肿瘤微环境pH值差异与膀胱癌的相关性

doi:10.3760/cma.j.cn371439-20220507-00137

摘要/Abstract

摘要：

与正常组织相比，肿瘤细胞的胞外间质pH值偏酸性。肿瘤细胞表面跨细胞膜的反向pH梯度与其不受控制的进展、血管生成和转移密切相关。尿pH的变化通过调节膀胱癌细胞的微环境，对膀胱癌的发生、进展和治疗产生影响。相关研究显示，尿pH值是预测膀胱癌患者联合碱化剂治疗最终临床疗效的重要因素，有助于反映体内酸碱平衡和免疫防御系统。持续监测尿pH值可以为膀胱癌患者的预后提供指导和决策。

关键词: 膀胱肿瘤, pH, 肿瘤微环境, 治疗, 预后

Abstract:

Compared with normal tissue， interstitial extracellular pH of tumor cells is acidic. The reverse transmembrane pH gradient around tumor cells is closely related to its uncontrolled progression， angiogenesis and metastasis. Changes in urinary pH have an impact on the occurrence， progression and treatment of bladder cancer by regulating the microenvironment of bladder cancer cells. Relevant studies have shown that urinary pH value is an important factor in predicting the final clinical efficacy of bladder cancer patients combined with alkalization agents， which helps to reflect the acid-base balance and immune defense system in the body. Continuous monitoring of urinary pH can provide guidance and decision-making for the prognosis of bladder cancer patients.

Key words: Urinary bladder neoplasms, pH, Tumor microenvironment, Therapy, Prognosis

徐希, 高红亮, 刘翔, 张振声, 许传亮. 肿瘤微环境pH值差异与膀胱癌的相关性[J]. 国际肿瘤学杂志, 2022, 49(11): 696-609.

Xu Xi, Gao Hongliang, Liu Xiang, Zhang Zhensheng, Xu Chuanliang. Correlations between different pH values in tumor microenvironment and bladder cancer[J]. Journal of International Oncology, 2022, 49(11): 696-609.

