Advertisement

Acidosis and proteolysis in the tumor microenvironment

Abstract

The glycolytic phenotype of the Warburg effect is associated with acidification of the tumor microenvironment. In this review, we describe how acidification of the tumor microenvironment may increase the invasive and degradative phenotype of cancer cells. As a template of an extracellular acidic microenvironment that is linked to proteolysis, we use the resorptive pit formed between osteoclasts and bone. We describe similar changes that have been observed in cancer cells in response to an acidic microenvironment and that are associated with proteolysis and invasive and metastatic phenotypes. This includes consideration of changes observed in the intracellular trafficking of vesicles, i.e., lysosomes and exosomes, and in specialized regions of the membrane, i.e., invadopodia and caveolae. Cancer-associated cells are known to affect what is generally referred to as tumor proteolysis but little direct evidence for this being regulated by acidosis; we describe potential links that should be verified.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2

References

  1. 1.

    Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57–70.

  2. 2.

    Paget, S. (1989). The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Reviews, 8(2), 98–101.

  3. 3.

    Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674. https://doi.org/10.1016/j.cell.2011.02.013.

  4. 4.

    Pietras, K., & Ostman, A. (2010). Hallmarks of cancer: interactions with the tumor stroma. Experimental Cell Research, 316(8), 1324–1331. https://doi.org/10.1016/j.yexcr.2010.02.045.

  5. 5.

    Hanahan, D., & Coussens, L. M. (2012). Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell, 21(3), 309–322. https://doi.org/10.1016/j.ccr.2012.02.022.

  6. 6.

    Pickup, M. W., Mouw, J. K., & Weaver, V. M. (2014). The extracellular matrix modulates the hallmarks of cancer. EMBO Reports, 15(12), 1243–1253. https://doi.org/10.15252/embr.201439246.

  7. 7.

    Kanada, M., Bachmann, M. H., & Contag, C. H. (2016). Signaling by extracellular vesicles advances cancer hallmarks. Trends Cancer, 2(2), 84–94. https://doi.org/10.1016/j.trecan.2015.12.005.

  8. 8.

    Meehan, K., & Vella, L. J. (2016). The contribution of tumour-derived exosomes to the hallmarks of cancer. Critical Reviews in Clinical Laboratory Sciences, 53(2), 121–131. https://doi.org/10.3109/10408363.2015.1092496.

  9. 9.

    Pavlova, N. N., & Thompson, C. B. (2016). The emerging hallmarks of cancer metabolism. Cell Metabolism, 23(1), 27–47. https://doi.org/10.1016/j.cmet.2015.12.006.

  10. 10.

    Harguindey, S., Orive, G., Luis Pedraz, J., Paradiso, A., & Reshkin, S. J. (2005). 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. Biochimica et Biophysica Acta, 1756(1), 1–24. https://doi.org/10.1016/j.bbcan.2005.06.004.

  11. 11.

    Ruan, K., Song, G., & Ouyang, G. (2009). Role of hypoxia in the hallmarks of human cancer. Journal of Cellular Biochemistry, 107(6), 1053–1062. https://doi.org/10.1002/jcb.22214.

  12. 12.

    Colotta, F., Allavena, P., Sica, A., Garlanda, C., & Mantovani, A. (2009). Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis, 30(7), 1073–1081. https://doi.org/10.1093/carcin/bgp127.

  13. 13.

    Warburg, O. (1925). The metabolism of carcinoma cells. Cancer Research, 9(1), 148–163. https://doi.org/10.1158/jcr.1925.148.

  14. 14.

    White, K. A., Grillo-Hill, B. K., & Barber, D. L. (2017). Cancer cell behaviors mediated by dysregulated pH dynamics at a glance. Journal of Cell Science, 130(4), 663–669. https://doi.org/10.1242/jcs.195297.

  15. 15.

    Peppicelli, S., Andreucci, E., Ruzzolini, J., Margheri, F., Laurenzana, A., Bianchini, F., & Calorini, L. (2017). Acidity of microenvironment as a further driver of tumor metabolic reprogramming. Journal of Clinical & Cellular Immunology, 8, 485. https://doi.org/10.4172/2155-9899.1000485.

  16. 16.

