Top

Published in:

01-06-2019 | Solid Tumor

Acidosis and cancer: from mechanism to neutralization

Authors: Arig Ibrahim-Hashim, Veronica Estrella

Published in: Cancer and Metastasis Reviews | Issue 1-2/2019

Abstract

The extracellular pH of solid tumors is unequivocally acidic due to a combination of high rates of lactic acid production (a consequence of fermentative glycolytic metabolism) and poor perfusion. This has been documented by us and others in a wide variety of solid tumor models, primarily using magnetic resonance spectroscopic imaging (MRSI). This acidity contributes to tumor progression by inducing genome instability, promoting local invasion and metastases, inhibiting anti-tumor immunity, and conferring resistance to chemo- and radio-therapies. Systemic buffer therapies can neutralize tumor acidity and has been shown to inhibit local invasion and metastasis and improve immune surveillance in a variety of cancer model systems. This review will revisit the causes and consequences of acidosis by summarizing strategies used by cancer cells to adapt to acidosis, and how this acidity associated with carcinogenesis, metastasis, and immune function. Finally, this review will discuss how neutralization of acidity can be used to inhibit carcinogenesis and metastasis and improve anti-cancer immunotherapy.

Gillies, R. J., Liu, Z., & Bhujwalla, Z. (1994). 31P-MRS measurements of extracellular pH of tumors using 3-aminopropylphosphonate. The American Journal of Physiology, 267(1 Pt 1), C195–C203. https://doi.org/10.1152/ajpcell.1994.267.1.C195.CrossRefPubMed

Zhang, X., Lin, Y., & Gillies, R. J. (2010). Tumor pH and its measurement. Journal of Nuclear Medicine, 51(8), 1167–1170. https://doi.org/10.2967/jnumed.109.068981.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

Mizushima, N., & Klionsky, D. J. (2007). Protein turnover via autophagy: implications for metabolism. Annual Review of Nutrition, 27, 19–40. https://doi.org/10.1146/annurev.nutr.27.061406.093749.CrossRefPubMed

Marino, M. L., Pellegrini, P., Di Lernia, G., Djavaheri-Mergny, M., Brnjic, S., Zhang, X., Hagg, M., Linder, S., Fais, S., Codogno, P., & De Milito, A. (2012). Autophagy is a protective mechanism for human melanoma cells under acidic stress. The Journal of Biological Chemistry, 287(36), 30664–30676.CrossRef

Wojtkowiak, J. W., Rothberg, J. M., Kumar, V., Schramm, K. J., Haller, E., Proemsey, J. B., Lloyd, M. C., Sloane, B. F., & Gillies, R. J. (2012). Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments. Cancer Research, 72(16), 3938–3947. https://doi.org/10.1158/0008-5472.CAN-11-3881.CrossRefPubMedPubMedCentral

Wojtkowiak, J. W., & Gillies, R. J. (2012). Autophagy on acid. Autophagy., 8(11), 1688–1689. https://doi.org/10.4161/auto.21501.CrossRefPubMedPubMedCentral

Pellegrini, P., Strambi, A., Zipoli, C., Hagg-Olofsson, M., Buoncervello, M., Linder, S., & De Milito, A. (2014). Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies. Autophagy, 10(4), 562–571. https://doi.org/10.4161/auto.27901.CrossRefPubMedPubMedCentral

Sousa, C. M., Biancur, D. E., Wang, X., Halbrook, C. J., Sherman, M. H., Zhang, L., Kremer, D., Hwang, R. F., Witkiewicz, A. K., Ying, H., Asara, J. M., Evans, R. M., Cantley, L. C., Lyssiotis, C. A., & Kimmelman, A. C. (2016). Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature., 536(7617), 479–483. https://doi.org/10.1038/nature19084.CrossRefPubMedPubMedCentral

10.

Johnson, D. E., Ostrowski, P., Jaumouille, V., & Grinstein, S. (2016). The position of lysosomes within the cell determines their luminal pH. The Journal of Cell Biology, 212(6), 677–692. https://doi.org/10.1083/jcb.201507112.CrossRefPubMedPubMedCentral

11.

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.CrossRef

12.

Rozhin, J., Sameni, M., Ziegler, G., & Sloane, B. F. (1994). Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Research, 54(24), 6517–6525.PubMed

13.

