1 Introduction
2 Causes and consequences of metabolic alterations and heterogeneity
2.1 Oncogenic activation
2.2 Stresses in tumor microenvironment
2.3 Tumor-stroma cross-talk
2.4 Links between pH control and metabolism
3 Carbonic anhydrase IX and its role in tumor metabolism
3.1 CA IX essentials
3.2 CA IX and metabolic reprogramming
3.3 CA IX as a surrogate marker of hypoxia, acidosis, and glycolytic metabolism
4 Challenges for characterizing metabolic heterogeneity in tumor tissues
4.1 Quality of antibodies
4.2 Identification of antibodies and data presentation
Brain | ||||||
Study | Antibody | Tissue | IHC staining | RI | HR (95% CI)/endpoint | NOS |
Dungwa, 2012 [102] | M75 ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ | 5 | 1.71 (0.80–3.65)/OS 1.73 (0.83–3.59)/PFS | 7 |
Korkolopoulou, 2007 [103] | M75 ✶ ✶R | T/TMA≧3 ✶ | ✶ ✶ ✶ | 6* | 4.04 (2.38–6.85)/OS | 6 |
Ameis, 2015 [104] | M75 ✶ ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ | 6 | 15.7 (2.04–121.1)/OS | 5 |
Jarvela, 2008 [105] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ | 5 | 2.98 (1.67–5.30)/OS | 5 |
Nordfors, 2010 [106] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ | 5 | 3.96 (1.20–13.0)/OS | 4 |
Haapasalo, 2006 [107] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 6 | 1.40 (1.01–1.94)/0S | 3 |
Erpolat, 2013 [108] | Abcam ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 6 | 2.34 (1.47–3.71)/OS | 5 |
Proescholdt, 2012 [109] | Novus ✶ ✶ | B/TMA < 3 | R | 2* | 3.67 (2.03–6.61)/OS | 6 |
Yoo, 2010 [110] | Novus ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ | 5 | 2.27 (1.29–4.00)/OS | 4 |
Abraham, 2012 [111] | †Santa Cruz ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 6 | 1.59 (0.35–7.15)/OS 1.65 (0.50–5.48)/PFS | 5 |
Abraham, 2012 [111] | †Santa Cruz ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 6 | 0.19 (0.02–1.61)/OS 0.47 (0.06–3.69)/PFS | 5 |
Jensen, 2012 [112] | †Santa Cruz ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 6 | 1.10 (0.62–1.95)/OS 1.31 (0.64–2.66)/PFS | 4 |
Sooman, 2015 [113] | Strategic Diagnostics ✶ ✶ ✶ | B/TMA < 3 | R | 3* | 3.35 (1.55–7.22)/OS | 4 |
Flynn, 2008 [114] | ? | T/TMA≧3 ✶ | ✶ ✶ ✶ | 4 | 1.19 (0.70–2.03)/OS | 4 |
Preuser, 2005 [115] | ? | T/TMA≧3 ✶ | ✶ ✶ | 3 | Inadequate data/OS | - |
Pancreas | ||||||
Study | Antibody | Tissue | IHC staining | RI | HR (95% CI)/endpoint | NOS |
Couvelard, 2005 [116] | M75 ✶ a | T/TMA≧3 ✶ | ✶ ✶ ✶ | 5 | 35.3 (10.3–121)/OS | 7 |
Couvelard, 2005 [117] | M75 ✶ a | T/TMA≧3 ✶ | ✶ ✶ ✶ | 5 | 1.86 (0.90–3.84)/OS | 7 |
Chang, 2010 [118] | M75 ✶ ✶ R | T/TMA≧3 ✶ | ✶ ✶ | 5* | 0.99 (0.54–1.80)/OS | 4 |
Hiraoka, 2010 [119] | M75 ✶ ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 7 | 1.33 (0.97–1.84)/DFS 1.49 (1.07–2.07)/DSS | 3 |
Li, 2016 [120] | Abcam ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 6 | 2.24 (1.26–3.96)/OS | 7 |
Schmitt, 2009 [121] | Abcam ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 6 | 7.36 (3.11–17.4)/DFS | 3 |
Yu, 2015 [122] | Epitomics ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 6 | 1.07 (0.63–1.81)/OS | 6 |
Breast | ||||||
Study | Antibody | Tissue | IHC staining | RI | HR (95% CI)/endpoint | NOS |