    Gatenby, R. A., Gawlinski, E. T., Gmitro, A. F., Kaylor, B., & Gillies, R. J. (2006). Acid-mediated tumor invasion: a multidisciplinary study. Cancer Research, 66(10), 5216–5223. https://doi.org/10.1158/0008-5472.CAN-05-4193.

  17. 17.

    Gillies, R. J., & Gatenby, R. A. (2015). Metabolism and its sequelae in cancer evolution and therapy. Cancer Journal, 21(2), 88–96. https://doi.org/10.1097/PPO.0000000000000102.

  18. 18.

    Webb, B. A., Chimenti, M., Jacobson, M. P., & Barber, D. L. (2011). Dysregulated pH: a perfect storm for cancer progression. Nature Reviews. Cancer, 11(9), 671–677. https://doi.org/10.1038/nrc3110.

  19. 19.

    Teitelbaum, S. L. (2000). Bone resorption by osteoclasts. Science, 289(5484), 1504–1508.

  20. 20.

    Georgess, D., Machuca-Gayet, I., Blangy, A., & Jurdic, P. (2014). Podosome organization drives osteoclast-mediated bone resorption. Cell Adhesion & Migration, 8(3), 191–204.

  21. 21.

    Murphy, D. A., & Courtneidge, S. A. (2011). The ‘ins’ and ‘outs’ of podosomes and invadopodia: characteristics, formation and function. Nature Reviews. Molecular Cell Biology, 12(7), 413–426. https://doi.org/10.1038/nrm3141.

  22. 22.

    Toyomura, T., Murata, Y., Yamamoto, A., Oka, T., Sun-Wada, G. H., Wada, Y., & Futai, M. (2003). From lysosomes to the plasma membrane: localization of vacuolar-type H+ -ATPase with the a3 isoform during osteoclast differentiation. The Journal of Biological Chemistry, 278(24), 22023–22030. https://doi.org/10.1074/jbc.M302436200.

  23. 23.

    Edwards, D., Hoyer-Hansen, G., Blasi, F., & Sloane, B. F. (2008). The cancer degradome: protease and cancer biology. New York: Springer.

  24. 24.

    DiCiccio, J. E., & Steinberg, B. E. (2011). Lysosomal pH and analysis of the counter ion pathways that support acidification. The Journal of General Physiology, 137(4), 385–390. https://doi.org/10.1085/jgp.201110596.

  25. 25.

    Roshy, S., Sloane, B. F., & Moin, K. (2003). Pericellular cathepsin B and malignant progression. Cancer Metastasis Reviews, 22(2–3), 271–286.

  26. 26.

    Sloane, B. F., Yan, S., Podgorski, I., Linebaugh, B. E., Cher, M. L., Mai, J., et al. (2005). Cathepsin B and tumor proteolysis: contribution of the tumor microenvironment. Seminars in Cancer Biology, 15(2), 149–157. https://doi.org/10.1016/j.semcancer.2004.08.001.

  27. 27.

    Mohamed, M. M., & Sloane, B. F. (2006). Cysteine cathepsins: multifunctional enzymes in cancer. Nature Reviews. Cancer, 6(10), 764–775. https://doi.org/10.1038/nrc1949.

  28. 28.

    Corbet, C., & Feron, O. (2017). Tumour acidosis: from the passenger to the driver’s seat. Nature Reviews. Cancer, 17(10), 577–593. https://doi.org/10.1038/nrc.2017.77.

  29. 29.

    Podgorski, I., & Sloane, B. F. (2003). Cathepsin B and its role(s) in cancer progression. Biochemical Society Symposium, 70(70), 263–276.

  30. 30.

    Aggarwal, N., & Sloane, B. F. (2014). Cathepsin B: multiple roles in cancer. Proteomics. Clinical Applications, 8(5–6), 427–437. https://doi.org/10.1002/prca.201300105.

  31. 31.

    Mason, S. D., & Joyce, J. A. (2011). Proteolytic networks in cancer. Trends in Cell Biology, 21(4), 228–237. https://doi.org/10.1016/j.tcb.2010.12.002.

  32. 32.

    Heuser, J. (1989). Changes in lysosome shape and distribution correlated with changes in cytoplasmic pH. The Journal of Cell Biology, 108(3), 855–864.

  33. 33.

    Kobayashi, H., Moniwa, N., Sugimura, M., Shinohara, H., Ohi, H., & Terao, T. (1993). Effects of membrane-associated cathepsin B on the activation of receptor-bound prourokinase and subsequent invasion of reconstituted basement membranes. Biochimica et Biophysica Acta, 1178(1), 55–62.

