Table 1.
Examples of acidity-triggered cellular responses
| Model | Method of manipulating pHe | Duration under acidosis | Target pHe | Reported cell response | Reference |
|---|---|---|---|---|---|
| Breast cancer: MCF‐7, MCF10‐AT, MDA‐mb‐231, MCF10, and MCF10AT | Medium supplemented with 25 mmol/L of PIPES and HEPES and the pH adjusted to 7.4 or 6.7 | Acute: 72 h and prolonged: 3 months | 6.7 | Resistance to anoikis, elevated collagen production, upregulated ECM remodelling enzymes: TGM2, LOXL2 | [82] |
| Colorectal cancer: HCT116, SW480, LoVo, SW620, and HT29 | Medium maintained in a 5% CO2 atmosphere at 37 °C. The medium was supplemented with 25 mM HEPES and PIPES and the pH was adjusted | Acute, 24 h | 6.5 | Increased ASIC2 expression, ASIC2-driven invasion | [92] |
| Glioma: U87MG, T98G, and U251 | Medium supplemented with 25 mM HEPES and the pH adjusted to 6.8; 6.7; 6.6; and 6.5 | Acute, 24 h | 6.8, 6.7, 6.6, 6.5 | Induced stem-cell phenotype, increased OXPHOS, upregulated IL22, GUCA2B, CYP24A1, OR6P1 | [93] |
| Breast cancer: MCF-7, ZR-75–1, T47D, MDA-MB-231, and MDA-MB-157 | Medium adjusted to acidic pH with HCl | Acute, 24 h | 6.7 | Metabolic reprogramming to oxidative PPP and glutaminolysis | [94] |
| Pancreatic cancer: PANC-1, AsPC-1; cervical cancer: HeLa; glioma: T98G; colorectal cancer: SW620 | pH was manipulated by varying concentrations of NaHCO3 in CO2-rich atmosphere. pH 7.4: 8 mM, pH 6.8 2 mM | Acute, 24 h | 6.8 | Decreased adhesion, SREBP2 activation, IDI1 and PDK4 upregulation | [86] |
| Mesenchymal stem cells; melanoma: A375M6 | Medium adjusted to acidic pH | Acute, 24 h | 6.6–6.7 | Low pH-exposed MSC enhanced in vivo melanoma growth, acidosis of tumour microenvironment potentiated the pro-tumoral activity of MSC | [95] |
| Melanoma: MV3 | NaHCO3-free medium supplemented with HEPES (10 mmol/L) and adjusted to the respective experimental pH | Acute, 24 h | 7.0; 6.8; 6.4 | Reduced cell to cell adhesion, invasion, increased cell-surface adhesion | [87] |
| Breast cancer: MCF7, SUM52PE | Medium supplemented with 25 mM HEPES, adjusted to the acidic pH | Acute, 24 h | 6.7 | Inhibition of canonical hypoxia response and activation of UPR and inflammation | [96] |
| Glioblastoma: U87-MG, HTB-14; cervical cancer: HeLa, CCL-2; Mouse Lewis lung carcinoma: LLC1, CRL-1642; glioma: GL261 | Medium adjusted to acidic pH | Acute, 24 h | 6.6; 6.2; 6.0 | Increased uptake of lipoproteins via proteoglycan-dependent endocytosis | [97] |
| Glioblastoma: LN229 | Medium adjusted to desired pH with 2 N HCl | Acute, 3 h | 6.2; 3.4 | Increased surface cholesterol elevated proliferative and stem-like potential | [98] |
| Breast cancer: MCF-7, MDA-MB-468, MDA-MB-231, and SkBr3 | Medium adjusted to pH 6.5 | Acute, 48 h | 6.5 | Decreased glycolysis, elevated glutaminolysis and fatty acid synthesis | [78] |
| Melanoma: Me30966, Mel501, WM793, A375, SK-Mel-28 | pH was manipulated by varying concentrations of NaHCO3 in CO2-rich atmosphere | Acute, up to 24 h | 6.8, 6.5 | Induced autophagy, mTOR inhibition, activated AMPK, reduced glucose and amino-acid uptake | [80] |
| Breast cancer: MDA-MB-231, MCF7; pancreatic cancer: PANC-1 | pH was manipulated by varying concentrations of NaHCO3 in CO2-rich atmosphere; the osmolality was maintained by adjusting NaCl | Prolonged, 1 month | 6.5 | Metabolic deregulation, ECM remodelling, altered cell cycle regulation, induced DNA damage response. Elevated expression of SCNN1A, CACNG4, ASIC1, SCN1B, IFITM1 | [75] |
| Melanoma: C8161 | Slow conditioning over the course of 1.5 months with 0.15 pH units drop every 2 weeks | Prolonged, 1.5 months | 6.7 | Increased invasion, motility, altered gene expression relating to: cell cycle, inflammation, Wnt signalling, apoptosis, IL-2, cell adhesion | [99] |
| Lewis lung carcinoma: LLCm1 | Cells were adapted to acidic pH by serial passaging through media of stepwise decreasing pH (7.0, 6.8, and 6.5) until pH 6.2 was reached. The cells were maintained for 2–4 weeks at each pH | Prolonged, 3 months | 6.2 | Increased metastatic activity through MMPs, increased migration and invasion | [100] |
| Colorectal cancer: SW480, SW620 | Medium supplemented with 25 mM HEPES and PIPES, pH adjusted to 6.5 | Prolonged, 3 months | 6.5 | Increased invasion and metastasis, altered chromatin accessibility including DNA remodelling-associated pathways, HDAC, SIRT1 pathway, DNA methylation | [101] |
| Breast cancer: MDA-MB-231, HS766T | Cells were cultured and passaged directly in acidic medium | Prolonged, 3 months | 6.7 | Cytoplasmic vacuolated phenotype, elevated autophagy, in mouse model autophagy was reduced by systemic treatment with sodium bicarbonate | [81] |
| Melanoma: Mel501; breast cancer: MCF7ac; prostate cancer: PC3ac | Cells allowed to acidify in unbuffered medium for 5 days, then passaged and moved to a medium of pH 6.5 | Prolonged, 3–4 weeks | 7; 6.75; 6.5 | Remodelled lipid composition towards longer, unsaturated acyl chains, upregulation of genes involved in acyl chain desaturation, elongation and phospholipid transfer | [79] |
| Melanoma: Me30966; prostate cancer: LNCaP; osteosarcoma: SaOS2; breast cancer: SKBR3; colorectal cancer: HCT116 | Cells allowed to acidify in unbuffered medium for 5 days, then passaged and moved to medium of pH 6.5 | Prolonged, 3–4 weeks | 6.5 | Increased exosome release | [102] |
| Cervical cancer: SiHa; head and neck cancer: FaDu; colorectal cancer: HCT-116 | Medium supplemented with 25 mmol/L of both PIPES and HEPES, pH adjusted to 6.5 | Prolonged, 8–10 weeks | 6.5 | Increased mitochondrial protein acetylation, switch to fatty acid oxidation | [103] |