Cancer and Metastasis Reviews

, Volume 38, Issue 1–2, pp 103–112 | Cite as

Acidosis and proteolysis in the tumor microenvironment

  • Kyungmin Ji
  • Linda Mayernik
  • Kamiar Moin
  • Bonnie F. SloaneEmail author


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.


Acidosis Lysosomes Exosomes Invadopodia Caveolae 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. 1.
    Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57–70.Google Scholar
  2. 2.
    Paget, S. (1989). The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Reviews, 8(2), 98–101.Google Scholar
  3. 3.
    Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674. Scholar
  4. 4.
    Pietras, K., & Ostman, A. (2010). Hallmarks of cancer: interactions with the tumor stroma. Experimental Cell Research, 316(8), 1324–1331. Scholar
  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. Scholar
  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. Scholar
  7. 7.
    Kanada, M., Bachmann, M. H., & Contag, C. H. (2016). Signaling by extracellular vesicles advances cancer hallmarks. Trends Cancer, 2(2), 84–94. Scholar
  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. Scholar
  9. 9.
    Pavlova, N. N., & Thompson, C. B. (2016). The emerging hallmarks of cancer metabolism. Cell Metabolism, 23(1), 27–47. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  13. 13.
    Warburg, O. (1925). The metabolism of carcinoma cells. Cancer Research, 9(1), 148–163. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  17. 17.
    Gillies, R. J., & Gatenby, R. A. (2015). Metabolism and its sequelae in cancer evolution and therapy. Cancer Journal, 21(2), 88–96. Scholar
  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. Scholar
  19. 19.
    Teitelbaum, S. L. (2000). Bone resorption by osteoclasts. Science, 289(5484), 1504–1508.Google Scholar
  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.Google Scholar
  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. Scholar
  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. Scholar
  23. 23.
    Edwards, D., Hoyer-Hansen, G., Blasi, F., & Sloane, B. F. (2008). The cancer degradome: protease and cancer biology. New York: Springer.Google Scholar
  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. Scholar
  25. 25.
    Roshy, S., Sloane, B. F., & Moin, K. (2003). Pericellular cathepsin B and malignant progression. Cancer Metastasis Reviews, 22(2–3), 271–286.Google Scholar
  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. Scholar
  27. 27.
    Mohamed, M. M., & Sloane, B. F. (2006). Cysteine cathepsins: multifunctional enzymes in cancer. Nature Reviews. Cancer, 6(10), 764–775. Scholar
  28. 28.
    Corbet, C., & Feron, O. (2017). Tumour acidosis: from the passenger to the driver’s seat. Nature Reviews. Cancer, 17(10), 577–593. Scholar
  29. 29.
    Podgorski, I., & Sloane, B. F. (2003). Cathepsin B and its role(s) in cancer progression. Biochemical Society Symposium, 70(70), 263–276.Google Scholar
  30. 30.
    Aggarwal, N., & Sloane, B. F. (2014). Cathepsin B: multiple roles in cancer. Proteomics. Clinical Applications, 8(5–6), 427–437. Scholar
  31. 31.
    Mason, S. D., & Joyce, J. A. (2011). Proteolytic networks in cancer. Trends in Cell Biology, 21(4), 228–237. Scholar
  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.Google Scholar
  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.Google Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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.Google Scholar
  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.Google Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  47. 47.
    Gould, C. M., & Courtneidge, S. A. (2014). Regulation of invadopodia by the tumor microenvironment. Cell Adhesion & Migration, 8(3), 226–235.Google Scholar
  48. 48.
    McNiven, M. A. (2013). Breaking away: matrix remodeling from the leading edge. Trends in Cell Biology, 23(1), 16–21. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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).
  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.Google Scholar
  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. Scholar
  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.Google Scholar
  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. Scholar
  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.Google Scholar
  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.Google Scholar
  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.Google Scholar
  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.Google Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  64. 64.
    Martinez-Outschoorn, U. E., Sotgia, F., & Lisanti, M. P. (2015). Caveolae and signalling in cancer. Nature Reviews. Cancer, 15(4), 225–237. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  68. 68.
    Palade, G. E. (1953). Fine structure of blood capillaries. Journal of Applied Physics, 24, 1424.Google Scholar
  69. 69.
    Nichols, B. (2018). The mystery of caveolae. The Scientist, 42–47.Google Scholar
  70. 70.
    Cheng, J. P. X., & Nichols, B. J. (2016). Caveolae: one function or many? Trends in Cell Biology, 26(3), 177–189. Scholar
  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.Google Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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.Google Scholar
  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.Google Scholar
  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.Google Scholar
  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.Google Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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. Scholar
  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.Google Scholar
  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. Scholar
  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. Scholar
  89. 89.
    Sloane, B. F., List, K., Fingleton, B., & Matrisian, L. (2013). Proteases: structure and function. New York: Springer.Google Scholar
  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. Scholar
  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.Google Scholar
  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. Scholar
  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. Scholar
  94. 94.
    Mills, G. B., & Moolenaar, W. H. (2003). The emerging role of lysophosphatidic acid in cancer. Nature Reviews. Cancer, 3(8), 582–591. Scholar
  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.Google Scholar
  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.Google Scholar
  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. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Kyungmin Ji
    • 1
  • Linda Mayernik
    • 1
  • Kamiar Moin
    • 1
  • Bonnie F. Sloane
    • 1
    Email author
  1. 1.Department of PharmacologyWayne State University School of MedicineDetroitUSA

Personalised recommendations