  34. 34.

    Andrade, L. O., & Andrews, N. W. (2005). The Trypanosoma cruzi-host-cell interplay: location, invasion, retention. Nature Reviews. Microbiology, 3(10), 819–823. https://doi.org/10.1038/nrmicro1249.

  35. 35.

    Chapman, H. A., Jr., Munger, J. S., & Shi, G. P. (1994). The role of thiol proteases in tissue injury and remodeling. American Journal of Respiratory and Critical Care Medicine, 150(6 Pt 2), S155–S159. https://doi.org/10.1164/ajrccm/150.6_Pt_2.S155.

  36. 36.

    Castro-Gomes, T., Corrotte, M., Tam, C., & Andrews, N. W. (2016). Plasma membrane repair is regulated extracellularly by proteases released from lysosomes. PLoS One, 11(3), e0152583. https://doi.org/10.1371/journal.pone.0152583.

  37. 37.

    Sameni, M., Elliott, E., Ziegler, G., Fortgens, P. H., Dennison, C., & Sloane, B. F. (1995). Cathepsin B and D are localized at the surface of human breast cancer cells. Pathology Oncology Research, 1(1), 43–53.

  38. 38.

    Glunde, K., Guggino, S. E., Solaiyappan, M., Pathak, A. P., Ichikawa, Y., & Bhujwalla, Z. M. (2003). Extracellular acidification alters lysosomal trafficking in human breast cancer cells. Neoplasia, 5(6), 533–545.

  39. 39.

    Damaghi, M., Tafreshi, N. K., Lloyd, M. C., Sprung, R., Estrella, V., Wojtkowiak, J. W., Morse, D. L., Koomen, J. M., Bui, M. M., Gatenby, R. A., & Gillies, R. J. (2015). Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane. Nature Communications, 6, 8752. https://doi.org/10.1038/ncomms9752.

  40. 40.

    Dovmark, T. H., Saccomano, M., Hulikova, A., Alves, F., & Swietach, P. (2017). Connexin-43 channels are a pathway for discharging lactate from glycolytic pancreatic ductal adenocarcinoma cells. Oncogene, 36, 4538–4550. https://doi.org/10.1038/onc.2017.71.

  41. 41.

    Bohn, T., Rapp, S., Luther, N., Klein, M., Bruehl, T. J., Kojima, N., Aranda Lopez, P., Hahlbrock, J., Muth, S., Endo, S., Pektor, S., Brand, A., Renner, K., Popp, V., Gerlach, K., Vogel, D., Lueckel, C., Arnold-Schild, D., Pouyssegur, J., Kreutz, M., Huber, M., Koenig, J., Weigmann, B., Probst, H. C., von Stebut, E., Becker, C., Schild, H., Schmitt, E., & Bopp, T. (2018). Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nature Immunology, 19(12), 1319–1329. https://doi.org/10.1038/s41590-018-0226-8.

  42. 42.

    Rohani, N., Hao, L., Alexis, M. S., Joughin, B. A., Krismer, K., Moufarrej, M. N., Soltis, A. R., Lauffenburger, D. A., Yaffe, M. B., Burge, C. B., Bhatia, S. N., & Gertler, F. B. (2019). Acidification of tumor at stromal boundaries drives transcriptome alterations associated with aggressive phenotypes. Cancer Research, 79, 1952–1966. https://doi.org/10.1158/0008-5472.CAN-18-1604.

  43. 43.

    Dykes, S. S., Steffan, J. J., & Cardelli, J. A. (2017). Lysosome trafficking is necessary for EGF-driven invasion and is regulated by p38 MAPK and Na+/H+ exchangers. BMC Cancer, 17(1), 672. https://doi.org/10.1186/s12885-017-3660-3.

  44. 44.

    Steffan, J. J., Williams, B. C., Welbourne, T., & Cardelli, J. A. (2010). HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity of Na+-H+ exchangers. Journal of Cell Science, 123(Pt 7, 1151–1159. https://doi.org/10.1242/jcs.063644.

  45. 45.

    Vasiljeva, O., Papazoglou, A., Kruger, A., Brodoefel, H., Korovin, M., Deussing, J., et al. (2006). Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer. Cancer Research, 66(10), 5242–5250. https://doi.org/10.1158/0008-5472.CAN-05-4463.