Steffan, J. J., Snider, J. L., Skalli, O., Welbourne, T., & Cardelli, J. A. (2009). Na+/H+ exchangers and RhoA regulate acidic extracellular pH-induced lysosome trafficking in prostate cancer cells. Traffic (Copenhagen, Denmark), 10(6), 737–753. https://doi.org/10.1111/j.1600-0854.2009.00904.x. CrossRef

14.

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.CrossRefPubMedPubMedCentral

15.

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(32), 4538–4550. https://doi.org/10.1038/onc.2017.71.CrossRefPubMedPubMedCentral

16.

Li, L., Wang, W., Zhang, R., Liu, J., Yu, J., Wu, X., Xu, Y., Ma, M., & Huang, J. (2017). High expression of LAMP2 predicts poor prognosis in patients with esophageal squamous cell carcinoma. Cancer Biomarkers, 19, 305–311. https://doi.org/10.3233/CBM-160469.CrossRefPubMed

17.

Walton ZE, Patel CH, Brooks RC, Yu Y, Ibrahim-Hashim A, Gillies RJ, Powell JD, Dang CV. Acid suspends the circadian clock in hypoxia through inhibition of mTOR. Cell. 2018;(in press), 174, 72, 87.e32.

18.

Delikatny, E. J., Chawla, S., Leung, D. J., & Poptani, H. (2011). MR-visible lipids and the tumor microenvironment. NMR in Biomedicine, 24(6), 592–611. https://doi.org/10.1002/nbm.1661.CrossRefPubMedPubMedCentral

19.

Pillai, S., Wojtkowiak, J. W., Damaghi, M., Gatenby, R., & Gillies, R. (2017). Abstract 3538: Enhanced dependence on lipid metabolism is a cellular adaptation to acidic microenvironment. Cancer Research, 77(13 Supplement), 3538. https://doi.org/10.1158/1538-7445.am2017-3538.CrossRef

20.

Tirinato, L., Pagliari, F., Limongi, T., Marini, M., Falqui, A., Seco, J., Candeloro, P., Liberale, C., & Di Fabrizio, E. (2017). An overview of lipid droplets in cancer and cancer stem cells. Stem Cells International, 2017, 1656053. https://doi.org/10.1155/2017/1656053.CrossRefPubMedPubMedCentral

21.

Krahmer, N., Farese, R. V., Jr., & Walther, T. C. (2013). Balancing the fat: lipid droplets and human disease. EMBO Molecular Medicine, 5(7), 973–983. https://doi.org/10.1002/emmm.201100671.CrossRefPubMed

22.

Carr, R. M., & Ahima, R. S. (2016). Pathophysiology of lipid droplet proteins in liver diseases. Experimental Cell Research, 340(2), 187–192. https://doi.org/10.1016/j.yexcr.2015.10.021.CrossRefPubMed

23.

Wallstab, C., Eleftheriadou, D., Schulz, T., Damm, G., Seehofer, D., Borlak, J., Holzhutter, H. G., & Berndt, N. (2017). A unifying mathematical model of lipid droplet metabolism reveals key molecular players in the development of hepatic steatosis. The FEBS Journal, 284(19), 3245–3261. https://doi.org/10.1111/febs.14189.CrossRefPubMed

24.

Antalis, C. J., Uchida, A., Buhman, K. K., & Siddiqui, R. A. (2011). Migration of MDA-MB-231 breast cancer cells depends on the availability of exogenous lipids and cholesterol esterification. Clinical & Experimental Metastasis, 28(8), 733–741. https://doi.org/10.1007/s10585-011-9405-9.CrossRef

25.

Persi, E., Duran-Firgola, M., Damaghi, M., Roush, W. R., Aloy, P., Cleveland, J. L., Gillies, R. J., & Ruppin, E. (2018). Systems analysis of intracellular pH vulnerabilities for cancer therapy. Nature Communications (in press).

26.

Gatenby, R. A., & Gillies, R. J. (2004). Why do cancers have high aerobic glycolysis? Nature Reviews Cancer., 4(11), 891–899. https://doi.org/10.1038/nrc1478.CrossRefPubMed

27.

