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PreprintCited by 0GDF15 and Related BiomarkersBone health and treatmentsProstate Cancer Treatment and Research

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GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment

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Yamamichi, Gaku, Kato, Taigo, Arakawa, Noriaki, Ino, Yoko, Ujike, Takeshi, Nakano, Kosuke, Koh, Yoko, Motoyama, Yuichi, Outani, Hidetatsu, Myoba, Shohei, Ishizuya, Yu, Yamamoto, Yoshiyuki, Hatano, Koji, Kawashima, Atsunari, Fukuhara, Shinichiro, Uemura, Hiroji, Okada, Seiji, Morii, Eiichi, Nonomura, Norio, Uemura, Motohide·2024·Research Square
DOI 10.21203/rs.3.rs-4834587/v1

Preprint — published as 10.1186/s40364-024-00695-6 · Paper page

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Abstract

Background Bone metastasis (BM) is a common and fatal condition in patients with castration-resistant prostate cancer (CRPC). However, there are no useful blood biomarkers for CRPC with BM, and the mechanism underlying BM is unclear. In this study, we investigated precise blood biomarkers for evaluating BM that can improve the prognosis of patients with CRPC. Methods We comprehensively examined culture supernatants from four prostate cancer (PCa) cell lines using Orbitrap mass spectrometry to identify specific proteins secreted abundantly by PCa cells. The effects of this protein to PCa cells, osteoblasts, osteoclasts were examined, and BM mouse model. In addition, we measured the plasma concentration of this protein in CRPC patients for whom bone scan index (BSI) by bone scintigraphy was performed. Results A total of 2,787 proteins were identified by secretome analysis. We focused on GDF15 propeptide (GDPP), which is secreted by osteoblasts, osteoclasts, and PCa cells. GDPP promoted the proliferation, invasion, and migration of PC3 and DU145 CRPC cells, and GDPP aggravated BM in a mouse model. Importantly, GDPP accelerated bone formation and absorption in the bone microenvironment by enhancing the proliferation of osteoblasts and osteoclasts by upregulating individual transcription factors such as RUNX2, OSX, ATF4, NFATc1, and DC-STAMP. In clinical settings, including a total of 386 patients, GDPP was more diagnostic of BM than prostate-specific antigen (PSA) (AUC = 0.92 and 0.78) and the seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide and mature GDF15) in patients with CRPC. The changes in BSI over time with systemic treatment were correlated with that of GDPP (r = 0.63) but not with that of PSA (r = -0.16). Conclusions GDPP promotes a vicious cycle in the BM microenvironment and is a novel blood biomarker of BM in CRPC, which could lead to early treatment interventions in patients with CRPC.

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Research works printed but not linked: 36

