Acidic extracellular microenvironment and cancer
Cancer Cell International
Acidic extracellular microenvironment and cancer
Yasumasa Kato 0
Shigeyuki Ozawa 2
Chihiro Miyamoto 1
Yojiro Maehata 1
Atsuko Suzuki 0
Toyonobu Maeda 0
Yuh Baba 3
0 Department of Oral Function and Molecular Biology, Ohu University School of Dentistry , 963-8611, Koriyama , Japan
1 Department of Oral Science, Kanagawa Dental University Graduate School of Dentistry , Yokosuka , Japan
2 Department of Oral Maxillofacial Surgery, Kanagawa Dental University Graduate School of Dentistry , Yokosuka , Japan
3 Department of General Clinical Medicine, Ohu University School of Dentistry , Koriyama , Japan
Acidic extracellular pH is a major feature of tumor tissue, extracellular acidification being primarily considered to be due to lactate secretion from anaerobic glycolysis. Clinicopathological evidence shows that transporters and pumps contribute to H+ secretion, such as the Na+/H+ exchanger, the H+-lactate co-transporter, monocarboxylate transporters, and the proton pump (H+-ATPase); these may also be associated with tumor metastasis. An acidic extracellular pH not only activates secreted lysosomal enzymes that have an optimal pH in the acidic range, but induces the expression of certain genes of pro-metastatic factors through an intracellular signaling cascade that is different from hypoxia. In addition to lactate, CO2 from the pentose phosphate pathway is an alternative source of acidity, showing that hypoxia and extracellular acidity are, while being independent from each other, deeply associated with the cellular microenvironment. In this article, the importance of an acidic extracellular pH as a microenvironmental factor participating in tumor progression is reviewed.
Acidic microenvironment; Cancer; Malignant phenotype
The extracellular pH (pHe) of tumor tissues is often
], and acidic metabolites, e.g. lactic acid caused
by anaerobic glycolysis in hypoxia, seem to be the main
cause. Accumulating evidence shows that an acidic
microenvironment is a regulator of cellular phenotype. Whereas
Na+-HCO-3 co-transporter and Cl-/HCO-3 exchanger
contribute a fall in intracellular pH, the Na+/H+ exchanger
], the H+-lactate co-transporter, monocarboxylate
transporters (MCTs), and the H+-ATPase (H+ pump) are
responsible for the secretion of H+ [
]. Because carbonic
anhydrase (CA) is widely distributed and can form H+ by
catalyzing hydration of CO2, an excess amount of CO2
production through the pentose phosphate pathway in
tumor cells is an alternative cause of a lower pH [
pHe increases not only the activation of some lysosomal
enzymes with acidic optimal pH, but also the expression
of some genes involved with pro-metastatic factors.
When melanoma cells pretreated with an acidic medium
were injected into the tail vein of mice, a significantly
higher frequency of them metastasized to the lungs [
Thus, an acidic microenvironment is closely associated
with tumor metastasis.
Acidity is found at the surface of skin and in
inflammatory sites. It is also associated with bone resorption. Thus,
an acidic microenvironment plays a role of homeostasis
and the immune defense system. We will review the roles
of acidic pHe in tumor progression along with other
physiological and pathological conditions.
Lactate and tumor
The “Warburg effect” is a well-accepted theory that says
that tumors tend to produce lactate by using the
anaerobic glycolytic pathway, even in the presence of
sufficient oxygen, rather than oxidative phosphorylation for
energy production [
]. High lactate levels indicate
metastases, tumor recurrence, and prognosis in some
cancer patients [
]. In the molecular mechanism relating
to these clinical contributions, lactate from tumor cells
contributes to their immune escape. High lactate
secretion from tumor cells inhibits its export from T cells,
thereby disturbing their metabolism and function .
