Reo Hamaguchi
Shinji Uemoto
Hiromi Wada- 1Clinical Cancer Research Team, Japanese Society on Inflammation and Metabolism in Cancer, Kyoto, Japan
- 2Department of Surgery, Shiga University of Medical Science, Otsu, Japan
Editorial on the Research Topic
The impact of alkalizing the acidic tumor microenvironment to improve efficacy of cancer treatment
In recent years, the acidic tumor microenvironment (TME) that is created by cancer-specific metabolism has attracted much attention in cancer therapy. In this Research Topic, we discuss the wide range of knowledge that has accumulated regarding cancer metabolism, focusing on the effects of acidity of the TME on cancer pathology. Points discussed include characteristics of the acidic TME (Bogdanov et al.), an overview of alkalization therapy (Hamaguchi et al., Wada et al.), a clinical trial of alkalizing agents on cancer patients (Gillies et al.), the association between acidic TME and glioblastoma (Seyfried et al.), the association between pH of the TME and the immunological state (Hosonuma and Yoshimura in press), role of the immunosuppressive TME in pancreatic cancer (Hashimoto et al.), Drosophila as an effective toolkit to investigate cancer metabolic abnormalities (Jiang et al.), acidic imaging positron emission tomography probes (89Zr-labeled pH-low insertion peptides) (Bauer et al.), role of the proton-sensing G protein-coupled receptor GPR68 in breast cancer (Elemam et al.), the association between cancer and chronic heart failure focusing on mitochondrial abnormalities (Takada et al.), and the association between cancer metabolism and ascorbic acid (Maekawa et al.). To address cancer metabolism and target it as a treatment, it is necessary to recognize how cancer develops, and what characteristics of the metabolic process are involved. Here, we will outline the origins and metabolism of cancer, how to deal with it, and the importance of alkalization of the TME.
How does cancer develop? The most important point was reported by Otto Warburg in “On the origin of cancer cells” (1). Cancer cells develop when there is a lack of oxygen, but a supply of nutrition. Cancer cells are primarily glycolytic, as they perform fermentation, meaning that they are dependent on the glycolytic system rather than oxidative phosphorylation by cellular respiration. The essence of this is the presence of mitochondria in eukaryotic cells. Cancers comprise cells that have been forced to choose their own path of life without working, but not failing, mitochondria. Gilles R. and Gatenby R. et al. reported in detail that cancer cells are dependent on aerobic glycolysis for survival as a result of Darwinian selection pressure (2). In addition, as Seyfried T. has stated, cancer can be considered as a metabolic disease (3). These points suggest that cancer cells try to survive on their own in an environment where there is a lack of oxygen but a supply of nutrients. In other words, cancer is comprised of cells that have lost their coordination with other cells in the body, and are living on their own.
How does cancer metabolism work? Cancer cells have a unique metabolism that differs from that of normal cells, and as enhanced glycolysis generates large amounts of acidic substances (protons) inside the cell, cancer cells expel protons to the outside of the cell by proton transporters, resulting in the inside of the cell being alkaline and the outside being acidic (4). The most important proton transporter that is involved in this phenomenon is sodium/proton (Na+/H+) exchanger isoform 1 (5). In the general biological environment, the extracellular pH of normal cells is maintained at pH 7.2 to 7.4, whereas the pH around cancer cells tends to be more acidic at pH 6.2 to 6.8 (6). This acidification of the TME has been reported to promote cancer progression. In this state, cancer cells become resistant to a variety of treatments, their proliferation is activated, and their metastatic potential is also increased (7, 8). In general, current cancer treatments do not target the pH balance of the TME that results from this cancer-specific metabolism. This means that adequate and satisfactory cancer treatment results have not yet been achieved.
What happens when the acidic TME is alkalized? Reversal of the pH gradient between the inside and the outside of cancer cells, i.e., extracellular acidification and intracellular alkalinization, attenuates the intracellular concentration of many anticancer drugs, and leads to resistance to anticancer drug treatments (5). For example, it has been reported that an increase in intracellular pH from 7.0 to 7.4, although in an experimental system, leads to a 2,000-fold increase in adriamycin resistance in human lung cancer cell lines (9). Conversely, lowering the intracellular pH (raising the extracellular pH) of cancer cells is expected to attenuate their resistance to various anticancer drugs, and to make anticancer drug therapy more effective. Furthermore, an acidic TME is known to decrease anticancer immune responses, and hence alkalinization of the acidic TME is expected to improve the function of immune cells, such as dendritic cells, natural killer cells, cytotoxic T cells, and macrophages (10, 11). In addition, this treatment method of lowering the intracellular pH (raising extracellular pH) may be sufficiently effective on its own (Wada et al.).