  1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48. · DOI · Paper page
  2. Bergengren O, Pekala KR, Matsoukas K, Fainberg J, Mungovan SF, Bratt O, et al. 2022 update on prostate cancer epidemiology and risk factors-A systematic review. Eur Urol. 2023;84(2):191–206. · DOI
  3. Hernandez RK, Wade SW, Reich A, Pirolli M, Liede A, Lyman GH. Incidence of bone metastasis in patients with solid tumor: analysis of oncology electronic medical records in the United States. BMC Cancer. 2018;18(1):44. · DOI
  4. Menges D, Yebyo HG, Sivec-Muniz S, Haile SR, Barbier MC, Tomonaga Y, et al. Treatments for Metastatic Hormone-sensitive Prostate Cancer: Systematic Review, Network Meta-analysis, and Benefit-harm assessment. Eur Urol Oncol. 2022;5(6):605–16. · DOI
  5. Boopathi E, Birbe R, Shoyele SA, Den RB, Thangavel C. Bone health management in the continuum of prostate cancer disease. Cancers. 2022;14(17):4305. · DOI
  6. Shibata H, Kato K, Sekine I, Abe K, Araki N, Iguchi H, et al. Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology. ESMO Open. 2016;1(2):e000037. · DOI
  7. Yamamichi G, Kato T, Yumiba S, Tomiyama S, Koh Y, Nakano K, et al. Diagnostic and prognostic significance of tartrate-resistant acid phosphatase type 5b in newly diagnosed prostate cancer with bone metastasis: A real-world multi-institutional study. Int J Urol. 2023;30(1):70–6. · DOI
  8. Yamamichi G, Kato T, Uemura U, Nonomura N. Diagnosing and prognosing bone metastasis in prostate cancer: clinical utility of blood biomarkers. Anticancer Res. 2023;43(1):283–90. · DOI
  9. Aggarwal R, Huang J, Alumkal JJ, Zhang L, Feng FY, Thomas GV, et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: A Multi-institutional Prospective Study. J Clin Oncol. 2018;36(24):2492–503. · DOI · Paper page
  10. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Prostate Cancer Clinical Trials Working Group 3, Trial design and objectives for castration-resistant prostate cancer: Updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402–18. · DOI
  11. Ploussard G, Rozet F, Roubaud G, Stanbury T, Sargos P, Roupret M, et al. Chromogranin A: a useful biomarker in castration-resistant prostate cancer. World J Urol. 2023;41(2):361–9. · DOI
  12. Bryce AH, Chen YH, Liu G, Carducci MA, Jarrard DM, Garcia JA, et al. Patterns of cancer progression of metastatic hormone-sensitive prostate cancer in the ECOG3805 CHAARTED Trial. Eur Urol Oncol. 2020;3(6):717–24. · DOI
  13. Armstrong AJ, Mottet N, Iguchi T, Szmulewitz RZ, Holzbeierlein J, Villers A. Radiographic progression in the absence of prostate-specific antigen (PSA) progression in patients with metastatic hormone-sensitive prostate cancer (mHSPC): Post hoc analysis of ARCHES. J Clin Oncol. 2022;40(16):5072. · DOI
  14. Ito K, Kubota Y, Suzuki K, Shimizu N, Fukabori Y, Kurokawa K, et al. Correlation of prostate-specific antigen before prostate cancer detection and clinicopathologic features: evaluation of mass screening populations. Urology. 2000;55(5):705–9. · DOI
  15. Stattin K, Sandin F, Bratt O, Lambe M, et al. The risk of distant metastases and cancer specific survival in men with serum prostate specific antigen values above 100 ng/ml. J Urol. 2015;194(6):1594–600. · DOI
  16. Gillessen S, Bossi A, Davis ID, Bono J, Fizazi K, James ND et al. Management of patients with advanced prostate cancer-metastatic and/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022. Eur J Cancer. 2023;185:178–215.
  17. Luan HH, Wang A, Hilliard BK, Carvalho F, Rosen CE, Ahasic AM, et al. GDF15 is an inflammation-induced central mediator of tissue tolerance. Cell. 2019;178(5):1231–44. e11. · DOI · Paper page
  18. Mullican SE, Lin-Schmidt X, Chin CN, Chavez JA, Furman JL, Armstrong AA, et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med. 2017;23(10):1150–7. · DOI · Paper page
  19. Lockhart SM, Saudek V, O'Rahilly S, et al. GDF15: A Hormone Conveying Somatic Distress to the Brain. Endocr Rev. 2020;41(4):bnaa007. · DOI · Paper page
  20. Wang D, Day EA, Townsend LK, Djordjevic D, Jørgensen SB, Steinberg GR. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nat Rev Endocrinol. 2021;17(10):592–607. · DOI
  21. Bauskin AR, Brown DA, Junankar S, Rasiah KK, Eggleton S, Hunter M, et al. The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome. Cancer Res. 2005;65(6):2330–6. · DOI
  22. Arakawa N, Miyagi E, Nomura A, Morita E, Ino Y, Ohtake N, et al. Secretome-based identification of TFPI2, a novel serum biomarker for detection of ovarian clear cell adenocarcinoma. J Proteome Res. 2013;12(10):4340–50. · DOI
  23. Rappsilber J, Mann M, Ishihama Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc. 2007;2(8):1896–906. · DOI · Paper page
  24. Kubo S, Ohtake N, Miyakawa K, Jeremiah SS, Yamaoka Y, Murohashi K, et al. Development of an automated chemiluminescence assay system for quantitative measurement of multiple anti-SARS-CoV-2 antibodies. Front Microbiol. 2021;11:628281. · DOI
  25. Lopez-Bujanda ZA, Obradovic A, Nirschl TR, Crowley L, Macedo R, Papachristodoulou A, et al. TGM4: an immunogenic prostate-restricted antigen. J Immunother Cancer. 2021;9(6):e001649. · DOI
  26. Liu S, Chai T, Garcia-Marques F, Yin Q, Hsu EC, Shen M, et al. UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas. Cell Rep Med. 2024;5(2):101381. · DOI
  27. Bonaterra GA, Schleper A, Skowronek M, Kilian LS, Rink T, Schwarzbach H, et al. Increased density of growth differentiation factor-15 + immunoreactive M1/M2 macrophages in prostate cancer of different gleason scores compared with benign prostate hyperplasia. Cancers (Basel). 2022;14(19):4591. · DOI
  28. Francini E, Montagnani F, Nuzzo PV, Gonzalez-Velez M, Alimohamed NS, Rosellini P, et al. Association of concomitant bone resorption inhibitors with overall survival among patients with metastatic castration-resistant prostate cancer and bone metastases receiving abiraterone acetate with prednisone as first-line therapy. JAMA Netw Open. 2021;4(7):e2116536. · DOI
  29. Yu Z, Zou H, Wang H, Li Q, Yu D. Identification of key gene signatures associated with bone metastasis in castration-resistant prostate cancer using co-expression analysis. Front Oncol. 2021;10:571524. · DOI
  30. Gillessen S, Attard G, Beer TM, Beltran H, Bjartell A, Bossi A et al. Management of patients with advanced prostate cancer: report of the advanced prostate cancer consensus conference 2019. Eur Urol. 2020;77(4):508–547.
  31. Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Sci U S A. 1997;94(21):11514–9. · DOI
  32. Lim YC, Bhatt MP, Kwon MH, Park D, Lee S, Choe J, et al. Prevention of VEGF-mediated microvascular permeability by C-peptide in diabetic mice. Cardiovasc Res. 2014;101(1):155–64. · DOI
  33. Walcher D, Babiak C, Poletek P, Rosenkranz S, Bach H, Betz S, et al. C-Peptide induces vascular smooth muscle cell proliferation: involvement of SRC-kinase, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinase 1/2. Circ Res. 2006;99(11):1181–7. · DOI
  34. . Lancet 1889;1:571–3.
  35. Guo P, Zhao KW, Dong XY, Sun X, Dong JT. Acetylation of KLF5 alters the assembly of p15 transcription factors in transforming growth factor-beta-mediated induction in epithelial cells. J Biol Chem. 2009;284(27):18184–93. · DOI
  36. Zhang B, Li Y, Wu Q, Xie L, Barwick B, Fu C, et al. Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer. Nat Commun. 2021;12(1):1714. · DOI