Tumor-derived lactate affects inflammation and immune
deficiency of tumor cells. Lactate itself functions as an
intrinsic inflammatory mediator that increases
interleukin (IL)-17A production by T-cells and macrophages,
resulting in the promotion of chronic inflammation in
tumor microenvironments [
]. Lactate inhibits dendritic
cell activation during antigen-specific autologous T-cell
]. It also enhances the motility of tumor
cells and inhibits monocyte migration and cytokine release
]. It can contribute to angiogenesis through induction
of IL-8 via nuclear factor-κB (NF-κB) [
] and induction
of vascular endothelial growth factor (VEGF/VEGF-A)
via hypoxia-inducible transcription factor (HIF)-1 [
Furthermore, lactate production contributes to
radioresistance of tumors due to its antioxidant properties [
Inhibition of the lactate transporter has been
considered a potential new therapeutic strategy. For example,
α-cyano-4-hydroxycinnamate, a specific inhibitor of the
lactate transporter MCT1, suppresses tumor
]. Quercetin (CYP2C9), which is an inhibitory
flavonoid, inhibits lactate transport and acts as a
hyperthermic sensitizer of HeLa cells [
Appearance of acidic microenvironments under physiological and pathological conditions
An oncogenic transformation assay by oncogenic-virus
infection shows that lactate production is correlated with
an increase in the number of transformed foci by viral
infection in a presence of 5% CO2 in 95% air [
high lactate corresponds to a high proton concentration,
an acidic pHe is a major feature of the solid tumor tissue
]. Lactic acid is a product of the anaerobic
glycolysis including the activity of lactate dehydrogenase
(LDH) 5 that generates lactic acid from pyruvate and the
expression of which has been strongly associated with
the poor prognosis of patients with non-small cell lung
] and colorectal cancers [
CO2 is a major source of acid in glycolytically impaired
]. The pentose phosphate pathway is seen as a
major productive pathway for CO2 which can be processed
to H+ and HCO-3 by the catalytic activity of CA. In
osteoclasts, CA II, a CA isozyme, is a major enzyme producing
H+ to decalcify bone hydroxyapatite. Osteoclasts secrete
H+ and create an acidic microenvironment below pH 5.5,
which is critical for the bone resorption [
] and the
proton can be secreted through H+-ATPase . Induction
of CA II expression itself is also induced by an acidic
]. Thus, secretion of acidic metabolites and/or
the pentose phosphate pathway-mediated CO2
production, and CA-mediated production of H2CO3 form acidic
Extracellular acidity is a pathological feature of
] and solid tumor tissue [
]. Acidity in
inflammatory tissue is due to production of proton from
macrophages, whereas tumor tissue acidity is due to
acidic metabolites, e.g., lactate, caused by anaerobic
glycolysis under the hypoxia [
]. The acidic
microenvironment acts as a trigger for pain in both inflammation
] and in cancer patients .
Ovarian cancer G-protein-coupled receptor 1 (OGR1), a
receptor for sphingosylphosphorylcholine, and GPR4, a
close relative of OGR1, also act as a proton-sensing
receptor in osteosarcoma cells and primary human osteoblast
]. OGR1 (GPR68) stimulates
cyclooxygenase2 expression and prostaglandin (PG) E2 production in
response to acidic pHe in a human osteoblastic cell line [
Because PGE2 is involved in osteoclastic differentiation
of precursor cells [
], inhibition of the OGR1
signaling negatively regulates osteoclastogenesis [
type of G-protein-coupled receptor, TDAG8 (GPR65), also
senses pHe [
Breast cancer frequently metastasizes to bone.
Osteoclasts can be activated by breast cancer-derived H+ such
that osteolysis occurs when cancer cells metastasize to bone
]. During this process, patients feel pain through
acidsensing ion channels (ASIC) 1a, 1b and 3 [
An acidic pHe is also found in the epidermis and plays
an important protective role against bacterial infection
]. Using the conditional knockout (KO) mice for
focal adhesion kinase (FAK) in keratinocytes, Ilic et al.
] showed that the stratum corneum pHe gradient of
keratinocytes in these mice had significantly more neutral
pH values, and that NHE1 failed to localize to the plasma
]. Thus, FAK controls pH-dependent
epidermal barrier homeostasis by regulating actin-directed NHE1
plasma membrane localization [
Lung liquid is acidic [
], which is worse in patients
with cystic fibrosis [
], although the airway pH is not
known for certain because different detecting methods
have been used [
CA expression in cancer
CA isoforms are associated with tumor malignancy,
including CA I [
], CA II [
], CA IX [
], CA XII
], and CA XIII [
]. Among them, CA IX in particular
has been well studied in association with hypoxia and
tumor survival through regulating intracellular pH [
In ovarian cancer, high expression of CA IX with a
concomitant increase in VEGF-A is associated with overall
survival rates positively . Overexpression of CA IX
increases tumor cell migration and invasion [
inhibitor suppresses invasion of renal cancer cells in vitro [
Based on the accumulated evidence, a new therapeutic
strategy targeting CA has been considered [
Acidic pHe activates proteinase activity and induces
Acidic pHe activates some proteinases. Although caries is
due to some bacterial acidic metabolites, Tjäderhane et al.