Clinical methods for alkalization of this acidic TME include alkalization therapy with alkalizing agents or proton pump inhibitors (Hamaguchi et al.). In addition, the influence of the daily diet should also be considered. Diets with alkalizing effects are rich in vegetables and fruits, which at the same time have anti-inflammatory and gut-regulating properties (12). Alkalization therapy is a treatment that acts on cancer metabolism, and can be used in combination with anticancer drugs, radiation therapy, and other therapies, and is also a safe treatment method. In the future, the combination of alkalization therapy and conventional therapy for the treatment of cancer needs to be further investigated in prospective clinical trials.
Author contributions
RH and HW performed the literature review and wrote the article. SU performed the literature review. All authors conceived and designed the study and gave final approval for publication.
Acknowledgments
The authors thank Dr. Helena Akiko Popiel of Tokyo Medical University for her editing of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Warburg O. On the origin of cancer cells. Science (1956) 123:309–14. doi: 10.1126/science.123.3191.309
2. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer (2004) 4:891–9. doi: 10.1038/nrc1478
3. Seyfried TN. Cancer as a mitochondrial metabolic disease. Front Cell Dev Biol (2015) 3:43. doi: 10.3389/fcell.2015.00043
4. Spugnini EP, Sonveaux P, Stock C, Perez-Sayans M, De Milito A, Avnet S, et al. Proton channels and exchangers in cancer. Biochim Biophys Acta (2015) 1848:2715–26. doi: 10.1016/j.bbamem.2014.10.015
5. Harguindey S, Orive G, Luis Pedraz J, Paradiso A, Reshkin SJ. The role of pH dynamics and the Na+/H+ antiporter in the etiopathogenesis and treatment of cancer. two faces of the same coin−one single nature. Biochim Biophys Acta (2005) 1756:1–24. doi: 10.1016/j.bbcan.2005.06.004
6. Cardone RA, Casavola V, Reshkin SJ. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer (2005) 5:786–95. doi: 10.1038/nrc1713
7. Vaupel P, Multhoff G. Revisiting the warburg effect: historical dogma versus current understanding. J Physiol (2020) 599:1745–57. doi: 10.1113/JP278810
8. Gillies RJ. Cancer heterogeneity and metastasis: life at the edge. Clin Exp Metastasis (2021) 39:15–9. doi: 10.1007/s10585-021-10101-2
9. Keizer HG, Joenje H. Increased cytosolic pH in multidrug-resistant human lung tumor cells: effect of verapamil. J Natl Cancer Inst (1989) 81:706–9. doi: 10.1093/jnci/81.9.706
10. Boedtkjer E, Pedersen SF. The acidic tumor microenvironment as a driver of cancer. Annu Rev Physiol (2020) 82:103–26. doi: 10.1146/annurev-physiol-021119-034627
11. Wang JX, Choi SYC, Niu X, Kang N, Xue H, Killam J, et al. Lactic acid and an acidic tumor microenvironment suppress anticancer immunity. Int J Mol Sci (2020) 21:8363. doi: 10.3390/ijms21218363
Keywords: cancer, cancer metabolism, tumor microenvironment, alkalization therapy, multi-drug resistance, pH
Citation: Hamaguchi R, Uemoto S and Wada H (2023) Editorial: The impact of alkalizing the acidic tumor microenvironment to improve efficacy of cancer treatment. Front. Oncol. 13:1223025. doi: 10.3389/fonc.2023.1223025
Received: 15 May 2023; Accepted: 23 May 2023;
Published: 31 May 2023.
Edited and Reviewed by:
Ubaldo Emilio Martinez-Outschoorn, Thomas Jefferson University, United StatesCopyright © 2023 Hamaguchi, Uemoto and Wada. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Reo Hamaguchi, reo-h@nifty.com