Hypoxia and anaerobic metabolism relate with immunologically cold breast cancer and poor prognosis.
Anaerobiosis
Biomarkers, Tumor
/ metabolism
Breast Neoplasms
/ genetics
Female
Humans
Hypoxia
/ metabolism
Isoenzymes
/ metabolism
Lactate Dehydrogenase 5
Lymphocytes, Tumor-Infiltrating
Neoplasm Recurrence, Local
/ genetics
Prognosis
Prospective Studies
Tertiary Lymphoid Structures
/ pathology
Triple Negative Breast Neoplasms
/ genetics
Tumor Microenvironment
Breast cancer
HIF1α
Immune response
LDH
Lymphocytes
Prognosis
Journal
Breast cancer research and treatment
ISSN: 1573-7217
Titre abrégé: Breast Cancer Res Treat
Pays: Netherlands
ID NLM: 8111104
Informations de publication
Date de publication:
Jul 2022
Jul 2022
Historique:
received:
20
01
2022
accepted:
13
04
2022
pubmed:
29
4
2022
medline:
9
6
2022
entrez:
28
4
2022
Statut:
ppublish
Résumé
Hypoxia-Inducible Factor HIF1α and lactate dehydrogenase LDHA drive anaerobic tumor metabolism and define clinical aggressiveness. We investigated their expression in breast cancer and their role in immune response and prognosis of breast cancer. Tissue material from 175 breast cancer patients treated in a prospective study were analyzed with immunohistochemistry for HIF1α and LDH5 expression, in parallel with the tumor-infiltrating lymphocyte TIL-density and tertiary lymphoid structure TLS-density. High LDH5 expression was noted in 48/175 tumors, and this was related to HIF1α overexpression (p < 0.0001), triple-negative TNBC histology (p = 0.01), poor disease-specific survival (p < 0.007), metastasis (p < 0.01), and locoregional recurrence (p = 0.03). High HIF1α expression, noted in 39/175 cases, was linked with low steroid receptor expression (p < 0.05), her2 overexpression (p = 0.01), poor survival (p < 0.04), and high metastasis rates (p < 0.004). High TIL-density in the invading tumor front (TILinv) was linked with low LDH5 and HIF expression (p < 0.0001) and better prognosis (p < 0.02). High TIL-density in inner tumor areas (TILinn) was significantly linked with TNBC. Multivariate analysis showed that PgR-status (p = 0.003, HR 2.99, 95% CI 1.4-6.0), TILinv (p = 0.02, HR 2.31, 95% CI 1.1-4.8), LDH5 (p = 0.01, HR 2.43, 95% CI 1.2-5.0), N-stage (p = 0.04, HR 2.42, 95% CI 1.0-5.8), T-stage (p = 0.04, HR 2.31, 95% CI 1.0-5.1), and her2 status (p = 0.05, HR 2.01, 95% CI 1.0-4.2) were independent variables defining death events. Overexpression of LDH5, an event directly related to HIF1α overexpression, characterizes a third of breast tumors, which is more frequent in TNBC. Both HIF1α and LDH5 define cold breast cancer microenvironment and poor prognosis. A rational is provided to study further whether metabolic manipulations targeting HIF and LDH5 may enhance the antitumor immune response in breast cancer.