] found that host-derived pro-matrix
metalloproteinase9 (proMMP-9), proMMP-2 and proMMP-8 in saliva could
be activated by acid, and thereby suggested that these
MMPs contribute to the disruption of dentin in caries.
Alternatively, host derived proMMP-9 could be activated
in the stomach, and this suggests it functions as a
digestive enzyme for collagenous foods [
]. Activation of
proMMP-9 by an acidic pHe also occurs in a human
melanoma model .
Lysosomal enzymes have an acidic optimal pH. Some
tumor cells have the ability to secrete them, such as
cathepsin B and cathepsin L [
]. Cathepsin K plays an
important role in osteoclast-mediated bone resorption
]; its inhibition prevents breast cancer-induced
osteolysis and skeletal tumor burden . Thus,
osteoclastmediated acidic pHe leads to mineral dissolution and
activation of cathepsins to digest bone matrix, such as type
I collagen. Podgorski et al. [
] reported that SPARC/
osteonectin, a major non-collagenous protein in bone, is
digested by cathepsin K and its fragments are associated
with bone-metastasis. Another lysosomal enzyme,
heparanase, has an acidic optimal pH; it degrades heparan
sulfate in the basement membrane and contributes to tumor
invasion and metastasis [
Also, acidic microenvironments affect the
expression of some genes, such as MMP-9 [
] and acidic
sphingomyelinase in mouse B16 melanoma ,
plateletderived endothelial cell growth factor (thymidine
phosphorylase) in human breast cancer cells [
], the inducible
isoform of nitric oxide synthase (iNOS) in macrophages
], VEGF-A in glioma [
] and glioblastoma [
and IL-8 expression in human pancreatic adenocarcinoma
] and ovarian carcinoma cells [
Acidic pHe signal transduction pathway
Thus, although acidic pHe occurs in several physiological
and pathological conditions, information on its signaling
remains limited. Transcription factors AP-1 and NF-κB,
independent of hypoxia, have important roles in the
acidic pHe-induced expression of VEGF-A [
]. p38 mitogen-activated protein kinase
(MAPK) is involved in acidic pHe signaling that induces
We also found involvement of phospholipase D (PLD)
in the acidic pHe-intracellular signaling to induce
MMP9 production [
]. Acidic pHe-induced PLD activation
was prolonged for at least for 24 h, different from
general growth factor signaling. Inhibition of PLD activity
by 1-butanol and Myr-ARF6 suppresses acidic
pHe-induced MMP-9 expression . Acidic pHe increases the
steady-state levels of phosphorylated ERK1/2 and p38,
and PLD inhibitors prevent these increases. Using
5′-deleted constructs of the MMP-9 promoter, we found that
the acidic pHe-responsive region was located at
nucleotides -670 to -531, a region containing the NF-κB
binding site. A mutation in the NFκB binding site reduced
acidic pHe-induced MMP-9 promoter activity, and
NFκB activity was induced by acidic pHe. Pharmacological
inhibitors specific for MEK1/2 (PD098059) and p38
(SB203580) attenuated acidic pHe-induced NF-κB activity
and MMP-9 expression. The data suggest that PLD,
MAPKs including ERK 1/2 and p38, and NF-κB mediate
acidic pHe signaling thereby inducing MMP-9 expression.
Activation of ERK1/2 and p38, followed by the NF-κB axis,
which is stimulated by tumor necrosis factor-α (TNF-α),
also occurs in cholangiocarcinoma [
]. This suggests that
acidic pHe signaling is, at least in part, the signaling
pathway for TNF-α. However, it has been reported that acidic
pHe activates p38, but not ERK1/2, in T-cell receptor
signaling in Jurkat cells [
]. This may be cell-type specific. In
a further contribution dealing with the intracellular
substances of acidic pHe, we have found that calcium influx
triggers acidic pHe-induced PLD activation and that acidic
sphingomyelinase mediates acidic pHe signaling to activate
NF-κB independently of the PLD-MAPK pathway [
OGR1 stimulates cyclooxygenase-2 expression and
PGE2 production in response to an acidic pHe in a
human osteoblastic cell line through G(q/11)/phospholipase
C/protein kinase C pathway [
] and in human aortic
smooth muscle cells through the phospholipase
C/cyclooxygenase/PGI2 pathway [
Acidic pH directly affects transcription factor activity;
DNA binding activity of the transcription factor, SP1, is
enhanced by intracellular acidic pH [
pH is maintained a constitutively neutral state but known
to become transiently acidic when pHe decreases to acidic.