Trastour, 2007 [123] | M75 ✶ ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ | 6 | Inadequate data/OS 2.57 (1.39–4.77)/DFS 2.70 (1.20–6.10)/MFS | 7 |
Hussain, 2007 [124] | M75 ✶ ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 7 | 2.63 (1.21–5.70)/OS | 6 |
Betof, 2012 [125] | M75 ✶ ✶a | B/TMA < 3 | ✶ ✶ ✶ | 5 | 2.20 (1.10–4.41)/OS 1.88 (1.13–3.13)/PFS | 5 |
Aomatsu, 2014 [126] | M75 ✶ ✶a | T/TMA≧3 ✶ | ✶ ✶ | 5 | 4.44 (1.80–10.9)/DFS | 4 |
Lou, 2011 [127] | M75 ✶ ✶R | B/TMA < 3 | ✶R | 3** | 1.93 (1.65–2.26)/DFS 2.28 (1.89–2.73)/DSS 2.06 (1.74–2.43)/MFS | 4 |
Tan, 2009 [128] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ | 5 | 5.02 (3.01–8.38)/OS 1.89 (1.19–3.00)/DFS | 4 |
Brennan, 2006 [129] | M75 ✶ ✶a | B/TMA < 3 | ✶ ✶ ✶ | 5 | 1.91 (1.12–3.26)/OS 1.99 (1.30–3.05)/DFS 1.85 (1.19–2.87)/DSS | 3 |
Generali, 2006 [130] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 6 | 1.93 (0.86–4.33)/OS 1.67 (0.89–3.14)/DFS | 3 |
Kyndi, 2008 [131] | M75 ✶ ✶R | B/TMA < 3 | ✶ ✶ ✶ | 5* | 1.30 (1.06–1.60)/OS 1.28 (0.82–2.01)/LC 1.29 (1.02–1.62)/DSS 1.23 (0.98–1.54)/MFS | 3 |
Neumeister, 2012 [132] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 6 | 2.21 (1.20–4.09)/DSS | 3 |
Neumeister, 2012 [132] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 6 | 1.36 (0.75–2.47)/DSS | 3 |
Tomes, 2003 [88] | M75 ✶ ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 7 | 0.78 (0.31–1.94)/OS | 2 |
Doyen, 2014 [133] | M75 ✶ ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ | 6 | Inadequate data/MFS | - |
Pinheiro, 2011 [134] | Abcam ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 6 | 2.22 (0.79–6.20)/DFS | 7 |
Garcia, 2007 [135] | Abcam ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ | 5 | 1.55 (1.19–2.01)/OS | 4 |
Bane, 2014 [136] | Abcam ✶ ✶ | T/TMA≧3 ✶ | ✶ | 4 | 1.53 (0.84–2.77)/LC | 4 |
Kim H, 2014 [137] | Abcam ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 5 | 1.43 (0.80–2.56)/OS | 4 |
Lancashire, 2010 [138] | Abcam ✶ ✶ ✶ | B/TMA < 3 T/TMA≧3 ✶ | ✶ ✶ ✶ | 6* | Inadequate data/OS 2.19 (0.78–6.16)/DFS | 3 |
Kornegoor, 2012 [139] | Abcam ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 6 | 0.62 (0.19–2.11)/OS | 3 |
Noh, 2014 [140] | Abcam ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 5 | Inadequate data/OS inadequate data/DFS | - |
Currie, 2013 [141] | Novus ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 6 | 1.05 (0.48–2.26)/OS 0.77 (0.39–1.55)/DFS | 6 |
Deb, 2014 [142] | Novus ✶ ✶ | B/TMA < 3 | ✶ ✶ | 4 | 2.20 (0.80–5.70)/OS | 3 |
Beketic-Oreskovic, 2011 [143] | †Santa Cruz ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 6 | 4.78 (2.15–10.6)/OS | 7 |
Kaya, 2012 [144] | †Santa Cruz ✶ ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 7 | 2.82 (1.71–4.64)/OS 0.84 (0.53–1.33)/DFS | 5 |
Head and neck | ||||||
Study | Reproducibility index | HR (95% CI)/endpoint | NOS | |||
Antibody | Tissue | IHC staining | RI | |||
Silva, 2010 [145] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 6 | 5.21 (2.48–10.9)/LC 5.08 (2.53–10.2)/DSS | 7 |
Hui, 2002 [87] | M75 ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 5 | 1.39 (0.64–3.01)/OS 1.28 (0.65–2.52)/PFS | 6 |
