LDH-A regulates the tumor microenvironment via HIF-signaling and modulates the immune response.
LDH-A regulates the tumor microenvironment via HIF-signaling and modulates the immune response.
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LDH-A 通过 HIF 信号调节肿瘤微环境，并调节免疫反应。
DOI：
10.1371/journal.pone.0203965
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Blasberg R
中科院分区：
文献类型：
--
作者：
Serganova I;Cohen IJ;Vemuri K;Shindo M;Maeda M;Mane M;Moroz E;Khanin R;Satagopan J;Koutcher JA;Blasberg R
Previous studies show that LDH-A knockdown reduces orthotopic 4T1 breast tumor lactate and delays tumor growth and the development of metastases in nude mice. Here, we report significant changes in the tumor microenvironment (TME) and a more robust anti-tumor response in immune competent BALB/c mice. 4T1 murine breast cancer cells were transfected with shRNA plasmids directed against LDH-A (KD) or a scrambled control plasmid (NC). Cells were also transduced with dual luciferase-based reporter systems to monitor HIF-1 activity and the development of metastases by bioluminescence imaging, using HRE-sensitive and constitutive promoters, respectively. The growth and metastatic profile of orthotopic 4T1 tumors developed from these cell lines were compared and a primary tumor resection model was studied to simulate the clinical management of breast cancer. Primary tumor growth, metastasis formation and TME phenotype were significantly different in LDH-A KD tumors compared with controls. In LDH-A KD cells, HIF-1 activity, hexokinase 1 and 2 expression and VEGF secretion were reduced. Differences in the TME included lower HIF-1α expression that correlated with lower vascularity and pimonidazole staining, higher infiltration of CD3+ and CD4+ T cells and less infiltration of TAMs. These changes resulted in a greater delay in metastases formation and 40% long-term survivors (>20 weeks) in the LDH-A KD cohort following surgical resection of the primary tumor. We show for the first time that LDH-depletion inhibits the formation of metastases and prolongs survival of mice through changes in tumor microenvironment that modulate the immune response. We attribute these effects to diminished HIF-1 activity, vascularization, necrosis formation and immune suppression in immune competent animals. Gene-expression analyses from four human breast cancer datasets are consistent with these results, and further demonstrate the link between glycolysis and immune suppression in breast cancer.
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影响因子：
3.7
作者：
Carlin S;Khan N;Ku T;Longo VA;Larson SM;Smith-Jones PM
通讯作者：
Smith-Jones PM
DOI：
10.1016/s0360-3016(01)01630-3
发表时间：
2001-10-01
影响因子：
7
作者：
Brizel, DM;Schroeder, T;Mueller-Klieser, W
通讯作者：
Mueller-Klieser, W
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
64.5
作者：
Faubert B;Li KY;Cai L;Hensley CT;Kim J;Zacharias LG;Yang C;Do QN;Doucette S;Burguete D;Li H;Huet G;Yuan Q;Wigal T;Butt Y;Ni M;Torrealba J;Oliver D;Lenkinski RE;Malloy CR;Wachsmann JW;Young JD;Kernstine K;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
乳酸和癌症：在乳酸穿梭时代重新审视Warburg效应。
影响因子：
5
作者：
Goodwin ML;Gladden LB;Nijsten MW;Jones KB
通讯作者：
Jones KB