Wykoff, C. C., Beasley, N., Watson, P. H., Campo, L., Chia, S. K., English, R., Pastorek, J., Sly, W. S., Ratcliffe, P., & Harris, A. L. (2001). Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast. The American Journal of Pathology, 158(3), 1011–1019. https://doi.org/10.1016/S0002-9440(10)64048-5.CrossRefPubMedPubMedCentral

28.

Gillies, R. J., & Gatenby, R. A. (2007). Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? Journal of Bioenergetics and Biomembranes, 39(3), 251–257. https://doi.org/10.1007/s10863-007-9085-y.CrossRefPubMed

29.

Gillies, R. J., Verduzco, D., & Gatenby, R. A. (2012). Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nature Reviews Cancer, 12(7), 487–493. https://doi.org/10.1038/nrc3298.CrossRefPubMedPubMedCentral

30.

Gatenby, R. A., & Gillies, R. J. (2008). A microenvironmental model of carcinogenesis. Nature reviews Cancer, 8(1), 56–61. https://doi.org/10.1038/nrc2255.CrossRefPubMed

31.

Gillies, R. J., Brown, J. S., Anderson, A. R. A., & Gatenby, R. A. (2018). Eco-evolutionary causes and consequences of temporal changes in intratumoural blood flow. Nature Reviews Cancer, 18, 576–585. https://doi.org/10.1038/s41568-018-0030-7.CrossRefPubMedPubMedCentral

32.

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.CrossRef

33.

Avnet, S., Di Pompo, G., Chano, T., Errani, C., Ibrahim-Hashim, A., Gillies, R. J., Donati, D. M., & Baldini, N. (2017). Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-kappaB activation. International Journal of Cancer, 140(6), 1331–1345. https://doi.org/10.1002/ijc.30540.CrossRefPubMedPubMedCentral

34.

Tafreshi, N. K., Bui, M. M., Bishop, K., Lloyd, M. C., Enkemann, S. A., Lopez, A. S., Abrahams, D., Carter, B. W., Vagner, J., Grobmyer, S. R., Gillies, R. J., & Morse, D. L. (2012). Noninvasive detection of breast cancer lymph node metastasis using carbonic anhydrases IX and XII targeted imaging probes. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 18(1), 207–219. https://doi.org/10.1158/1078-0432.CCR-11-0238.CrossRef

35.

Tafreshi, N. K., Lloyd, M., Bui, M., Gillies, R. J., & Morse, D. (2013). Carbonic Anhydrase IX as an Imaging and Therapeutic Target for Tumors and Metastases. In S. Frost & R. McKenna (Eds.), Carbonic Anhydrases.

36.

Lloyd, M. C., Alfarouk, K. O., Verduzco, D., Bui, M. M., Gillies, R. J., Ibrahim, M. E., Brown, J. S., & Gatenby, R. A. (2014). Vascular measurements correlate with estrogen receptor status. BMC Cancer, 14(1), 279. https://doi.org/10.1186/1471-2407-14-279.CrossRefPubMedPubMedCentral

37.

Lloyd, M. C., Cunningham, J. J., Bui, M. M., Gillies, R. J., Brown, J. S., & Gatenby, R. A. (2016). Darwinian dynamics of intratumoral heterogeneity: not solely random mutations but also variable environmental selection forces. Cancer Research, 76(11), 3136–3144. https://doi.org/10.1158/0008-5472.CAN-15-2962.CrossRefPubMedPubMedCentral

38.

Tafreshi, N. K., Lloyd, M. C., Bui, M. M., Gillies, R. J., & Morse, D. L. (2014). Carbonic anhydrase IX as an imaging and therapeutic target for tumors and metastases. Sub-cellular biochemistry, 75, 221–254. https://doi.org/10.1007/978-94-007-7359-2_12.CrossRefPubMedPubMedCentral

39.

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.CrossRefPubMedPubMedCentral

40.

Gerlinger, M., Rowan, A. J., Horswell, S., Math, M., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., Varela, I., Phillimore, B., Begum, S., McDonald, N. Q., Butler, A., Jones, D., Raine, K., Latimer, C., Santos, C. R., Nohadani, M., Eklund, A. C., Spencer-Dene, B., Clark, G., Pickering, L., Stamp, G., Gore, M., Szallasi, Z., Downward, J., Futreal, P. A., & Swanton, C. (2012). Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England Journal of Medicine, 366(10), 883–892. https://doi.org/10.1056/NEJMoa1113205.CrossRefPubMedPubMedCentral

41.

van Sluis, R., Bhujwalla, Z. M., Raghunand, N., Ballesteros, P., Alvarez, J., Cerdan, S., Galons, J. P., & Gillies, R. J. (1999). In vivo imaging of extracellular pH using 1H MRSI. Magnetic Resonance in Medicine, 41(4), 743–750.CrossRef

42.

