Jian Hao*

The role of acidic microenvironment in the tumor aggressive phenotypes and the treatment

Jian Hao1*

1Clincal Center of Tumor Therapy, the Fourth Central Hospital Affiliated to Nankai University, Tianjin, China.

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.

1. Kato Y, Ozawa S, Miyamoto C, et al. Acidic extracellular microenvironment and cancer. Cancer cell int 2013, 13: 89.

2. Wang L, Li C. pH responsive fluorescence nanoprobe imaging of tumors by sensing the acidic microenvironment. J Mater Chem 2011, 21: 15862–15871.

3. Peppicelli S, Andreucci E, Ruzzolini J, et al. The acidic microenvironment as a possible niche of dormant tumor cells. Cell Mol Life Sci 2017, 74: 2761-2771.

4. Frérart F, Sonveaux P, Rath G, et al. The acidic tumor microenvironment promotes the reconversion of nitrite into nitric oxide: towards a new and safe radiosensitizing strategy. Clin Cancer Res, 2008, 14: 2768–2774.

5. Fields ALA, Wolman SL, Halperin ML. Chronic lactic acidosis in a patient with cancer: therapy and metabolic consequences. Cancer, 1981, 47: 2026–2029.

6. Huber V, Camisaschi C, Berzi A, et al. Cancer acidity: an ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol 2017, 43: 74–89.

7. Magalhaes MAO, Larson DR, Mader CC, et al. Cortactin phosphorylation regulates cell invasion through a pH-dependent pathway. J Cell Biol 2011, 195: 903–920.

8. Rohani N, Hao L, Alexis M S, et al. Acidification of tumor at stromal boundaries drives transcriptome alterations associated with aggressive phenotypes. Cancer Res 2019, 79: 1952–1966.

9. Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res 2016, 76: 1381–1390.

10. Shah T, Ryu S, Lee HJ, et al. Pronounced radiosensitization of cultured human cancer cells by COX inhibitor under acidic microenvironment. Int J Radiat Oncol Biol Phys 2002, 53: 1314–1318.

11. Deacon JC, Engelman DM, Barrera FN. Targeting acidity in diseased tissues: mechanism and applications of the membrane-inserting peptide, pHLIP. Arch Biochem Biophys 2015, 565: 40–48.

12. Milito A,Canese R, Marino ML, et a1. pH·dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int J Cancer 2010, 127: 207–219

13. Cecchi A, Hulikova A, Pastorek J, et al. Carbonic anhydrase inhibitors. Design of fluorescent sulfonamides as probes of tumor-associated carbonic anhydrase IX that inhibit isozyme IX-mediated acidification of hypoxic tumors. J Med Chem 2005, 48: 4834–4841.

:

This work was supported by National Science Foundation of China No. 81903934.

:

pHLIP, pH (low) insertion peptide.

:

The author declares that she has no conflict of interest.

:

Jian Hao. The role of acidic microenvironment in the tumor aggressive phenotypes and the treatment. Traditional Medicine Research 2020, 5 (1): 4–6.

:Xiaohong Sheng, Nuoxi Pi.

:30 November 2019,

31 December 2019,

:1 January 2020

Jian Hao.Clincal Center of Tumor Therapy, the Fourth Central Hospital Affiliated to Nankai University, No.1 Zhongshan Road, Hebei District, Tianjin, China. Email:haojian1111520@126.com.