mitogen-
presses cytotoxic CD8+ T-cells activity, which promoted activated protein kinase kinase kinase; MAPK: Mitogen-activated protein
the disseminated cancer cell’s survival in the secondary kinase; MDSC: Myeloid-derived suppressor cell; MMP: Matrix
metalloproteinase; NADPH: Nicotinamide adenine dinucleotide phosphate;
tumor site [70, 101]. NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells;
The involvement of ROS in various steps of metas- NOX: NADPH oxidase; Nrf2: Nuclear factor (erythroid-derived 2)-like 2;
tasis makes it an integral player in the metastasis of PDGF: Platelet-derived growth factor; PI3K: Phosphoinositide 3-kinases;
PTEN: Phosphatase and tensin homolog; ROS: Reactive oxygen species;
tumors. The finding is important in guiding the way SCC: Squamous cell carcinoma; SOD: Superoxide dismutase; TAK1: TGF-β-
future clinical trials may be conducted as well as the activated kinase 1; TAM: Tumor-associated macrophage; TGF-β: Transforming
Liao et al. Molecular Cancer (2019) 18:65 Page 8 of 10

growth factor beta; TME: Tumor microenvironment; uPA: Urokinase-type 12. Raza MH, et al. ROS-modulated therapeutic approaches in cancer treatment.
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13. Assi M. The differential role of reactive oxygen species in early and late
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Ministry of Education, Singapore (2014-T2–1-012 and 2017-T1–002–103) to 17. Liu T, et al. NF-κB signaling in inflammation. Signal Transduction Targeted
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Availability of data and materials ubiquitination of phosphorylated IκBα in TNFα-stimulated HEK293 cells. Exp
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