The tumor microenvironment plays a critical role in prostate cancer (PC) development and progression. Inappropriate activation of the stroma potentiates the growth and transformation of epithelial tumor cells. Here, we show that upregulation of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, in stromal cells elevates production of reactive oxygen species, triggers an inflammatory response including activation of IL-6, and promotes tumorigenesis in vitro and in vivo. Mechanistically, MAOA enhances IL-6 transcription through direct Twist1 binding to a conserved E-box element at the IL-6 promoter. MAOA in stromal fibroblasts provides tumor cell growth advantages through paracrine IL-6/STAT3 signaling. Tissue microarray analysis revealed co-expression correlations between individual pairs of proteins of the stromal MAOA-induced Twist1/IL-6/STAT3 pathway in clinical specimens. Downstream of stromal MAOA, STAT3 also promotes cell stemness and transcriptionally activates expression of cancer stem cell marker CD44 in PC cells. MAOA inhibitor treatment effectively suppressed prostate tumor growth in mice in a stroma-specific targeted manner. Collectively, these findings characterize the contribution of MAOA to stromal activation in PC pathogenesis and provide a rationale for targeting MAOA in stromal cells to treat PC.
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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.
Barron DA, Rowley DR. The reactive stroma microenvironment and prostate cancer progression. Endocr-Relat Cancer. 2012;19:R187–204.
Franco OE, Hayward SW. Targeting the tumor stroma as a novel therapeutic approach for prostate cancer. Adv Pharm. 2012;65:267–313.
Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell. 2010;17:135–47.
Valencia T, Kim JY, Abu-Baker S, Moscat-Pardos J, Ahn CS, Reina-Campos M, et al. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell. 2014;26:121–35.
Azevedo A, Cunha V, Teixeira AL, Medeiros R. IL-6/IL-6R as a potential key signaling pathway in prostate cancer development. World J Clin Oncol. 2011;2:384–96.
De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, Drake CG, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7:256–69.
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.
Bromberg J, Wang TC. Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell. 2009;15:79–80.
Studebaker AW, Storci G, Werbeck JL, Sansone P, Sasser AK, Tavolari S, et al. Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. Cancer Res. 2008;68:9087–95.
Culig Z, Puhr M. Interleukin-6 and prostate cancer: current developments and unsolved questions. Mol Cell Endocrinol. 2018;462:25–30.
Dumont N, Liu B, Defilippis RA, Chang H, Rabban JT, Karnezis AN, et al. Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia. 2013;15:249–62.
Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999;59:5002–11.
Shih JC, Chen K, Ridd MJ. Monoamine oxidase: from genes to behavior. Annu Rev Neurosci. 1999;22:197–217.
Policastro LL, Ibanez IL, Notcovich C, Duran HA, Podhajcer OL. The tumor microenvironment: characterization, redox considerations, and novel approaches for reactive oxygen species-targeted gene therapy. Antioxid Redox Signal. 2013;19:854–95.
Flamand V, Zhao H, Peehl DM. Targeting monoamine oxidase A in advanced prostate cancer. J Cancer Res Clin Oncol. 2010;136:1761–71.
True L, Coleman I, Hawley S, Huang CY, Gifford D, Coleman R, et al. A molecular correlate to the Gleason grading system for prostate adenocarcinoma. Proc Natl Acad Sci USA. 2006;103:10991–6.
Wu JB, Shao C, Li X, Li Q, Hu P, Shi C, et al. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. J Clin Investig. 2014;124:2891–908.
Wu JB, Yin L, Shi C, Li Q, Duan P, Huang JM, et al. MAOA-dependent activation of Shh-IL6-RANKL signaling network promotes prostate cancer metastasis by engaging tumor-stromal cell interactions. Cancer Cell. 2017;31:368–82.
Kawada M, Inoue H, Masuda T, Ikeda D. Insulin-like growth factor I secreted from prostate stromal cells mediates tumor-stromal cell interactions of prostate cancer. Cancer Res. 2006;66:4419–25.
Tanner MJ, Welliver RC Jr, Chen M, Shtutman M, Godoy A, Smith G, et al. Effects of androgen receptor and androgen on gene expression in prostate stromal fibroblasts and paracrine signaling to prostate cancer cells. PLoS ONE. 2011;6:e16027.
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927–39.
Lee KW, Yeo SY, Sung CO, Kim SH. Twist1 is a key regulator of cancer-associated fibroblasts. Cancer Res. 2015;75:73–85.
Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 2005;41:2502–12.
Ishihara K, Hirano T. Molecular basis of the cell specificity of cytokine action. Biochimica et Biophysica Acta. 2002;1592:281–96.
Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.
Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011;17:211–5.
Galoczova M, Coates P, Vojtesek B. STAT3, stem cells, cancer stem cells and p63. Cell Mol Biol Lett. 2018;23:12.
Meng E, Mitra A, Tripathi K, Finan MA, Scalici J, McClellan S, et al. ALDH1A1 maintains ovarian cancer stem cell-like properties by altered regulation of cell cycle checkpoint and DNA repair network signaling. PLoS ONE. 2014;9:e107142.
