Abstract
There is abundant evidence that the phenotype of cells the tumor at the stromal interface is distinct from the tumor cells that are within the core. Molecular phenotyping of cells at the edge show that they express higher levels of proteins associated with elevated glycolytic metabolism, including GLUT-1, HIF-1, and CA-IX. An end product of glycolysis is the production of acid, and acidosis of tumors is strongly associated with increased metastatic potential across a wide variety of tumor types. The molecular machinery promoting this export of acid is being defined, with close collaboration between carbonic anhydrases, sodium dependent bicarbonate and monocarboxylate transporters. Neutralization of this acidity can prevent local invasion and metastasis, and this has led to the “acid-mediated invasion hypothesis” wherein export of acid from the tumor into the stroma leads to matrix remodeling, which can promote local invasion.
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References
Gerlinger M et al (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892
Napel S et al (2018) Quantitative imaging of cancer in the postgenomic era: Radio(geno)mics, deep learning, and habitats. Cancer 124(24):4633–4649
Hao JJ et al (2016) Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma. Nat Genet 48(12):1500–1507
Ibrahim AN et al (2020) Intratumoral spatial heterogeneity of BTK kinomic activity dictates distinct therapeutic response within a single glioblastoma tumor. J Neurosurg 133(6):1–12
Akram F et al (2020) Exploring MRI based radiomics analysis of intratumoral spatial heterogeneity in locally advanced nasopharyngeal carcinoma treated with intensity modulated radiotherapy. PLoS ONE 15(10):e0240043
Comba A et al (2020) Laser capture microdissection of glioma subregions for spatial and molecular characterization of intratumoral heterogeneity, oncostreams, and invasion. J Vis Exp. https://doi.org/10.3791/60939
Hou W et al (2020) Microenvironment-derived FGF-2 stimulates renal cell carcinoma cell proliferation through modulation of p27Kip1: implications for spatial niche formation and functional intratumoral heterogeneity. Pathobiology 87(2):114–124
Grove O et al (2015) Quantitative computed tomographic descriptors associate tumor shape complexity and intratumor heterogeneity with prognosis in lung adenocarcinoma. PLoS ONE 10(3):e0118261
Perez-Morales J et al (2020) Peritumoral and intratumoral radiomic features predict survival outcomes among patients diagnosed in lung cancer screening. Sci Rep 10(1):10528
Wu J et al (2018) Intratumoral spatial heterogeneity at perfusion MR imaging predicts recurrence-free survival in locally advanced breast cancer treated with neoadjuvant chemotherapy. Radiology 288(1):26–35
Hosny A et al (2018) Deep learning for lung cancer prognostication: a retrospective multi-cohort radiomics study. PLoS Med 15(11):e1002711
Mu W et al (2020) Non-invasive decision support for NSCLC treatment using PET/CT radiomics. Nat Commun 11(1):5228
Lloyd MC et al (2016) Darwinian dynamics of intratumoral heterogeneity: not solely random mutations but also variable environmental selection forces. Cancer Res 76(11):3136–3144
Tafreshi NK et al (2016) Evaluation of CAIX and CAXII expression in breast cancer at varied O2 levels: CAIX is the superior surrogate imaging biomarker of tumor hypoxia. Mol Imaging Biol 18(2):219–231
Tafreshi NK et al (2014) Carbonic anhydrase IX as an imaging and therapeutic target for tumors and metastases. SubCell Biochem 75:22–254
Lee SH et al (2018) Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo. Br J Cancer 119(5):622–630
Schito L, Semenza GL (2016) Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2(12):758–770
Russell S et al (2017) Pseudohypoxia: life at the edge. In: Ujbari B, Roche B, Thomas F (eds) Ecology and evolution of cancer, vol 1. Academic Press, pp 57–69
Song J, Yang X, Yan LJ (2019) Role of pseudohypoxia in the pathogenesis of type 2 diabetes. Hypoxia (Auckl) 7:33–40
Williamson JR et al (1993) Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 42(6):801–813
Hayashi Y et al (2018) Pathobiological pseudohypoxia as a putative mechanism underlying myelodysplastic syndromes. Cancer Discov 8(11):1438–1457