  46. 46.

    Sevenich, L., Schurigt, U., Sachse, K., Gajda, M., Werner, F., Muller, S., Vasiljeva, O., Schwinde, A., Klemm, N., Deussing, J., Peters, C., & Reinheckel, T. (2010). Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice. Proceedings of the National Academy of Sciences of the United States of America, 107(6), 2497–2502. https://doi.org/10.1073/pnas.0907240107.

  47. 47.

    Gould, C. M., & Courtneidge, S. A. (2014). Regulation of invadopodia by the tumor microenvironment. Cell Adhesion & Migration, 8(3), 226–235.

  48. 48.

    McNiven, M. A. (2013). Breaking away: matrix remodeling from the leading edge. Trends in Cell Biology, 23(1), 16–21. https://doi.org/10.1016/j.tcb.2012.08.009.

  49. 49.

    Di Martino, J., Henriet, E., Ezzoukhry, Z., Goetz, J. G., Moreau, V., & Saltel, F. (2016). The microenvironment controls invadosome plasticity. Journal of Cell Science, 129(9), 1759–1768. https://doi.org/10.1242/jcs.182329.

  50. 50.

    Paterson, E. K., & Courtneidge, S. A. (2018). Invadosomes are coming: new insights into function and disease relevance. The FEBS Journal, 285(1), 8–27. https://doi.org/10.1111/febs.14123.

  51. 51.

    Tu, C., Ortega-Cava, C. F., Chen, G., Fernandes, N. D., Cavallo-Medved, D., Sloane, B. F., Band, V., & Band, H. (2008). Lysosomal cathepsin B participates in the podosome-mediated extracellular matrix degradation and invasion via secreted lysosomes in v-Src fibroblasts. Cancer Research, 68(22), 9147–9156. https://doi.org/10.1158/0008-5472.CAN-07-5127.

  52. 52.

    Kryczka, J., Papiewska-Pajak, I., Kowalska, M. A., & Boncela, J. (2019). Cathepsin B is upregulated and mediates ECM degradation in colon adenocarcinoma HT29 cells overexpressing snail. Cells, 8(3). https://doi.org/10.3390/cells8030203.

  53. 53.

    Stachowiak, K., Tokmina, M., Karpinska, A., Sosnowska, R., & Wiczk, W. (2004). Fluorogenic peptide substrates for carboxydipeptidase activity of cathepsin B. Acta Biochimica Polonica, 51(1), 81–92.

  54. 54.

    Busco, G., Cardone, R. A., Greco, M. R., Bellizzi, A., Colella, M., Antelmi, E., Mancini, M. T., Dell'Aquila, M. E., Casavola, V., Paradiso, A., & Reshkin, S. J. (2010). NHE1 promotes invadopodial ECM proteolysis through acidification of the peri-invadopodial space. The FASEB Journal, 24(10), 3903–3915. https://doi.org/10.1096/fj.09-149518.

  55. 55.

    Rothberg, J. M., Bailey, K. M., Wojtkowiak, J. W., Ben-Nun, Y., Bogyo, M., Weber, E., Moin, K., Blum, G., Mattingly, R. R., Gillies, R. J., & Sloane, B. F. (2013). Acid-mediated tumor proteolysis: contribution of cysteine cathepsins. Neoplasia, 15(10), 1125–1137.

  56. 56.

    Greco, M. R., Antelmi, E., Busco, G., Guerra, L., Rubino, R., Casavola, V., et al. (2014). Protease activity at invadopodial focal digestive areas is dependent on NHE1-driven acidic pHe. Oncology Reports, 31(2), 940–946. https://doi.org/10.3892/or.2013.2923.

  57. 57.

    Gasic, G. J., Boettiger, D., Catalfamo, J. L., Gasic, T. B., & Stewart, G. J. (1978). Aggregation of platelets and cell membrane vesiculation by rat cells transformed in vitro by Rous sarcoma virus. Cancer Research, 38(9), 2950–2955.

  58. 58.

    Dvorak, H. F., Quay, S. C., Orenstein, N. S., Dvorak, A. M., Hahn, P., Bitzer, A. M., et al. (1981). Tumor shedding and coagulation. Science, 212(4497), 923–924.

