Recently, the scammer who advocated "acid constitution" as the source of all diseases was fined 105 million US dollars, and the "acid-base balance" theory he founded was also criticized. Although the "acid constitution" of the human body is full of pseudoscience, many tumors are indeed "acid constitution". Increased glycolysis, hypoxia, and insufficient tissue perfusion as well as a large amount of acid and metabolite metabolites that accumulated in the tumor microenvironment, making the tumor microenvironment acidic [1–3]. Microenvironment acidification plays an important role in tumor progression and can provide a favorable environment for tumor cell generation [4]. Acidosis is one of the basic characteristics of tumor microenvironment. Unlike normal cells, cancer cells can adapt to a low pH environment by increasing glycolysis, while activating the activity and expression of proton transporters that normalize the pH in the cell [1–4]. Acidosis-driven adaptation also triggers the emergence of aggressive tumor cells in subpopulations that exhibit increased invasion, proliferation, and resistance [5]. Acidosis can also promote immune escape and thus maintain tumor growth [6, 7]. Although there is an important relationship between too much lactic acid in tumor microenvironment and tumor cell invasion, few studies have explored which areas in the tumor are acidic and how too much lactate affects gene expression to promote tumor invasion.

1. COMMENT
doi: 10.12032/TMR20191231153
TMR | January 2020 | vol. 5 | no. 1 | 4 Submit a manuscript: https://www.tmrjournals.com/tmr
Traditional Chinese Medicine
Acknowledgments:
This work was supported by National Science Foundation of China No. 81903934.
Abbreviations:
pHLIP, pH (low) insertion peptide.
Competing interests:
The author declares that she has no conflict of interest.
Citation:
Jian Hao. The role of acidic microenvironment in the tumor aggressive phenotypes and the treatment.
Traditional Medicine Research 2020, 5 (1): 4–6.
Executive Editor: Xiaohong Sheng, Nuoxi Pi.
Submitted: 30 November 2019, Accepted: 31 December 2019, Online: 1 January 2020

2. COMMENT
Submit a manuscript: https://www.tmrjournals.com/tmr
doi: 10.12032/TMR20191231153
TMR | January 2020 | vol. 5 | no. 1 | 5
Recently, the scammer who advocated "acid
constitution" as the source of all diseases was fined 105
million US dollars, and the "acid-base balance" theory
he founded was also criticized. Although the "acid
constitution" of the human body is full of pseudoscience,
many tumors are indeed "acid constitution". Increased
glycolysis, hypoxia, and insufficient tissue perfusion as
well as a large amount of acid and metabolite
metabolites that accumulated in the tumor
microenvironment, making the tumor
microenvironment acidic [1–3]. Microenvironment
acidification plays an important role in tumor
progression and can provide a favorable environment
for tumor cell generation [4]. Acidosis is one of the
basic characteristics of tumor microenvironment.
Unlike normal cells, cancer cells can adapt to a low pH
environment by increasing glycolysis, while activating
the activity and expression of proton transporters that
normalize the pH in the cell [1–4]. Acidosis-driven
adaptation also triggers the emergence of aggressive
tumor cells in subpopulations that exhibit increased
invasion, proliferation, and resistance [5]. Acidosis can
also promote immune escape and thus maintain tumor
growth [6, 7]. Although there is an important
relationship between too much lactic acid in tumor
microenvironment and tumor cell invasion, few studies
have explored which areas in the tumor are acidic and
how too much lactate affects gene expression to
promote tumor invasion.
Researchers have conducted in-depth research on this
issue and found that the slightly acidic environment in
tumors can help cancer cells produce proteins that make
them more malignant. Related research results have
been published in Cancer Research [8]. Researchers
determined the acidic sites in tumors by injecting a
tumor-tagged mouse with a fluorescently labeled pH-
responsive polypeptide. Unexpectedly, the researchers
found that the acidic region not only overlapped with
the hypoxic region, but also with the highly proliferative
and highly invasive cell regions at the tumor matrix
interface. These regions were characterized by
increased expression of matrix metalloproteinase and
degradation of the basement membrane degree. By
performing RNA sequencing of cells in the low pH
region, the researchers found that the reset of the
transcriptome involved in RNA splicing increased the
targets of RNA-binding proteins that specifically bind
to AU-rich sequences. The low-pH signature indicated
extensive changes in alternative splicing and was
notably enriched for splicing of genes implicated in
regulation of adhesion and cell migration. Surprisingly,
this selective shear could be reversed by experiments
that neutralize the acidic environment in vitro and in
vivo. These findings reveal the impact of local acidity
in tumor microenvironment on tumor invasion and
metastasis.
The extracellular acidic microenvironment is a
challenge for tumor treatment, but it also opens up new
possibilities for tumor cell-specific treatments. In recent
years, there have been some advances in treatment
strategies for the acidic microenvironment: (1) weakly
acidic compounds that can enter the core of solid tumors
are designed to easily spread in the acidic
microenvironment and produce curative effects. For
example, under extracellular acidic conditions, the
uptake of weakly acidic chemotherapeutic drugs such as
melphalan is enhanced [9]; (2) the use of buffers such
as sodium bicarbonate to alkalinize the tumor
microenvironment. Studies have shown that oral
sodium bicarbonate treatment increases the
extracellular pH value of mouse metastatic breast cancer
models and reduces the formation of metastases;
neutralizing tumor pH with oral sodium bicarbonate
buffer can also improve the efficacy of immunotherapy
[10]; (3) pH (low) insertion peptide (pHLIP): in the
acidic microenvironment, pHLIP inserts the c-terminus
into the membrane to form a stable transmembrane helix.
Therapeutic molecules combination with pHLIP allow
the chemotherapy drug to be released directly into the
cell [11]; (4) inhibit the acidic microenvironment
transport system, normalize the extracellular pH value,
reduce the intracellular pH value, and also interfere with
cancer cells. Proton pump inhibitors, such as
esmeprazole, etc, are activated under acidic conditions
and increase the extracellular pH of the tumor by
inhibiting the pumping of protons [12]. Studies show
that esmeprazole inhibits melanoma cell proliferation
and induces tumor cell death by acidification of tumor
cells. Carbonic anhydrase IX inhibitors such as
sulfamate can also reduce the extracellular pH by
inhibiting the activity of carbonic anhydrase IX [13].
In conclusion, the acidic microenvironment outside
the tumor cell can stimulate cell proliferation, activate
transcription factors, enhance target gene expression,
and promote tumorigenesis, thereby regulating the
acidic microenvironment of the tumor can inhibit tumor
growth, promote its apoptosis, and change the
malignant biology of tumor cells behavior. However,
whether improving the acidic microenvironment of
tumors affects tumor immunity and tumor metabolism,
and how long these cell treatment methods can last
under the acid-base balance system, remains to be
explored.
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3. COMMENT
doi: 10.12032/TMR20191231153
TMR | January 2020 | vol. 5 | no. 1 | 6 Submit a manuscript: https://www.tmrjournals.com/tmr
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