Reshetnyak YK et al (2008) Energetics of peptide (pHLIP) binding to and folding across a lipid bilayer membrane. Proc Natl Acad Sci USA 105(40):15340–15345
Damaghi M et al (2015) Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane. Nat Commun 6:8752
Rofstad EK et al (2006) Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res 66(13):6699–6707
Moellering RE et al (2008) Acid treatment of melanoma cells selects for invasive phenotypes. Clin Exp Metastasis 25(4):411–425
Riemann A et al (2014) Acidic priming enhances metastatic potential of cancer cells. Pflugers Arch 466(11):2127–2138
Riemann A et al (2016) Acidosis Promotes Metastasis Formation by Enhancing Tumor Cell Motility. Adv Exp Med Biol 876:215–220
Riemann A et al (2019) Extracellular Acidosis Modulates the Expression of Epithelial-Mesenchymal Transition (EMT) Markers and Adhesion of Epithelial and Tumor Cells. Neoplasia 21(5):450–458
Gatenby RA et al (2006) Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res 66(10):5216–5223
Estrella V et al (2013) Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 73(5):1524–1535
Robey IF et al (2009) Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res 69(6):2260–2268
Bailey KM et al (2014) Mechanisms of buffer therapy resistance. Neoplasia 16(4):354–64
Ibrahim-Hashim A et al (2012) Systemic buffers inhibit carcinogenesis in TRAMP mice. The Journal of urology 188(2):624–631
Ibrahim-Hashim A et al (2012) Reduction of metastasis using a non-volatile buffer. Clin Exp Metastasis 28(8):841–849
Ibrahim-Hashim A et al (2017) Tris-base buffer: a promising new inhibitor for cancer progression and metastasis. Cancer Med 6(7):1720–1729
Hamaguchi R, Narui R, Wada H (2020) Effects of alkalization therapy on chemotherapy outcomes in metastatic or recurrent pancreatic cancer. Anticancer Res 40(2):873–880
Hedlund EE et al (2019) Harnessing Induced Essentiality: Targeting Carbonic Anhydrase IX and Angiogenesis Reduces Lung Metastasis of Triple Negative Breast Cancer Xenografts. Cancers (Basel) 11:7
Boedtkjer E et al (2013) Contribution of Na+,HCO3(-)-cotransport to cellular pH control in human breast cancer: a role for the breast cancer susceptibility locus NBCn1 (SLC4A7). Int J Cancer 132(6):1288–1299
Forero-Quintero LS et al (2019) Membrane-anchored carbonic anhydrase IV interacts with monocarboxylate transporters via their chaperones CD147 and GP70. J Biol Chem 294(2):593–607
Noor SI et al (2018) A surface proton antenna in carbonic anhydrase II supports lactate transport in cancer cells. Elife 7:e35176
Ibrahim-Hashim A et al (2017) Defining cancer subpopulations by adaptive strategies rather than molecular properties provides novel insights into intratumoral evolution. Cancer Res 77(9):2242–2254
Freischel AR et al (2021) Frequency-dependent interactions determine outcome of competition between two breast cancer cell lines. Scientific reports 11(1):4908
Damaghi M, Gillies RJ (2016) Lysosomal protein relocation as an adaptation mechanism to extracellular acidosis. Cell cycle 15(13):1659–1660
Rothberg JM et al (2013) Acid-mediated tumor proteolysis: contribution of cysteine cathepsins. Neoplasia 15(10):1125–1137
Mohamed MM, Sloane BF (2006) Cysteine cathepsins: multifunctional enzymes in cancer. Nature reviews Cancer 6(10):764–775
Mason SD, Joyce JA (2011) Proteolytic networks in cancer. Trends Cell Biol 21(4):228–237
Ji K et al (2019) Acidosis and proteolysis in the tumor microenvironment. Cancer Metastasis Rev 38(1–2):103–12
Swayampakula M et al (2017) The interactome of metabolic enzyme carbonic anhydrase IX reveals novel roles in tumor cell migration and invadopodia/MMP14-mediated invasion. Oncogene 36(45):6244–6261
Colegio OR et al (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513(7519):559–563
El-Kenawi A et al (2019) Acidity promotes tumour progression by altering macrophage phenotype in prostate cancer. Br J Cancer 121(7):556–566
Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315(26):1650–1659
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Gillies, R.J. Cancer heterogeneity and metastasis: life at the edge. Clin Exp Metastasis 39, 15–19 (2022). https://doi.org/10.1007/s10585-021-10101-2
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DOI: https://doi.org/10.1007/s10585-021-10101-2