  59. 59.

    Dvorak, H. F., Van DeWater, L., Bitzer, A. M., Dvorak, A. M., Anderson, D., Harvey, V. S., et al. (1983). Procoagulant activity associated with plasma membrane vesicles shed by cultured tumor cells. Cancer Research, 43(9), 4434–4442.

  60. 60.

    Honn, K. V., Cavanaugh, P., Evens, C., Taylor, J. D., & Sloane, B. F. (1982). Tumor cell-platelet aggregation: induced by cathepsin B-like proteinase and inhibited by prostacyclin. Science, 217(4559), 540–542.

  61. 61.

    Becker, A., Thakur, B. K., Weiss, J. M., Kim, H. S., Peinado, H., & Lyden, D. (2016). Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell, 30(6), 836–848. https://doi.org/10.1016/j.ccell.2016.10.009.

  62. 62.

    Parolini, I., Federici, C., Raggi, C., Lugini, L., Palleschi, S., De Milito, A., et al. (2009). Microenvironmental pH is a key factor for exosome traffic in tumor cells. The Journal of Biological Chemistry, 284(49), 34211–34222. https://doi.org/10.1074/jbc.M109.041152.

  63. 63.

    Ban, J. J., Lee, M., Im, W., & Kim, M. (2015). Low pH increases the yield of exosome isolation. Biochemical and Biophysical Research Communications, 461(1), 76–79. https://doi.org/10.1016/j.bbrc.2015.03.172.

  64. 64.

    Martinez-Outschoorn, U. E., Sotgia, F., & Lisanti, M. P. (2015). Caveolae and signalling in cancer. Nature Reviews. Cancer, 15(4), 225–237. https://doi.org/10.1038/nrc3915.

  65. 65.

    Felicetti, F., Parolini, I., Bottero, L., Fecchi, K., Errico, M. C., Raggi, C., Biffoni, M., Spadaro, F., Lisanti, M. P., Sargiacomo, M., & Carè, A. (2009). Caveolin-1 tumor-promoting role in human melanoma. International Journal of Cancer, 125(7), 1514–1522. https://doi.org/10.1002/ijc.24451.

  66. 66.

    Schillaci, O., Fontana, S., Monteleone, F., Taverna, S., Di Bella, M. A., Di Vizio, D., et al. (2017). Exosomes from metastatic cancer cells transfer amoeboid phenotype to non-metastatic cells and increase endothelial permeability: their emerging role in tumor heterogeneity. Scientific Reports, 7(1), 4711. https://doi.org/10.1038/s41598-017-05002-y.

  67. 67.

    Boussadia, Z., Lamberti, J., Mattei, F., Pizzi, E., Puglisi, R., Zanetti, C., Pasquini, L., Fratini, F., Fantozzi, L., Felicetti, F., Fecchi, K., Raggi, C., Sanchez, M., D’Atri, S., Carè, A., Sargiacomo, M., & Parolini, I. (2018). Acidic microenvironment plays a key role in human melanoma progression through a sustained exosome mediated transfer of clinically relevant metastatic molecules. Journal of Experimental & Clinical Cancer Research, 37(1), 245. https://doi.org/10.1186/s13046-018-0915-z.

  68. 68.

    Palade, G. E. (1953). Fine structure of blood capillaries. Journal of Applied Physics, 24, 1424.

  69. 69.

    Nichols, B. (2018). The mystery of caveolae. The Scientist, 42–47.

  70. 70.

    Cheng, J. P. X., & Nichols, B. J. (2016). Caveolae: one function or many? Trends in Cell Biology, 26(3), 177–189. https://doi.org/10.1016/j.tcb.2015.10.010.

  71. 71.

    Cavallo-Medved, D., Dosescu, J., Linebaugh, B. E., Sameni, M., Rudy, D., & Sloane, B. F. (2003). Mutant K-ras regulates cathepsin B localization on the surface of human colorectal carcinoma cells. Neoplasia, 5(6), 507–519.

  72. 72.

    Bydoun, M., & Waisman, D. M. (2014). On the contribution of S100A10 and annexin A2 to plasminogen activation and oncogenesis: an enduring ambiguity. Future Oncology, 10(15), 2469–2479. https://doi.org/10.2217/fon.14.163.

  73. 73.