Therefore an acidic pH can activate SP1.
Acidic pHe stimulates disruption of adherence junctions
When tumor cells move into their surrounding tissue,
cell-cell junctions become dissociated. Acidic pH
disrupts adherence junction by Src activation, resulting in
E-cadherin degradation through the protein kinase Cδ
]. Acidic pHe also induces motility of
tumor cells, and inhibits monocyte migration and cytokine
Acidic pHe stimulates metastatic potential
Brockton et al. [
] have shown that high stromal CA IX
expression is associated with nodal metastasis. The high
activity produces an acidic microenvironment that leads
to increased metastatic ability of the tumor cells. We
have reported that induction rate of MMP-9 secretion
correlates with metastatic potential of mouse B16
melanoma clones, and an acidic pHe stimulates invasion
through a type-IV collagen barrier [
]. In human
melanoma models, an acidic pHe increases both
migration and invasiveness in vitro, accompanied by MMP-9
activation . NHE1 is also associated with the
metastatic ability of tumor cells; it is accumulated in leading
edge of the cell and is activated by CD44 (a hyaluronan
(HA) receptor) -binding to HA [
]. Because HA directs
membrane-type 1 matrix metalloproteinase (MT1-MMP)
to the invasion front (invadopodia) [
], NHE1 might
interact with MT1-MMP through CD44 at an acidic
Pretreatment of the tumor cells in an acidic medium
induces production of proteinases (MMPs and cathepsins)
and proangiogenic factors (VEGF-A and IL-8) and
promotes experimental metastasis to the lung after injection
into the tail vein of nude mice [
]; elevation of pH by one
unit following injection of sodium bicarbonate prevents
spontaneous metastases [
]. Furthermore, using P-31
magnetic resonance spectroscopic evaluation, it was found
that acidic pHe in spontaneous soft tissue sarcomas
predicts metastasis in dogs [
Acidic pHe sensing systems
ASICs are voltage-independent and proton-activated
channels found in tumor cells and associated tumor
]. Transient receptor potential (TRP) V
isoforms, TRPV1, TRPV5 and TRPV6, also act as
acidsensitive channels [
]. ERK1/2 plays as a downstream
target of ASICs and TRPVs [
]. Another subfamily
of TRP, TRPM7 has proton conductivity . TRPM7
regulates EGF signaling to induce STAT3 activation and
vimentin expression during epithelial-mesenchymal
]. OGR1 also acts as a proton-sensing receptor,
stimulating inositol phosphate formation [
pHe gradient formation by H+ pumps and exchangers
NHE1 accumulates at the leading edge to make a pHe
gradient associated with cell migration [
RhoROCK pathway contributes to NHE1 activation and focal
]. Protons stabilize the collagen–α2β1
integrin bond, but alkalosis, a lack of protons or an
inhibited NHE activity, prevents adhesion .
Furthermore, the cell forms an individual pHe gradient to
facilitate movement: i.e. at leading edge or invadopodia, cells
preferentially attach to the substrate due to the acidic
pHe induced by NHE1, while cell-matrix interaction at
the rear end is weak due to a mid-alkaline pHe [
Mutation studies clearly showed that downregulation of
NHE1 function suppresses cell polarity, migration, and
invasion through matrigel™ [
]. Inhibition of NHE1
activity by HOE642 (cariporide) reduced migration and
adhesion activities [
To secrete acidic metabolites, NHE1 and the
H+-lactate co-transporter are involved [
]. H+-ATPase (the
H+ pump) and cell surface ATP synthase also play a role
in extracellular acidification [
contributing to tumor metastasis . Therefore, inhibition of the
H+ pump can be a new strategy for cancer treatment
]. Angiostatin has anti-tumor efficacy by inhibiting
cell surface ATP synthase activity through binding its
β subunit [
]. In particular, treatment of the cells with
angiostatin proved more cytotoxicity at an acidic pHe than
a neutral pHe.
