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From biology to the clinic — exploring liver metastasis in prostate cancer

Nature Reviews Urology (2024)Cite this article

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Abstract

Liver metastases from prostate cancer are associated with an aggressive disease course and poor prognosis. Results from autopsy studies indicate a liver metastasis prevalence of up to 25% in patients with advanced prostate cancer. Population data estimate that ~3–10% of patients with metastatic castration-resistant prostate cancer harbour liver metastases at the baseline, rising to 20–30% in post-treatment cohorts, suggesting that selective pressure imposed by novel therapies might promote metastatic spread to the liver. Liver metastases are associated with more aggressive tumour biology than lung metastases. Molecular profiling of liver lesions showed an enrichment of low androgen receptor, neuroendocrine phenotypes and high genomic instability. Despite advancements in molecular imaging modalities such as prostate-specific membrane antigen PET–CT, and liquid biopsy markers such as circulating tumour DNA, early detection of liver metastases from prostate cancer remains challenging, as both approaches are hampered by false positive and false negative results, impeding the accurate identification of early liver lesions. Current therapeutic strategies showed limited efficacy in this patient population. Emerging targeted radionuclide therapies, metastasis-directed therapy, and novel systemic agents have shown preliminary activity against liver metastases, but require further validation. Treatment with various novel prostate cancer therapies might lead to an increase in the prevalence of liver metastasis, underscoring the urgent need for coordinated efforts across preclinical and clinical researchers to improve characterization, monitoring, and management of liver metastases from prostate cancer. Elucidating molecular drivers of liver tropism and interactions with the liver microenvironment might ultimately help to identify actionable targets to enhance survival in this high-risk patient group.

Key points

  • The prevalence of liver metastasis increases in correlation with the progression of prostate cancer, escalating from ~3% in initial metastatic hormone-sensitive prostate cancer (mHSPC) to over 20% in post-therapeutic metastatic castration-resistant prostate cancer (mCRPC). Furthermore, the ratio of liver to lung metastasis also shifts from 1:3 in initial mHSPC to over 1:1 in post-therapeutic mCRPC.

  • The manifestation of liver metastases confers a dismal prognosis, approximately doubling the risk of death compared with other metastatic locations.

  • Liver metastasis progression involves changes in cancer cell phenotype (such as low androgen receptor, neuroendocrine conversion and increased genomic instability), organotropism factors, pre-metastatic niche elements (including liver injury), and intricate interactions with the hepatic microenvironment.

  • Novel molecular imaging such as prostate-specific membrane antigen (PSMA) PET–CT and liquid biopsy have greatly improved liver metastasis detection, but occult liver metastases remain common, as PSMA-PET–CT is still associated with a false-negative rate of ~20% for liver lesions. However, most PSMA-negative liver metastases were shown to be fluorodeoxyglucose-positive and could be successfully detected using fluorodeoxyglucose PET–CT.

  • Current therapies, including androgen deprivation therapy, novel hormone therapies, chemotherapy, and radioligand therapy showed limited efficacy in patients with liver metastases. However, novel molecular targeted radionuclide therapy, metastasis-directed therapy and immunological combination therapy have shown promising preliminary activity against liver metastases.

  • The establishment of multi-omics databases, animal models, real-time monitoring techniques, and the exploration of therapeutic strategies tailored to target specific molecular subtypes of liver metastases should be prioritized in future research.

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Fig. 1: Proportion of patients with baseline liver metastases stratified by disease stage across various clinical trials.
Fig. 2: Metastatic invasion of prostate tumour cells into the liver.
Fig. 3: PSMA-negative liver metastases can be FDG positive.
Fig. 4: Flowchart for the treatment of liver metastasis.
Fig. 5: Favourable response after olaparib treatment in a patient with multiple liver metastases.

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References

  1. Siegel, R. L., Miller, K. D., Wagle, N. S. & Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 73, 17–48 (2023).

    Article  PubMed  Google Scholar 

  2. Ma, B., Wells, A., Wei, L. & Zheng, J. Prostate cancer liver metastasis: dormancy and resistance to therapy. Semin. Cancer Biol. 71, 2–9 (2021).

    Article  CAS  PubMed  Google Scholar 

  3. Tsilimigras, D. I. et al. Liver metastases. Nat. Rev. Dis. Prim. 7, 27 (2021).

    Article  PubMed  Google Scholar 

  4. Gandaglia, G. et al. Impact of the site of metastases on survival in patients with metastatic prostate cancer. Eur. Urol. 68, 325–334 (2015).

    Article  PubMed  Google Scholar 

  5. Pond, G. R. et al. The prognostic importance of metastatic site in men with metastatic castration-resistant prostate cancer. Eur. Urol. 65, 3–6 (2014).