    Madureira, P. A., Bharadwaj, A. G., Bydoun, M., Garant, K., O'Connell, P., Lee, P., & Waisman, D. M. (2016). Cell surface protease activation during RAS transformation: critical role of the plasminogen receptor, S100A10. Oncotarget, 7(30), 47720–47737. https://doi.org/10.18632/oncotarget.10279.

  74. 74.

    Zakrzewicz, D., Didiasova, M., Zakrzewicz, A., Hocke, A. C., Uhle, F., Markart, P., Preissner, K. T., & Wygrecka, M. (2014). The interaction of enolase-1 with caveolae-associated proteins regulates its subcellular localization. The Biochemical Journal, 460(2), 295–307. https://doi.org/10.1042/BJ20130945.

  75. 75.

    Stahl, A., & Mueller, B. M. (1995). The urokinase-type plasminogen activator receptor, a GPI-linked protein, is localized in caveolae. The Journal of Cell Biology, 129(2), 335–344.

  76. 76.

    Schwab, W., Gavlik, J. M., Beichler, T., Funk, R. H., Albrecht, S., Magdolen, V., et al. (2001). Expression of the urokinase-type plasminogen activator receptor in human articular chondrocytes: association with caveolin and beta 1-integrin. Histochemistry and Cell Biology, 115(4), 317–323.

  77. 77.

    Kwon, M., MacLeod, T. J., Zhang, Y., & Waisman, D. M. (2005). S100A10, annexin A2, and annexin a2 heterotetramer as candidate plasminogen receptors. Frontiers in Bioscience, 10, 300–325.

  78. 78.

    Mai, J., Finley, R. L., Jr., Waisman, D. M., & Sloane, B. F. (2000). Human procathepsin B interacts with the annexin II tetramer on the surface of tumor cells. The Journal of Biological Chemistry, 275(17), 12806–12812.

  79. 79.

    Guo, M., Mathieu, P. A., Linebaugh, B., Sloane, B. F., & Reiners, J. J., Jr. (2002). Phorbol ester activation of a proteolytic cascade capable of activating latent transforming growth factor-betaL a process initiated by the exocytosis of cathepsin B. The Journal of Biological Chemistry, 277(17), 14829–14837. https://doi.org/10.1074/jbc.M108180200.

  80. 80.

    Cavallo-Medved, D., Mai, J., Dosescu, J., Sameni, M., & Sloane, B. F. (2005). Caveolin-1 mediates the expression and localization of cathepsin B, pro-urokinase plasminogen activator and their cell-surface receptors in human colorectal carcinoma cells. Journal of Cell Science, 118(Pt 7), 1493–1503. https://doi.org/10.1242/jcs.02278.

  81. 81.

    Deryugina, E. I., & Quigley, J. P. (2012). Cell surface remodeling by plasmin: a new function for an old enzyme. Journal of Biomedicine & Biotechnology, 2012, 564259. https://doi.org/10.1155/2012/564259.

  82. 82.

    Capello, M., Ferri-Borgogno, S., Riganti, C., Chattaragada, M. S., Principe, M., Roux, C., Zhou, W., Petricoin, E. F., Cappello, P., & Novelli, F. (2016). Targeting the Warburg effect in cancer cells through ENO1 knockdown rescues oxidative phosphorylation and induces growth arrest. Oncotarget, 7(5), 5598–5612. https://doi.org/10.18632/oncotarget.6798.

  83. 83.

    Laurenzana, A., Chilla, A., Luciani, C., Peppicelli, S., Biagioni, A., Bianchini, F., et al. (2017). uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells. International Journal of Cancer, 141(6), 1190–1200. https://doi.org/10.1002/ijc.30817.

  84. 84.

    Brisson, L., Gillet, L., Calaghan, S., Besson, P., Le Guennec, J. Y., Roger, S., et al. (2011). Na(V)1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H(+) efflux in caveolae. Oncogene, 30(17), 2070–2076. https://doi.org/10.1038/onc.2010.574.

  85. 85.

    Parton, R. G., & del Pozo, M. A. (2013). Caveolae as plasma membrane sensors, protectors and organizers. Nature Reviews. Molecular Cell Biology, 14(2), 98–112. https://doi.org/10.1038/nrm3512.

  86. 86.