Drug efficacy and acidic pHe
Two analogues of camptothecin (CPT), topotecan (TPT)
and irinotecan (CPT-11), have significant anti-tumor
activity in the clinic, although their abilities depend on the
CPT E ring lactone, which forms an inactive hydroxy
acid at physiological pH. The reaction is reversible at an
acidic pHe, which provides a rationale for selectivity
because many solid tumors, while creating an acidic
extracellular environment, maintain a normal intracellular
]. An acidic pHe inhibits cellular uptake of
mitoxantrone and topotecan, so that elevation of pHe in
tumor tissue enhances those drugs’ efficacy [
Because the buffer action is weaker in tumor tissue than
normal tissue, NaHCO3 has much potential to raise pHe
relatively specifically in tumor tissue [
]. Acidic pHe
also plays a role in the resistance of tumor cells to
drugs by increasing the expression of p-glycoprotein,
thereby increasing drug efflux [
]. Recently, an
acidic pHe-specific drug-releasing system has been
]. A novel polymeric micelle constituted
of 2 block copolymers of poly (L-lactic acid)-b-poly
(ethylene glycol) b-poly (L-histidine) - TAT
(transactivator of transcription) and poly(L-histidine)-b-poly
(ethylene glycol) increases the cytotoxicity of doxorubicin
in several multidrug-resistant tumor cell lines [
measure pHe, a magnetic resonance image technique
has been developed using acidic pHe specific probes
]. Thus, clinicians should pay attention to tumor
pHe in selecting drugs and helping to maximize their
chemotherapeutic action. Vasodilating drugs, such as
hydralazine and captopril, inhibit tumor growth rate
in vivo by reducing tumor blood flow . Although the
reduction in tumor growth by those drugs also reduces
the oxygen supply, it reduces pHe. In patients given
vasodilating drugs, anti-tumor drugs with weak acidic pKa
value, such as 5-fluorouracil (5FU) and cyclophosphamide,
may have increased efficacy at an acidic pHe. In contrast,
the anti-tumor drugs with weak base pKa values, such as
doxorubicin, mitoxantrone and daunorubicin, may not be
fully functioned because acidic pHe reduces their
]. In early-stage breast cancer, high CAIX is a
predictive marker of doxorubicin resistance .
Because cis-diamminedichloroplatinum (II) (CDDP)
solution has an acidic pH, NaHCO3 is used to prevent the
angialgia in the cancer patients coming from the acidic pH
solution injection because it increases pH [
However, CDDP is frequently used for co-injection with other
chemotherapeutic drugs, such as 5FU. In some cases,
coinjection of NaHCO3 (depends on the concentration) may
reduce the clinical efficacy of 5FU + CDDP regimen.
Hyperthermia and acidic pHe
Hyperthermic treatment (42.5°C) for JB-1-E plasmacytoma
tumor cells in vitro enhances the colony formation index
when cells are maintained at pH 6.4, regardless oxygen
]. Melanoma cells growing at low pH are
sensitized to hyperthermia because of the altered intracellular
pH threshold for the heat sensitization in vitro [
Acidic pHe is toxic to many cells, including tumors [
However, if tumors have successfully adapted to their
condition, and use it for their own cellular activation, this
increases drug resistance and leads to more aggressive
behavior. Therefore, management of tumor pHe and
inhibition of blockade of proton-sensing system are important
in not only raising drug efficacy, e.g. mitoxantrone, but in
pHe: Extracellular pH; NHE: Na+/H+ exchanger; MCT: Monocarboxylate
transporter; CA: Carbonic anhydrase; IL: Interleukin; NF-κB: Nuclear factor κB;
VEGF: Vascular endothelial growth factor; HIF: Hypoxia inducible factor;
LDH: Lactate dehydrogenase; OGR: Ovarian cancer G-protein-coupled
receptor; PG: Prostaglandin; ASIC: Acid-sensing ion channel; KO: Knockout;
FAK: Focal adhesion kinase; MMP: Matrix-metalloproteinase; iNOS: Nitric oxide
synthase; PLD: Phospholipase D; MAPK: Mitogen-activated protein kinase;
TNF-α: Tumor necrosis factor-α; HA: Hyaluronan; MT1-MMP: Membrane-type
1 matrix metalloproteinase; TRP: Transient receptor potential; CDDP:
The authors declare no competing financial interests.
YK designed the study. SO, CM, YM, AS and TM were involved in discussion.
YK drafted the manuscript. YB revised the manuscript. All authors read and
approved the final manuscript.
We thank Profs. Masaichi-Chang-Il Lee, Eiro Kubota, Kaoru Miyazaki, and
Ryu-Ichiro Hata for their critical comments.
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