Identifiants
pubmed: 35482128
doi: 10.1007/s10549-022-06609-0
pii: 10.1007/s10549-022-06609-0
doi:
Substances chimiques
Biomarkers, Tumor
0
Isoenzymes
0
Lactate Dehydrogenase 5
EC 1.1.1.27.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
13-23Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386. https://doi.org/10.1002/ijc.29210
doi: 10.1002/ijc.29210
pubmed: 25220842
Ali HR, Glont SE, Blows FM, Provenzano E, Dawson SJ, Liu B, Hiller L, Dunn J, Poole CJ, Bowden S, Earl HM, Pharoah PD, Caldas C (2015) PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Ann Oncol 26:1488–1493. https://doi.org/10.1093/annonc/mdv19
doi: 10.1093/annonc/mdv19
pubmed: 25897014
Dias AS, Almeida CR, Helguero LA, Duarte IF (2019) Metabolic crosstalk in the breast cancer microenvironment. Eur J Cancer 121:154–171. https://doi.org/10.1016/j.ejca.2019.09.002
doi: 10.1016/j.ejca.2019.09.002
pubmed: 31581056
Naik A, Decock J (2020) Lactate metabolism and immune modulation in breast cancer: a focused review on triple-negative breast tumors. Front Oncol 10:598626. https://doi.org/10.3389/fonc.2020.598626
doi: 10.3389/fonc.2020.598626
pubmed: 33324565
pmcid: 7725706
Semenza GL (2013) HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest 123:3664–3671. https://doi.org/10.1172/JCI67230
doi: 10.1172/JCI67230
pubmed: 23999440
pmcid: 3754249
Vaupel P, Schmidberger H, Mayer A (2019) The Warburg effect: essential part of metabolic reprogramming and central contributor to cancer progression. Int J Radiat Biol 95(7):912–919. https://doi.org/10.1080/09553002.2019.15896
doi: 10.1080/09553002.2019.15896
pubmed: 30822194
Johnson JM, Cotzia P, Fratamico R, Mikkilineni L, Chen J, Colombo D, Mollaee M, Whitaker-Menezes D, Domingo-Vidal M, Lin Z, Zhan T, Tuluc M, Palazzo J, Birbe RC, Martinez-Outschoorn UE (2017) MCT1 in invasive ductal carcinoma: monocarboxylate metabolism and aggressive breast cancer. Front Cell Dev Biol 5:27. https://doi.org/10.3389/fcell.2017.00027
doi: 10.3389/fcell.2017.00027
pubmed: 28421181
pmcid: 5376582
Cheung SM, Husain E, Masannat Y, Miller ID, Wahle K, Heys SD, He J (2020) Lactate concentration in breast cancer using advanced magnetic resonance spectroscopy. Br J Cancer 123:261–267. https://doi.org/10.1038/s41416-020-0886-7
doi: 10.1038/s41416-020-0886-7
pubmed: 32424149
pmcid: 7374160
Damgaci S, Ibrahim-Hashim A, Enriquez-Navas PM, Pilon-Thomas S, Guvenis A, Gillies RJ (2018) Hypoxia and acidosis: immune suppressors and therapeutic targets. Immunology 154:354–362. https://doi.org/10.1111/imm.12917
doi: 10.1111/imm.12917
pubmed: 29485185
pmcid: 6002221
Koukourakis IM, Panteliadou M, Giakzidis AG, Nanos C, Abatzoglou I, Giatromanolaki A, Koukourakis MI (2021) Long-term results of postoperative hypofractionated accelerated breast and lymph node radiotherapy (HypoAR) with hypofractionated boost. Curr Oncol 28(5):3474–3487. https://doi.org/10.3390/curroncol28050300
doi: 10.3390/curroncol28050300
pubmed: 34590607
pmcid: 8482084
Koukourakis MI, Tsoutsou PG, Abatzoglou IM, Sismanidou K, Giatromanolaki A, Sivridis E (2009) Hypofractionated and accelerated radiotherapy with subcutaneous amifostine cytoprotection as short adjuvant regimen after breast-conserving surgery: interim report. Int J Radiat Oncol Biol Phys 74(4):1173–1180. https://doi.org/10.1016/j.ijrobp.2008.09.016
doi: 10.1016/j.ijrobp.2008.09.016
pubmed: 19058920
Koukourakis MI, Giatromanolaki A, Sivridis E, Bougioukas G, Didilis V, Gatter KC, Harris AL, Tumour and Angiogenesis Research Group (2003) Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer 89(5):877–885. https://doi.org/10.1038/sj.bjc.6601205
doi: 10.1038/sj.bjc.6601205
pubmed: 12942121
pmcid: 2394471
Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157:411–421. https://doi.org/10.1016/s0002-9440(10)64554-3
doi: 10.1016/s0002-9440(10)64554-3
pubmed: 10934146
pmcid: 1850121