参考文献 36

[1]	Teoh JY, Huang J, Ko WY, et al. Global trends of bladder cancer incidence and mortality, and their associations with tobacco use and gross domestic product per capita[J]. Eur Urol, 2020, 78(6): 893-906. DOI: 10.1016/j.eururo.2020.09.006. doi: 10.1016/j.eururo.2020.09.006
[2]	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016[J]. CA Cancer J Clin, 2016, 66(1): 7-30. DOI: 10.3322/caac.21332. doi: 10.3322/caac.21332
[3]	Lieske JC, Turner ST, Edeh SN, et al. Heritability of urinary traits that contribute to nephrolithiasis[J]. Clin J Am Soc Nephrol, 2014, 9(5): 943-950. DOI: 10.2215/CJN.08210813. doi: 10.2215/CJN.08210813
[4]	Asgharzadeh MR, Barar J, Pourseif MM, et al. Molecular machine-ries of pH dysregulation in tumor microenvironment: potential targets for cancer therapy[J]. Bioimpacts, 2017, 7(2): 115-133. DOI: 10.15171/bi.2017.15. doi: 10.15171/bi.2017.15 pmid: 28752076
[5]	Kamphuis GM, Wouter van Hattum J, de Bie P, et al. Method of alkalization and monitoring of urinary pH for prevention of recurrent uric acid urolithiasis: a systematic review[J]. Transl Androl Urol, 2019, 8(Suppl 4): S448-S456. DOI: 10.21037/tau.2019.05.01. doi: 10.21037/tau.2019.05.01
[6]	Heer F, Dobenecker B, Kienzle E. Effect of cation-anion balance in feed on urine pH in rabbits in comparison with other species[J]. J Anim Physiol Anim Nutr (Berl), 2017, 101(6): 1324-1330. DOI: 10.1111/jpn.12653. doi: 10.1111/jpn.12653
[7]	Böswald LF, Matzek D, Kienzle E, et al. Influence of strain and diet on urinary pH in laboratory mice[J]. Animals (Basel), 2021, 11(3): 702. DOI: 10.3390/ani11030702. doi: 10.3390/ani11030702
[8]	Worcester EM, Bergsland KJ, Gillen DL, et al. Mechanism for higher urine pH in normal women compared with men[J]. Am J Physiol Renal Physiol, 2018, 314(4): F623-F629. DOI: 10.1152/ajprenal.00494.2017. doi: 10.1152/ajprenal.00494.2017
[9]	Seisen T, Granger B, Colin P, et al. A systematic review and meta-analysis of clinicopathologic factors linked to intravesical recurrence after radical nephroureterectomy to treat upper tract urothelial carcinoma[J]. Eur Urol, 2015, 67(6): 1122-1133. DOI: 10.1016/j.eururo.2014.11.035. doi: S0302-2838(14)01218-4 pmid: 25488681
[10]	Tsai MJ, Chang WA, Huang MS, et al. Tumor microenvironment: a new treatment target for cancer[J]. ISRN Biochem, 2014, 2014: 351959. DOI: 10.1155/2014/351959. doi: 10.1155/2014/351959
[11]	Xie R, Wang H, Jin H, et al. NHE1 is upregulated in gastric cancer and regulates gastric cancer cell proliferation, migration and invasion[J]. Oncol Rep, 2017, 37(3): 1451-1460. DOI: 10.3892/or.2017.5386. doi: 10.3892/or.2017.5386 pmid: 28098891
[12]	Chan JCY, Diakos CI, Engel A, et al. Serum bicarbonate is a marker of peri-operative mortality but is not associated with long term survival in colorectal cancer[J]. PLoS One, 2020, 15(1): e0228466. DOI: 10.1371/journal.pone.0228466. doi: 10.1371/journal.pone.0228466
[13]	Hamaguchi R, Narui R, Wada H. Effects of alkalization therapy on chemotherapy outcomes in metastatic or recurrent pancreatic cancer[J]. Anticancer Res, 2020, 40(2): 873-880. DOI: 10.21873/anticanres.14020. doi: 10.21873/anticanres.14020 pmid: 32014931
[14]	Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy[J]. Cancer Res, 2016, 76(6): 1381-1390. DOI: 10.1158/0008-5472.CAN-15-1743. doi: 10.1158/0008-5472.CAN-15-1743 pmid: 26719539
[15]	Ibrahim-Hashim A, Estrella V. Acidosis and cancer: from mechanism to neutralization[J]. Cancer Metastasis Rev, 2019, 38(1/2):149-155. DOI: 10.1007/s10555-019-09787-4. doi: 10.1007/s10555-019-09787-4
[16]	Ando H, Emam SE, Kawaguchi Y, et al. Increasing tumor extracellular pH by an oral alkalinizing agent improves antitumor responses of anti-PD-1 antibody: implication of relationships between serum bicarbonate concentrations, urinary pH, and therapeutic outcomes[J]. Biol Pharm Bull, 2021, 44(6): 844-852. DOI: 10.1248/bpb.b21-00076. doi: 10.1248/bpb.b21-00076 pmid: 34078817
[17]	Calcinotto A, Filipazzi P, Grioni M, et al. Modulation of micro-environment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes[J]. Cancer Res, 2012, 72(11): 2746-2756. DOI: 10.1158/0008-5472.CAN-11-1272. doi: 10.1158/0008-5472.CAN-11-1272 pmid: 22593198
[18]	Kolosenko I, Avnet S, Baldini N, et al. Therapeutic implications of tumor interstitial acidification[J]. Semin Cancer Biol, 2017, 43: 119-133. DOI: 10.1016/j.semcancer.2017.01.008. doi: S1044-579X(17)30016-0 pmid: 28188829
[19]	Demirbas A, Sarici H, Kilinc MF, et al. The relationship between acidic urinary pH and overactive bladder; alkalization of urine improves the symptoms of overactive bladder[J]. Urol Int, 2015, 95(2): 223-226. DOI: 10.1159/000375322. doi: 10.1159/000375322 pmid: 25766740