    Dulhunty, A. F., & Franzini-Armstrong, C. (1975). The relative contributions of the folds and caveolae to the surface membrane of frog skeletal muscle fibres at different sarcomere lengths. The Journal of Physiology, 250(3), 513–539.

  87. 87.

    Nwosu, Z. C., Ebert, M. P., Dooley, S., & Meyer, C. (2016). Caveolin-1 in the regulation of cell metabolism: a cancer perspective. Molecular Cancer, 15(1), 71. https://doi.org/10.1186/s12943-016-0558-7.

  88. 88.

    Shin, H., Haga, J. H., Kosawada, T., Kimura, K., Li, Y. S., Chien, S., & Schmid-Schönbein, G. W. (2019). Fine control of endothelial VEGFR-2 activation: caveolae as fluid shear stress shelters for membrane receptors. Biomechanics and Modeling in Mechanobiology, 18(1), 5–16. https://doi.org/10.1007/s10237-018-1063-2.

  89. 89.

    Sloane, B. F., List, K., Fingleton, B., & Matrisian, L. (2013). Proteases: structure and function. New York: Springer.

  90. 90.

    Estrella, V., Chen, T., Lloyd, M., Wojtkowiak, J., Cornnell, H. H., Ibrahim-Hashim, A., Bailey, K., Balagurunathan, Y., Rothberg, J. M., Sloane, B. F., Johnson, J., Gatenby, R. A., & Gillies, R. J. (2013). Acidity generated by the tumor microenvironment drives local invasion. Cancer Research, 73(5), 1524–1535. https://doi.org/10.1158/0008-5472.CAN-12-2796.

  91. 91.

    Giusti, I., D'Ascenzo, S., Millimaggi, D., Taraboletti, G., Carta, G., Franceschini, N., et al. (2008). Cathepsin B mediates the pH-dependent proinvasive activity of tumor-shed microvesicles. Neoplasia, 10(5), 481–488.

  92. 92.

    Pavlides, S., Whitaker-Menezes, D., Castello-Cros, R., Flomenberg, N., Witkiewicz, A. K., Frank, P. G., Casimiro, M. C., Wang, C., Fortina, P., Addya, S., Pestell, R. G., Martinez-Outschoorn, U. E., Sotgia, F., & Lisanti, M. P. (2009). The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle, 8(23), 3984–4001. https://doi.org/10.4161/cc.8.23.10238.

  93. 93.

    Radhakrishnan, R., Ha, J. H., Jayaraman, M., Liu, J., Moxley, K. M., Isidoro, C., Sood, A. K., Song, Y. S., & Dhanasekaran, D. N. (2019). Ovarian cancer cell-derived lysophosphatidic acid induces glycolytic shift and cancer-associated fibroblast-phenotype in normal and peritumoral fibroblasts. Cancer Letters, 442, 464–474. https://doi.org/10.1016/j.canlet.2018.11.023.

  94. 94.

    Mills, G. B., & Moolenaar, W. H. (2003). The emerging role of lysophosphatidic acid in cancer. Nature Reviews. Cancer, 3(8), 582–591. https://doi.org/10.1038/nrc1143.

  95. 95.

    Pustilnik, T. B., Estrella, V., Wiener, J. R., Mao, M., Eder, A., Watt, M. A., et al. (1999). Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells. Clinical Cancer Research, 5(11), 3704–3710.

  96. 96.

    Fishman, D. A., Liu, Y., Ellerbroek, S. M., & Stack, M. S. (2001). Lysophosphatidic acid promotes matrix metalloproteinase (MMP) activation and MMP-dependent invasion in ovarian cancer cells. Cancer Research, 61(7), 3194–3199.

  97. 97.

    Jeong, K. J., Park, S. Y., Cho, K. H., Sohn, J. S., Lee, J., Kim, Y. K., Kang, J., Park, C. G., Han, J. W., & Lee, H. Y. (2012). The rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion. Oncogene, 31(39), 4279–4289. https://doi.org/10.1038/onc.2011.595.

Download references

Author information

Correspondence to Bonnie F. Sloane.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ji, K., Mayernik, L., Moin, K. et al. Acidosis and proteolysis in the tumor microenvironment. Cancer Metastasis Rev 38, 103–112 (2019) doi:10.1007/s10555-019-09796-3

Download citation

Keywords

  • Acidosis
  • Lysosomes
  • Exosomes
  • Invadopodia
  • Caveolae