O'Connor, J. P., Rose, C. J., Waterton, J. C., Carano, R. A., Parker, G. J., & Jackson, A. (2015). Imaging intratumor heterogeneity: role in therapy response, resistance, and clinical outcome. Clinical Cancer Research, 21(2), 249–257. https://doi.org/10.1158/1078-0432.CCR-14-0990.CrossRefPubMed

43.

Wu, J., Cao, G., Sun, X., Lee, J., Rubin, D. L., Napel, S., Kurian, A. W., Daniel, B. L., & Li, R. (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. https://doi.org/10.1148/radiol.2018172462.CrossRefPubMedPubMedCentral

44.

Grove, O., Berglund, A. E., Schabath, M. B., Aerts, H. J., Dekker, A., Wang, H., Velazquez, E. R., Lambin, P., Gu, Y., Balagurunathan, Y., Eikman, E., Gatenby, R. A., Eschrich, S., & Gillies, R. J. (2015). Quantitative computed tomographic descriptors associate tumor shape complexity and intratumor heterogeneity with prognosis in lung adenocarcinoma. PLoS One, 10(3), e0118261. https://doi.org/10.1371/journal.pone.0118261.CrossRefPubMedPubMedCentral

45.

Beig, N., Khorrami, M., Alilou, M., Prasanna, P., Braman, N., Orooji, M., Rakshit, S., Bera, K., Rajiah, P., Ginsberg, J., Donatelli, C., Thawani, R., Yang, M., Jacono, F., Tiwari, P., Velcheti, V., Gilkeson, R., Linden, P., & Madabhushi, A. (2018). Perinodular and intranodular radiomic features on lung CT images distinguish adenocarcinomas from granulomas. Radiology, 180910. https://doi.org/10.1148/radiol.2018180910.

46.

Gatenby, R. A., Grove, O., & Gillies, R. J. (2013). Quantitative imaging in cancer evolution and ecology. Radiology, 269(1), 8–15. https://doi.org/10.1148/radiol.13122697.CrossRefPubMedPubMedCentral

47.

Gillies, R. J., Kinahan, P. E., & Hricak, H. (2016). Radiomics: images are more than pictures, they are data. Radiology, 278(2), 563–577. https://doi.org/10.1148/radiol.2015151169.CrossRefPubMed

48.

Farhidzadeh, H., Chaudhury, B., Scott, J. G., Goldgof, D., Hall, L. O., Gatenby, R. A., Gillies, R. J., & Raghavan, M. (2016). Signal intensity analysis of ecological defined habitat in soft tissue sarcomas to predict metastasis development. SPIE Medial Imaging, 2016. https://doi.org/10.1117/12.2216961.

49.

Stoyanova, R., Pollack, A., Takhar, M., Lynne, C., Parra, N., Lam, L. L., Alshalalfa, M., Buerki, C., Castillo, R., Jorda, M., Ashab, H. A., Kryvenko, O. N., Punnen, S., Parekh, D. J., Abramowitz, M. C., Gillies, R. J., Davicioni, E., Erho, N., & Ishkanian, A. (2016). Association of multiparametric MRI quantitative imaging features with prostate cancer gene expression in MRI-targeted prostate biopsies. Oncotarget, 7, 53362–53376. https://doi.org/10.18632/oncotarget.10523.CrossRefPubMedPubMedCentral

50.

Aerts, H. J., Velazquez, E. R., Leijenaar, R. T., Parmar, C., Grossmann, P., Cavalho, S., Bussink, J., Monshouwer, R., Haibe-Kains, B., Rietveld, D., Hoebers, F., Rietbergen, M. M., Leemans, C. R., Dekker, A., Quackenbush, J., Gillies, R. J., & Lambin, P. (2014). Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nature Communications, 5, 4006. https://doi.org/10.1038/ncomms5006.CrossRefPubMedPubMedCentral

51.