[20]	Ceylan C, Doluoglu OG, Yahşi S. A different perspective: can urine pH be important in the diagnosis of prostate cancer?[J]. Urologia, 2020, 87(1): 19-22. DOI: 10.1177/0391560319865724. doi: 10.1177/0391560319865724 pmid: 31364489
[21]	Kondo A, Yamamoto S, Nakaki R, et al. Extracellular acidic pH activates the sterol regulatory element-binding protein 2 to promote tumor progression[J]. Cell Rep, 2017, 18(9): 2228-2242. DOI: 10.1016/j.celrep.2017.02.006. doi: S2211-1247(17)30171-7 pmid: 28249167
[22]	Xue L, Qi H, Zhang H, et al. Targeting SREBP-2-regulated mevalonate metabolism for cancer therapy[J]. Front Oncol, 2020, 10: 1510. DOI: 10.3389/fonc.2020.01510. doi: 10.3389/fonc.2020.01510 pmid: 32974183
[23]	Burgess EF, Livasy C, Trufan S, et al. Clinical outcomes asso-ciated with expression of aurora kinase and p53 family members in muscle-invasive bladder cancer[J]. Mol Clin Oncol, 2022, 16(5): 102. DOI: 10.3892/mco.2022.2535. doi: 10.3892/mco.2022.2535 pmid: 35463214
[24]	Andrade DL, Moretti TBC, Neto WA, et al. Smoke load prognostic impact on bacillus Calmette-Guérin (BCG) treated non-muscle invasive bladder cancer[J]. Int Urol Nephrol, 2020, 52(8): 1471-1476. DOI: 10.1007/s11255-020-02438-6. doi: 10.1007/s11255-020-02438-6 pmid: 32157620
[25]	Zhao X, Wang Y, Liang C. Cigarette smoking and risk of bladder cancer: a dose-response meta-analysis[J]. Int Urol Nephrol, 2022, 54(6): 1169-1185. DOI: 10.1007/s11255-022-03173-w. doi: 10.1007/s11255-022-03173-w
[26]	Alguacil J, Kogevinas M, Silverman DT, et al. Urinary pH, cigarette smoking and bladder cancer risk[J]. Carcinogenesis, 2011, 32(6): 843-847. DOI: 10.1093/carcin/bgr048. doi: 10.1093/carcin/bgr048 pmid: 21402590
[27]	Ide H, Kikuchi E, Ogihara K, et al. Urinary pH is an independent predictor of upper tract recurrence in non-muscle-invasive bladder cancer patients with a smoking history[J]. Sci Rep, 2021, 11(1): 20675. DOI: 10.1038/s41598-021-00184-y. doi: 10.1038/s41598-021-00184-y pmid: 34667220
[28]	Ogihara K, Kikuchi E, Yuge K, et al. Refraining from smoking for 15 years or more reduced the risk of tumor recurrence in non-muscle invasive bladder cancer patients[J]. Ann Surg Oncol, 2016, 23(5): 1752-1759. DOI: 10.1245/s10434-015-5016-z. doi: 10.1245/s10434-015-5016-z
[29]	Ide H, Kikuchi E, Hagiwara M, et al. Urinary pH levels are strongly associated with bladder recurrence after nephroureterectomy in upper tract urothelial carcinoma patients with a smoking history[J]. Ann Surg Oncol, 2016, 23(Suppl 5): 1029-1038. DOI: 10.1245/s10434-016-5555-y. doi: 10.1245/s10434-016-5555-y pmid: 27613550
[30]	González-Padilla DA, Subiela JD, González-Díaz A, et al. Mitomycin C allergy after passive and device-assisted hyperthermia for non-muscle invasive bladder cancer treatment: a retrospective cohort from a high-volume center[J]. Urol Oncol, 2022, 40(7): 345. e19-345.e23. DOI: 10.1016/j.urolonc.2022.02.018. doi: 10.1016/j.urolonc.2022.02.018
[31]	Maeda T, Kikuchi E, Matsumoto K, et al. Urinary pH is highly associated with tumor recurrence during intravesical mitomycin C therapy for nonmuscle invasive bladder tumor[J]. J Urol, 2011, 185(3): 802-806. DOI: 10.1016/j.juro.2010.10.081. doi: 10.1016/j.juro.2010.10.081 pmid: 21239010
[32]	Miyata Y, Tsurusaki T, Hayashida Y, et al. Intravesical mitomycin C (MMC) and MMC+ cytosine arabinoside for non-muscle-invasive bladder cancer: a randomised clinical trial[J]. BJU Int, 2022, 129(4): 534-541. DOI: 10.1111/bju.15571. doi: 10.1111/bju.15571
[33]	Seo HK, Kim SH, Ahn KO, et al. Recommended oral sodium bicarbonate administration for urine alkalinization did not affect the concentration of mitomycin-C in non-muscle invasive bladder cancer patients[J]. Oncotarget, 2017, 8(56): 96117-96125. DOI: 10.18632/oncotarget.21755. doi: 10.18632/oncotarget.21755 pmid: 29221191
[34]	Witjes JA, Palou J, Soloway M, et al. Current clinical practice gaps in the treatment of intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) with emphasis on the use of bacillus Calmette-Guérin (BCG): results of an international individual patient data survey (IPDS)[J]. BJU Int, 2013, 112(6): 742-750. DOI: 10.1111/bju.12012. doi: 10.1111/bju.12012 pmid: 23452187
[35]	Stone BV, Ayangbesan A, Taylor BL, et al. Urinary pH and the risk of recurrence in patients with non-muscle invasive bladder cancer[J]. Can J Urol, 2018, 25(4): 9407-9412. pmid: 30125520
[36]	周邓婧, 姚颐, 宋启斌, 等. 肿瘤细胞对肿瘤微环境的影响[J]. 国际肿瘤学杂志, 2021, 48(7): 424-428. DOI: 10.3760/cma.j.cn371439-20201216-00081. doi: 10.3760/cma.j.cn371439-20201216-00081