Metadata

Authors
Yamamichi, G., Kato, T., Arakawa, N., Ino, Y., Ujike, T., Nakano, K., Koh, Y., Motoyama, Y., Outani, H., Myoba, S., Ishizuya, Y., Yamamoto, Y., Hatano, K., Kawashima, A., Fukuhara, S., Uemura, H., Okada, S., Morii, E., Nonomura, N., & Uemura, M.
Affiliations
  • The University of Osaka (JP)
  • National Institute of Health Sciences (JP)
  • Yokohama City University (JP)
  • Tosoh (Japan) (JP)
  • Yokohama City University Medical Center (JP)
  • Fukushima Medical University (JP)
ORCID
Venue
Research Square
Publisher
Springer Science and Business Media LLC
Published
2024-09-08
Volume
12
Pages
147
DOI
10.21203/rs.3.rs-4834587/v1
OpenAlex
W4402339883
Cited by
0
References
3
Type
posted content
Language
en
Open access
Licence
Locations
  • Research Square (acceptedVersion, cc-by)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
Funders
Japan Society for the Promotion of Science (21K09396, 24K12436, 20K23002)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › GDF15 and Related Biomarkers
  • Health Sciences › Medicine › Oncology › Bone health and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
Keywords
bone metastasis, castration-resistant prostate cancer, blood biomarkers, bone microenvironment, secretome, osteoblasts, osteoclasts, bone formation and resorption, Runx2, ATF4, NFATc1, DC-STAMP, bone scan index, tumor cell migration and invasion

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