Damgaci, S., Ibrahim-Hashim, A., Enriquez-Navas, P. M., Pilon-Thomas, S., Guvenis, A., & Gillies, R. J. (2018). Hypoxia and acidosis: immune suppressors and therapeutic targets. Immunology, 154(3), 354–362. https://doi.org/10.1111/imm.12917.CrossRefPubMedPubMedCentral

52.

Lardner, A. (2001). The effects of extracellular pH on immune function. Journal of Leukocyte Biology, 69(4), 522–530.PubMed

53.

Huber, V., Camisaschi, C., Berzi, A., Ferro, S., Lugini, L., Triulzi, T., Tuccitto, A., Tagliabue, E., Castelli, C., & Rivoltini, L. (2017). Cancer acidity: an ultimate frontier of tumor immune escape and a novel target of immunomodulation. Seminars in Cancer Biology, 43, 74–89. https://doi.org/10.1016/j.semcancer.2017.03.001.CrossRefPubMed

54.

Husain, Z., Huang, Y. N., Seth, P., & Sukhatme, V. P. (2013). Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. Journal of Immunology, 191(3), 1486–1495. https://doi.org/10.4049/jimmunol.1202702.CrossRef

55.

Pilon-Thomas, S., Kodumudi, K. N., El-Kenawi, A. E., Russell, S., Weber, A. M., Luddy, K., Damaghi, M., Wojtkowiak, J. W., Mule, J. J., Ibrahim-Hashim, A., & Gillies, R. J. (2016). Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Research, 76(6), 1381–1390. https://doi.org/10.1158/0008-5472.CAN-15-1743.CrossRefPubMed

56.

Calcinotto, A., Filipazzi, P., Grioni, M., Iero, M., De Milito, A., Ricupito, A., Cova, A., Canese, R., Jachetti, E., Rossetti, M., Huber, V., Parmiani, G., Generoso, L., Santinami, M., Borghi, M., Fais, S., Bellone, M., & Rivoltini, L. (2012). Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Research, 72(11), 2746–2756. https://doi.org/10.1158/0008-5472.CAN-11-1272.CrossRefPubMed

57.

Damaghi, M., Wojtkowiak, J. W., & Gillies, R. J. (2013). pH sensing and regulation in cancer. Frontiers in Physiology, 4, 370. https://doi.org/10.3389/fphys.2013.00370.CrossRefPubMedPubMedCentral

58.

Tong, J., Wu, W. N., Kong, X., Wu, P. F., Tian, L., Du, W., Fang, M., Zheng, F., Chen, J. G., Tan, Z., & Gong, F. (2011). Acid-sensing ion channels contribute to the effect of acidosis on the function of dendritic cells. Journal of Immunology, 186(6), 3686–3692. https://doi.org/10.4049/jimmunol.1001346.CrossRef

59.

Mahoney, B. P., Raghunand, N., Baggett, B., & Gillies, R. J. (2003). Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro. Biochemical Pharmacology, 66(7), 1207–1218.CrossRef

60.

Raghunand, N., Mahoney, B. P., & Gillies, R. J. (2003). Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. Biochemical Pharmacology, 66(7), 1219–1229.CrossRef

61.

Robey, I. F., Baggett, B. K., Kirkpatrick, N. D., Roe, D. J., Dosescu, J., Sloane, B. F., Hashim, A. I., Morse, D. L., Raghunand, N., Gatenby, R. A., & Gillies, R. J. (2009). Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Research, 69(6), 2260–2268. https://doi.org/10.1158/0008-5472.CAN-07-5575.CrossRefPubMedPubMedCentral

62.

Ibrahim Hashim, A., Cornnell, H. H., Coelho Ribeiro Mde, L., Abrahams, D., Cunningham, J., Lloyd, M., Martinez, G. V., Gatenby, R. A., & Gillies, R. J. (2011). Reduction of metastasis using a non-volatile buffer. Clinical & Experimental Metastasis, 28(8), 841–849. https://doi.org/10.1007/s10585-011-9415-7.CrossRef

63.

Ribeiro, M., Silva, A. S., Bailey, K., Kumar, N. B., Sellers, T. A., Gatenby, R. A., Ibrahim Hashim, A., & Gillies, R. J. (2012). Buffer therapy for cancer. Journal of Nutrition & Food Sciences, S2, 1–7.

64.