Zhang G, Wang Z, Luo W, Jiao H, Wu J, Jiang C. Expression of potential cancer stem cell marker ABCG2 is associated with malignant behaviors of hepatocellular carcinoma. Gastroenterol Res Pr. 2013;2013:782581.
Lin L, Jou D, Wang Y, Ma H, Liu T, Fuchs J, et al. STAT3 as a potential therapeutic target in ALDH+ and CD44+/CD24+ stem cell-like pancreatic cancer cells. Int J Oncol. 2016;49:2265–74.
Moreira MP, da Conceicao Braga L, Cassali GD, Silva LM. STAT3 as a promising chemoresistance biomarker associated with the CD44(+/high)/CD24(-/low)/ALDH(+) BCSCs-like subset of the triple-negative breast cancer (TNBC) cell line. Exp Cell Res. 2018;363:283–90.
Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999;98:295–303.
Caldenhoven E, van Dijk TB, Solari R, Armstrong J, Raaijmakers JA, Lammers JW, et al. STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription. J Biol Chem. 1996;271:13221–7.
Leach DA, Buchanan G. Stromal androgen receptor in prostate cancer development and progression. Cancers. 2017;9:E10.
Acharya A, Das I, Chandhok D, Saha T. Redox regulation in cancer: a double-edged sword with therapeutic potential. Oxid Med Cell Longev. 2010;3:23–34.
Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov. 2009;8:579–91.
Wassmann S, Stumpf M, Strehlow K, Schmid A, Schieffer B, Bohm M, et al. Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor. Circ Res. 2004;94:534–41.
Mathy-Hartert M, Hogge L, Sanchez C, Deby-Dupont G, Crielaard JM, Henrotin Y. Interleukin-1beta and interleukin-6 disturb the antioxidant enzyme system in bovine chondrocytes: a possible explanation for oxidative stress generation. Osteoarthr Cartil. 2008;16:756–63.
Kumari N, Dwarakanath BS, Das A, Bhatt AN. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol. 2016;37:11553–72.
Zhu Y, Liu C, Cui Y, Nadiminty N, Lou W, Gao AC. Interleukin-6 induces neuroendocrine differentiation (NED) through suppression of RE-1 silencing transcription factor (REST). Prostate. 2014;74:1086–94.
Dobrian AD. A tale with a Twist: a developmental gene with potential relevance for metabolic dysfunction and inflammation in adipose tissue. Front Endocrinol. 2012;3:108.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–8.
Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S, et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene. 2006;25:1696–708.
Yan Y, Zuo X, Wei D. Concise review: emerging role of CD44 in cancer stem cells: a promising biomarker and therapeutic target. Stem Cells Transl Med. 2015;4:1033–43.
Lee JL, Wang MJ, Chen JY. Acetylation and activation of STAT3 mediated by nuclear translocation of CD44. J Cell Biol. 2009;185:949–57.
Marotta LL, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, et al. The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(-) stem cell-like breast cancer cells in human tumors. J Clin Investig. 2011;121:2723–35.
Sun X, He H, Xie Z, Qian W, Zhau HE, Chung LW, et al. Matched pairs of human prostate stromal cells display differential tropic effects on LNCaP prostate cancer cells. In Vitro Cell Dev Biol Anim. 2010;46:538–46.
Thalmann GN, Anezinis PE, Chang SM, Zhau HE, Kim EE, Hopwood VL, et al. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res. 1994;54:2577–81.
Zhau HY, Chang SM, Chen BQ, Wang Y, Zhang H, Kao C, et al. Androgen-repressed phenotype in human prostate cancer. Proc Natl Acad Sci USA. 1996;93:15152–7.
Wu JB, Chen K, Ou XM, Shih JC. Retinoic acid activates monoamine oxidase B promoter in human neuronal cells. J Biol Chem. 2009;284:16723–35.
Li Y, He L, Zeng N, Sahu D, Cadenas E, Shearn C, et al. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling regulates mitochondrial biogenesis and respiration via estrogen-related receptor alpha (ERRalpha). J Biol Chem. 2013;288:25007–24.
Cheng N, Lambert DL. Mammary transplantation of stromal cells and carcinoma cells in C57BL/6J mice. J Vis Exp. 2011;12:2716.
Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med. 2012;18:1359–68.
We thank Yang Li (University of Southern California), Yanping Wang (CSMC), and Yidi Xu (Washington State University) for technical help, Leland W.K. Chung (CSMC) for comprehensive support of this study, and Gary Mawyer for editorial assistance. This work was supported by a Concern Foundation CONquer canCER Now Award, the Department of Defense Prostate Cancer Research Program grant W81XWH-15-1-0493, the NIH/NCI grant R37CA233658, and the WSU start-up fund to B.J.W.
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Li, J., Pu, T., Yin, L. et al. MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness. Oncogene 39, 3305–3321 (2020). https://doi.org/10.1038/s41388-020-1217-4
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