Koukourakis, 2001 [146] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ | 5 | 2.47 (1.23–4.98)/OS 3.05 (1.46–6.35)/LC | 6 |
Koukourakis, 2006 [147] | M75 ✶ ✶ | B/TMA < 3 | ✶ ✶ | 4 | 1.79 (1.21–2.64)/OS 1.84 (1.24–2.75)/LC | 6 |
Bernstein, 2015 [148] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 6 | 1.67 (0.77–3.61)/LC 2.31 (1.04–5.12)DSS | 5 |
Choi, 2008 [149] | M75 ✶ ✶ ✶ | T/TMA≧3 | ✶ ✶ | 6 | 1.91 (0.77–4.71)/OS | 5 |
De Schutter, 2005 [150] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 6 | 1.68 (0.94–2.99)/DFS 1.72 (0.94–3.14)/LC | 5 |
Douglas, 2013 [151] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 6 | 1.76 (0.87–3.56)/LC | 5 |
Heo, 2012 [152] | M75 ✶ ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ | 6 | 4.95 (1.39–17.5)/DFS | 5 |
Kim S, 2007 [153] | M75 ✶ ✶a | T/TMA≧3 ✶ | ✶ ✶ ✶ | 6 | 2.99 (1.39–6.45)/OS 1.76 (0.89–3.51)/DFS | 5 |
Perez-Sayans, 2012 [154] | M75 ✶ ✶ ✶ | B/TMA < 3 | ✶ ✶ ✶ | 6 | 1.36 (0.43–4.26)/OS | 4 |
Wachters, 2013 [155] | M75 ✶ ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ | 6 | 0.83 (0.31–2.22)/OS 0.34 (0.04–2.58)/LC | 4 |
Eriksen, 2007 [156] | M75 ✶ ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ ✶ | 7 | 1.10 (0.74–1.64)/LC | 3 |
Le, 2005 [157] | M75 ✶ ✶R | B/TMA < 3 | ✶ R | 3** | 1.73 (0.91–3.29)/OS 2.21 (1.11–4.39)/DFS | 3 |
Nordsmark, 2007 [158] | M75 ✶ ✶a | T/TMA≧3 ✶ | ✶ ✶ | 5 | 1.27 (0.62–2.62)/LC | 2 |
Winter, 2006 [159] | M75 ✶ ✶R | B/TMA < 3 | ✶ ✶ ✶ | 5* | Inadequate data/OS inadequate data/DFS inadequate data/DSS | - |
Koukourakis, 2008 [160] | Abcam ✶ ✶ | T/TMA≧3 ✶ B/TMA < 3 | ✶ ✶ | 4* | 1.64 (0.62–4.32)/OS 4.41 (1.72–11.3)/LC | 5 |
Kondo, 2011 [161] | Abcam ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ | 5 | 3.36 (0.97–11.7)/OS | 4 |
Brockton, 2011 [162] | Abcam ✶ ✶ | T/TMA≧3 ✶ | ✶ ✶ | 5 | 1.20 (0.46–3.12)/OS | 4 |
Brockton, 2012 [163] | Abcam ✶ ✶ ✶ M75 ✶ ✶a | T/TMA≧3 ✶ | ✶ ✶ ✶ | 7 | 2.04 (0.76–5.49)/DSS | 3 |
Zheng, 2015 [164] | Cell Signaling ✶ | B/TMA < 3 | ✶ ✶ | 3 | 4.27 (2.37–7.72)/OS | 4 |
Sakata, 2008 [165] | Novus ✶ | B/TMA < 3 | R | 1* | 0.91 (0.32–2.61)/LC | 7 |
Chen, 2014 [166] | Novus ✶ ✶ | B/TMA < 3 | ✶ ✶ | 4 | 1.97 (1.02–3.81)/OS 1.96 (1.01–3.78)/LC 1.96 (1.02–3.76)/MFS 2.01 (1.05–3.86)/PFS | 6 |
Hwa, 2015 [167] | Novus ✶ ✶ | B/TMA < 3 | ✶ ✶ | 4 | 0.29 (0.05–1.77)/DSS | 4 |
Kwon, 2015 [168] | Novus ✶ ✶ | B/TMA < 3 | ✶ ✶ | 4 | 8.65 (1.01–74.1)/LC | 4 |
Han, 2012 [169] | R&D Systems ✶ ✶ ✶ | B/TMA < 3 | ✶ | 4 | 0.65 (0.12–3.67)/OS 0.50 (0.80–3.15)/DFS | 6 |
Roh, 2008 [170] | R&D Systems ✶ ✶ ✶ | B/TMA < 3 | - | 3 | 0.71 (0.23–2.22)/OS 1.77 (0.56–5.56)/DFS 1.20 (0.34–4.18)/LC | 5 |
Roh, 2009 [171] | R&D Systems ✶ ✶ ✶ | B/TMA < 3 | - | 3 | 1.09 (0.43–2.76)/LC 2.13 (0.74–6.13)/DSS | 4 |
Yang, 2015 [172] | †Santa Cruz ✶ ✶ | B/TMA < 3 | ✶ ✶ | 4 | 1.76 (1.07–2.87)/OS | 7 |
Eckert, 2010 [173] | †Santa Cruz ✶ ✶ ✶ | B/TMA < 3 | ✶ | 4 | 1.34 (0.65–2.76)/OS | 5 |
Jonathan, 2006 [174] | ? | B/TMA < 3 | ✶ ✶ | 2 | 0.27 (0.08–0.93)/LC 0.27 (0.09–0.83)/MFS | 2 |
Rademakers, 2013 [175] | ? | B/TMA < 3 | ✶ ✶ | 2 | 0.70 (0.50–1.10)/OS 0.50 (0.20–1.10)/LC 0.70 (0.40–1.50)/MFS | 1 |