Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness

Oncogene volume 39, pages 3305–3321 (2020)Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Increased MAOA levels in PC-associated stroma.
Fig. 2: Genetic silencing of MAOA in stromal cells reduces PC growth, migration, and invasion.
Fig. 3: MAOA promotes stromal cell reactivity and activates IL-6.
Fig. 4: MAOA upregulates IL-6 directly through Twist1 in prostate stromal cells.
Fig. 5: Stromal MAOA confers growth advantages on adjacent PC in a STAT3-dependent manner.
Fig. 6: Stromal MAOA/Twist1/IL-6 demonstrate co-expression correlations with adjacent tumor pSTAT3/STAT3 in PC tissue microarrays.
Fig. 7: MAOA in stromal cells promotes PC stemness via STAT3.
Fig. 8: Pharmacological inhibition of MAOA in stromal cells reduces PC growth in mice.

Similar content being viewed by others

References

  1. 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.

    PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    PubMed  Google Scholar 

  3. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Barron DA, Rowley DR. The reactive stroma microenvironment and prostate cancer progression. Endocr-Relat Cancer. 2012;19:R187–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Franco OE, Hayward SW. Targeting the tumor stroma as a novel therapeutic approach for prostate cancer. Adv Pharm. 2012;65:267–313.

    CAS  Google Scholar 

  6. 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.

    CAS  PubMed  Google Scholar 

  7. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 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.

    PubMed  PubMed Central  Google Scholar 

  9. 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.

    PubMed  PubMed Central  Google Scholar 

  10. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Bromberg J, Wang TC. Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell. 2009;15:79–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 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.

    CAS  PubMed  Google Scholar 

  13. Culig Z, Puhr M. Interleukin-6 and prostate cancer: current developments and unsolved questions. Mol Cell Endocrinol. 2018;462:25–30.

    CAS  PubMed  Google Scholar 

  14. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 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.

    CAS  PubMed  Google Scholar 

  16. Shih JC, Chen K, Ridd MJ. Monoamine oxidase: from genes to behavior. Annu Rev Neurosci. 1999;22:197–217.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 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.

    CAS  PubMed  Google Scholar 

  18. Flamand V, Zhao H, Peehl DM. Targeting monoamine oxidase A in advanced prostate cancer. J Cancer Res Clin Oncol. 2010;136:1761–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 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.

    CAS  PubMed  Google Scholar 

  22. 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.

    CAS  PubMed  Google Scholar 

  23. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 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.

    CAS  PubMed  Google Scholar 

  25. Lee KW, Yeo SY, Sung CO, Kim SH. Twist1 is a key regulator of cancer-associated fibroblasts. Cancer Res. 2015;75:73–85.

    CAS  PubMed  Google Scholar 

  26. Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 2005;41:2502–12.

    CAS  PubMed  Google Scholar 

  27. Ishihara K, Hirano T. Molecular basis of the cell specificity of cytokine action. Biochimica et Biophysica Acta. 2002;1592:281–96.

    CAS  PubMed  Google Scholar 

  28. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.

    CAS  PubMed  Google Scholar 

  29. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Galoczova M, Coates P, Vojtesek B. STAT3, stem cells, cancer stem cells and p63. Cell Mol Biol Lett. 2018;23:12.

    PubMed  PubMed Central  Google Scholar 

  31. 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.

    PubMed  PubMed Central  Google Scholar 

  32. 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.

    Google Scholar 

  33. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 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.

    CAS  PubMed  Google Scholar 

  35. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999;98:295–303.

    CAS  PubMed  Google Scholar 

  36. 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.

    CAS  PubMed  Google Scholar 

  37. Leach DA, Buchanan G. Stromal androgen receptor in prostate cancer development and progression. Cancers. 2017;9:E10.

    PubMed  Google Scholar 

  38. 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.

    PubMed  PubMed Central  Google Scholar 

  39. 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.

    CAS  PubMed  Google Scholar 

  40. 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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  42. Kumari N, Dwarakanath BS, Das A, Bhatt AN. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol. 2016;37:11553–72.

    CAS  PubMed  Google Scholar 

  43. 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.

    CAS  PubMed  Google Scholar 

  44. 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.

    Google Scholar 

  45. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 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.

    CAS  PubMed  Google Scholar 

  47. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee JL, Wang MJ, Chen JY. Acetylation and activation of STAT3 mediated by nuclear translocation of CD44. J Cell Biol. 2009;185:949–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 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.

    PubMed  PubMed Central  Google Scholar 

  51. 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.

    CAS  PubMed  Google Scholar 

  52. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Cheng N, Lambert DL. Mammary transplantation of stromal cells and carcinoma cells in C57BL/6J mice. J Vis Exp. 2011;12:2716.

    Google Scholar 

  56. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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.

Author information

Author notes

  1. These authors contributed equally: Jingjing Li, Tianjie Pu

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, 205 E Spokane Falls Blvd, PBS 421, Spokane, WA, 99202, USA

    Jingjing Li, Tianjie Pu & Boyang Jason Wu

  2. Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China

    Jingjing Li

  3. Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China

    Tianjie Pu & Lijuan Yin

  4. Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Lijuan Yin

  5. Department of Pathology, Xijing Hospital, Medical University of the Air Force, Xi’an, Shaanxi, 710032, China

    Qinlong Li

  6. Lawrence J. Ellison Institute for Transformative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA

    Chun-Peng Liao

Authors
  1. Jingjing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tianjie Pu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lijuan Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qinlong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chun-Peng Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Boyang Jason Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: BJW. Development of methodology: JL, TP, LY, QL, and BJW. Acquisition of data: JL, TP, LY, QL, C-PL, and BJW. Analysis and interpretation of data: JL, TP, LY, QL, and BJW. Writing of the manuscript: BJW. Study supervision: BJW.

Corresponding author

Correspondence to Boyang Jason Wu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-020-1217-4

This article is cited by

Search

Advanced search

Quick links