Ibrahim-Hashim, A., Cornnell, H. H., Abrahams, D., Lloyd, M., Bui, M., Gillies, R. J., & Gatenby, R. A. (2012). Systemic buffers inhibit carcinogenesis in TRAMP mice. The Journal of Urology, 188(2), 624–631. https://doi.org/10.1016/j.juro.2012.03.113.CrossRefPubMedPubMedCentral

65.

Ibrahim-Hashim, A., Robertson-Tessi, M., Enriquez-Navas, P. M., Damaghi, M., Balagurunathan, Y., Wojtkowiak, J. W., Russell, S., Yoonseok, K., Lloyd, M. C., Bui, M. M., Brown, J. S., Anderson, A. R. A., Gillies, R. J., & Gatenby, R. A. (2017). Defining cancer subpopulations by adaptive strategies rather than molecular properties provides novel insights into intratumoral evolution. Cancer Research, 77(9), 2242–2254. https://doi.org/10.1158/0008-5472.CAN-16-2844.CrossRefPubMedPubMedCentral

66.

Ibrahim-Hashim, A., Wojtkowiak, J. W., de Lourdes Coelho Ribeiro, M., Estrella, V., Bailey, K. M., Cornnell, H. H., Gatenby, R. A., & Gillies, R. J. (2011). Free base lysine increases survival and reduces metastasis in prostate cancer model. J Cancer Sci Ther, 4(Suppl 1).

67.

Ibrahim-Hashim, A., Abrahams, D., Enriquez-Navas, P. M., Luddy, K., Gatenby, R. A., & Gillies, R. J. (2017). Tris-base buffer: a promising new inhibitor for cancer progression and metastasis. Cancer Medicine, 6(7), 1720–1729. https://doi.org/10.1002/cam4.1032.CrossRefPubMedPubMedCentral

68.

Ibrahim Hashim, A., Zhang, X., Wojtkowiak, J. W., Martinez, G. V., & Gillies, R. J. (2011). Imaging pH and metastasis. NMR in Biomedicine, 24(6), 582–591. https://doi.org/10.1002/nbm.1644.CrossRef

69.

Bohme, I., & Bosserhoff, A. K. (2016). Acidic tumor microenvironment in human melanoma. Pigment Cell & Melanoma Research, 29, 508–523. https://doi.org/10.1111/pcmr.12495.CrossRef

70.

Pilon-Thomas, S., Kodumudi, K. N., El-Kenawi, A. E., Russell, S., Weber, A. M., Luddy, K., Damaghi, M., Wojtkowiak, J. W., Mule, J. J., Ibrahim-Hashim, A., & Gillies, R. J. (2015). Neutralization of tumor acidity improves antitumor responses to immunotherapeutic interventions. Cancer Research, 76, 1381–1390. https://doi.org/10.1158/0008-5472.CAN-15-1743. CrossRefPubMedPubMedCentral

71.

Pilot, C., Mahipal, A., & Gillies, R. J. (2018). Buffer Therapy-->Buffer Diet. K Nutr. Food Science, 8(2), 684–688.

72.

Tian, B., Wong, W. Y., Hegmann, E., Gaspar, K., Kumar, P., & Chao, H. (2015). Production and characterization of a camelid single domain antibody-urease enzyme conjugate for the treatment of cancer. Bioconjugate Chemistry, 26(6), 1144–1155. https://doi.org/10.1021/acs.bioconjchem.5b00237.CrossRefPubMed

Title: Acidosis and cancer: from mechanism to neutralization
Authors: Arig Ibrahim-Hashim
Veronica Estrella
Publication date: 01-06-2019
Publisher: Springer US
Keywords: Solid Tumor
Metastasis
Acidosis
Published in: Cancer and Metastasis Reviews / Issue 1-2/2019
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI: https://doi.org/10.1007/s10555-019-09787-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1-2/2019

Molecular and functional imaging insights into the role of hypoxia in cancer aggression

Cause and effect of microenvironmental acidosis on bone metastases

Acidosis promotes tumorigenesis by activating AKT/NF-κB signaling

The Warburg metabolism fuels tumor metastasis

It is not just the drugs that matter: the nocebo effect

Tumor pH and metastasis: a malignant process beyond hypoxia

Keynote webinar | Spotlight on antibody–drug conjugates in cancer