Giatromanolaki A, Harris AL, Koukourakis MI (2021) The prognostic and therapeutic implications of distinct patterns of argininosuccinate synthase 1 (ASS1) and arginase-2 (ARG2) expression by cancer cells and tumor stroma in non-small-cell lung cancer. Cancer Metab 9:28. https://doi.org/10.1186/s40170-021-00264-7
doi: 10.1186/s40170-021-00264-7
pubmed: 34344457
pmcid: 8336070
Koukourakis MI, Bentzen SM, Giatromanolaki A, Wilson GD, Daley FM, Saunders MI, Dische S, Sivridis E, Harris AL (2006) Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial. J Clin Oncol 24(5):727–735. https://doi.org/10.1200/JCO.2005.02.7474
doi: 10.1200/JCO.2005.02.7474
pubmed: 16418497
Masoud GN, Li W (2015) HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B 5:378–389. https://doi.org/10.1016/j.apsb.2015.05.007
doi: 10.1016/j.apsb.2015.05.007
pubmed: 26579469
pmcid: 4629436
Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E (2003) Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node-negative breast carcinoma. Cancer 97:1573–1581. https://doi.org/10.1002/cncr.11246
doi: 10.1002/cncr.11246
pubmed: 12627523
Giatromanolaki A, Koukourakis MI, Simopoulos C, Polychronidis A, Gatter KC, Harris AL, Sivridis E (2004) c-erbB-2 related aggressiveness in breast cancer is hypoxia-inducible factor-1alpha dependent. Clin Cancer Res 10:7972–7977. https://doi.org/10.1158/1078-0432.CCR-04-1068
doi: 10.1158/1078-0432.CCR-04-1068
pubmed: 15585632
Wang W, He YF, Sun QK, Wang Y, Han XH, Peng DF, Yao YW, Ji CS, Hu B (2014) Hypoxia-inducible factor 1α in breast cancer prognosis. Clin Chim Acta 428:32–37. https://doi.org/10.1016/j.cca.2013.10.018
doi: 10.1016/j.cca.2013.10.018
pubmed: 24482805
Wyss CB, Duffey N, Peyvandi S, Barras D, Martinez Usatorre A, Coquoz O, Romero P, Delorenzi M, Lorusso G, Rüegg C (2021) Gain of HIF1 activity and Loss of miRNA let-7d promote breast cancer metastasis to the brain via the PDGF/PDGFR axis. Cancer Res 81:594–605. https://doi.org/10.1158/0008-5472.CAN-19-3560
doi: 10.1158/0008-5472.CAN-19-3560
pubmed: 33526470
Semenza GL, Jiang BH, Leung SW, Passantino R, Concordat JP, Maire P, Giallongo A (1996) Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271:32529–32537. https://doi.org/10.1074/jbc.271.51.32529
doi: 10.1074/jbc.271.51.32529
pubmed: 8955077
Koukourakis MI, Giatromanolaki A (2019) Warburg effect, lactate dehydrogenase, and radio/chemotherapy efficacy. Int J Radiat Biol 95:408–426. https://doi.org/10.1080/09553002.2018
doi: 10.1080/09553002.2018
pubmed: 29913092
Brown JE, Cook RJ, Lipton A, Coleman RE (2012) Serum lactate dehydrogenase is prognostic for survival in patients with bone metastases from breast cancer: a retrospective analysis in bisphosphonate-treated patients. Clin Cancer Res 18:6348–6355. https://doi.org/10.1158/1078-0432.CCR-12-1397
doi: 10.1158/1078-0432.CCR-12-1397
pubmed: 22952345
Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70. https://doi.org/10.1038/nature11412
doi: 10.1038/nature11412
Dang CV, Le A, Gao P (2009) MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res 15(21):6479–6483. https://doi.org/10.1158/1078-0432.CCR-09-0889
doi: 10.1158/1078-0432.CCR-09-0889
pubmed: 19861459
pmcid: 2783410
Liu X, Meng QH, Ye Y, Hildebrandt MA, Gu J, Wu X (2015) Prognostic significance of pretreatment serum levels of albumin, LDH and total bilirubin in patients with non-metastatic breast cancer. Carcinogenesis 36:243–248. https://doi.org/10.1093/carcin/bgu247
doi: 10.1093/carcin/bgu247
pubmed: 25524924
Wang S, Ma L, Wang Z, He H, Chen H, Duan Z, Li Y, Si Q, Chuang TH, Chen C, Luo Y (2021) Lactate dehydrogenase-A (LDH-A) preserves cancer stemness and recruitment of tumor-associated macrophages to promote breast cancer progression. Front Oncol 11:654452. https://doi.org/10.3389/fonc.2021.654452
doi: 10.3389/fonc.2021.654452
pubmed: 34178639
pmcid: 8225328
Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109:3812–3819. https://doi.org/10.1182/blood-2006-07-035972
doi: 10.1182/blood-2006-07-035972
pubmed: 17255361
Cascone T, McKenzie JA, Mbofung RM, Punt S, Wang Z, Xu C, Williams LJ, Wang Z, Bristow CA, Carugo A, Peoples MD, Li L, Karpinets T, Huang L, Malu S, Creasy C, Leahey SE, Chen J, Chen Y, Pelicano H, Bernatchez C, Gopal YNV, Heffernan TP, Hu J, Wang J, Amaria RN, Garraway LA, Huang P, Yang P, Wistuba II, Woodman SE, Roszik J, Davis RE, Davies MA, Heymach JV, Hwu P, Peng W (2018) Increased Tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab 27:977-987.e4. https://doi.org/10.1016/j.cmet.2018.02.02499
doi: 10.1016/j.cmet.2018.02.02499
pubmed: 29628419
pmcid: 5932208
Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D’Acquisto F, Bland EJ, Bombardieri M, Pitzalis C, Perretti M, Marelli-Berg FM, Mauro C (2015) Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol 13:e1002202. https://doi.org/10.1371/journal.pbio.1002202
doi: 10.1371/journal.pbio.1002202
pubmed: 26181372
pmcid: 4504715
Angelin A, Gil-de-Gómez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ 3rd, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH (2017) Foxp3 reprograms T cell metabolism to function in low-glucose. High-Lactate Environ Cell Metab 25:1282-1293.e7. https://doi.org/10.1016/j.cmet.2016.12.018
doi: 10.1016/j.cmet.2016.12.018
Li N, Kang Y, Wang L, Huff S, Tang R, Hui H, Agrawal K, Gonzalez GM, Wang Y, Patel SP, Rana TM (2020) ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in the tumor microenvironment. Proc Natl Acad Sci U S A 117:20159–20170. https://doi.org/10.1073/pnas.1918986117
doi: 10.1073/pnas.1918986117
pubmed: 32747553
pmcid: 7443867
Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, Budczies J, Huober J, Klauschen F, Furlanetto J, Schmitt WD, Blohmer JU, Karn T, Pfitzner BM, Kümmel S, Engels K, Schneeweiss A, Hartmann A, Noske A, Fasching PA, Jackisch C, van Mackelenbergh M, Sinn P, Schem C, Hanusch C, Untch M, Loibl S (2018) Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol 19:40–50. https://doi.org/10.1016/S1470-2045(17)30904-X
doi: 10.1016/S1470-2045(17)30904-X
pubmed: 29233559
Zhang NN, Qu FJ, Liu H, Li ZJ, Zhang YC, Han X, Zhu ZY, Lv Y (2021) Prognostic impact of tertiary lymphoid structures in breast cancer prognosis: a systematic review and meta-analysis. Cancer Cell Int 21:536. https://doi.org/10.1186/s12935-021-02242-x
doi: 10.1186/s12935-021-02242-x
pubmed: 34654433
pmcid: 8520238
Miligy I, Mohan P, Gaber A, Aleskandarany MA, Nolan CC, Diez-Rodriguez M, Mukherjee A, Chapman C, Ellis IO, Green AR, Rakha EA (2017) Prognostic significance of tumour infiltrating B lymphocytes in breast ductal carcinoma in situ. Histopathology 71(2):258–268. https://doi.org/10.1111/his.13217
doi: 10.1111/his.13217
pubmed: 28326600
Qian F, Qingping Y, Linquan W, Xiaojin H, Rongshou W, Shanshan R, Wenjun L, Yong H, Enliang L (2017) High tumor-infiltrating FoxP3
doi: 10.1016/j.ejso.2017.01.011
pubmed: 28214052
Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, Kastenberger M, Bogdan C, Schleicher U, Mackensen A, Ullrich E, Fichtner-Feigl S, Kesselring R, Mack M, Ritter U, Schmid M, Blank C, Dettmer K, Oefner PJ, Hoffmann P, Walenta S, Geissler EK, Pouyssegur J, Villunger A, Steven A, Seliger B, Schreml S, Haferkamp S, Kohl E, Karrer S, Berneburg M, Herr W, Mueller-Klieser W, Renner K, Kreutz M (2016) LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 24:657–671. https://doi.org/10.1016/j.cmet.2016.08.011
doi: 10.1016/j.cmet.2016.08.011
pubmed: 27641098
Li W, Tanikawa T, Kryczek I, Xia H, Li G, Wu K, Wei S, Zhao L, Vatan L, Wen B, Shu P, Sun D, Kleer C, Wicha M, Sabel M, Tao K, Wang G, Zou W (2018) Aerobic glycolysis controls myeloid-derived suppressor cells and tumor immunity via a specific CEBPB Isoform in triple-negative breast cancer. Cell Metab 28:87-103.e6. https://doi.org/10.1016/j.cmet.2018.04.022
doi: 10.1016/j.cmet.2018.04.022
pubmed: 29805099
pmcid: 6238219