    Article  PubMed  Google Scholar 

  6. Halabi, S. et al. Meta-analysis evaluating the impact of site of metastasis on overall survival in men with castration-resistant prostate cancer. J. Clin. Oncol. 34, 1652–1659 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Heck, M. M. et al. Treatment outcome, toxicity, and predictive factors for radioligand therapy with (177)Lu-PSMA-I&T in metastatic castration-resistant prostate cancer. Eur. Urol. 75, 920–926 (2019).

    Article  CAS  PubMed  Google Scholar 

  8. Rahbar, K. et al. PSMA targeted radioligand therapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A retrospective analysis of overall survival. Eur. J. Nucl. Med. Mol. Imaging 45, 12–19 (2018).

    Article  CAS  PubMed  Google Scholar 

  9. Beltran, H. et al. A phase II trial of the Aurora kinase A inhibitor alisertib for patients with castration-resistant and neuroendocrine prostate cancer: efficacy and biomarkers. Clin. Cancer Res. 25, 43–51 (2019).

    Article  CAS  PubMed  Google Scholar 

  10. Gandaglia, G. et al. Distribution of metastatic sites in patients with prostate cancer: a population-based analysis. Prostate 74, 210–216 (2014).

    Article  PubMed  Google Scholar 

  11. Haffner, M. C. et al. Tracking the clonal origin of lethal prostate cancer. J. Clin. Invest. 123, 4918–4922 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. van Dessel, L. F. et al. Application of circulating tumor DNA in prospective clinical oncology trials — standardization of preanalytical conditions. Mol. Oncol. 11, 295–304 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  13. von Eyben, F. E., Picchio, M., von Eyben, R., Rhee, H. & Bauman, G. 68Ga-labeled prostate-specific membrane antigen ligand positron emission tomography/computed tomography for prostate cancer: a systematic review and meta-analysis. Eur. Urol. Focus. 4, 686–693 (2018).

    Article  PubMed  Google Scholar 

  14. Damjanovic, J. et al. 68Ga-PSMA-PET/CT for the evaluation of liver metastases in patients with prostate cancer. Cancer Imaging 19, 37 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Roviello, G., Petrioli, R., Villari, D. & D’Angelo, A. Treating de novo metastatic castration-sensitive prostate cancer with visceral metastases: an evolving issue. Clin. Genitourin. Cancer 19, 83–86 (2021).

    Article  PubMed  Google Scholar 

  16. Khreish, F. et al. Response and outcome of liver metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing 177Lu-PSMA-617 radioligand therapy. Eur. J. Nucl. Med. Mol. Imaging 48, 103–112 (2021).

    Article  CAS  PubMed  Google Scholar 

  17. Bubendorf, L. et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum. Pathol. 31, 578–583 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Shah, R. B. et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. 64, 9209–9216 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Pezaro, C. et al. Visceral disease in castration-resistant prostate cancer. Eur. Urol. 65, 270–273 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. van den Bergh, G. P. A. et al. Incidence and survival of castration-resistant prostate cancer patients with visceral metastases: results from the Dutch CAPRI-registry. Prostate Cancer Prostatic Dis. 26, 162–169 (2023).

    Article  PubMed  Google Scholar 

  21. Deng, Y. et al. A surveillance, epidemiology and end results database analysis of the prognostic value of organ-specific metastases in patients with advanced prostatic adenocarcinoma. Oncol. Lett. 18, 1057–1070 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Shou, J., Zhang, Q., Wang, S. & Zhang, D. The prognosis of different distant metastases pattern in prostate cancer: a population based retrospective study. Prostate 78, 491–497 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. Cotogno, P. M., Ranasinghe, L. K., Ledet, E. M., Lewis, B. E. & Sartor, O. Laboratory-based biomarkers and liver metastases in metastatic castration-resistant prostate cancer. Oncologist 23, 791–797 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ranasinghe, L. et al. Relationship between serum markers and volume of liver metastases in castration-resistant prostate cancer. Cancer Treat. Res. Commun. 20, 100151 (2019).

    Article  PubMed  Google Scholar 

  25. Rahbar, K. et al. German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients. J. Nucl. Med. 58, 85–90 (2017).

    Article  CAS  PubMed  Google Scholar 

  26. Ahmadzadehfar, H. et al. Prior therapies as prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients treated with [177Lu]Lu-PSMA-617. A WARMTH multicenter study (the 617 trial). Eur. J. Nucl. Med. Mol. Imaging 48, 113–122 (2021).

    Article  CAS  PubMed  Google Scholar 

  27. Kessel, K. et al. Second line chemotherapy and visceral metastases are associated with poor survival in patients with mCRPC receiving 177Lu-PSMA-617. Theranostics 9, 4841–4848 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Luna-Gutierrez, M. et al. Improving overall survival and quality of life in patients with prostate cancer and neuroendocrine tumors using 177Lu-iPSMA and 177Lu-DOTATOC: experience after 905 treatment doses. Pharmaceutics 15, 1988 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fendler, W. P. et al. Prostate-specific membrane antigen ligand positron emission tomography in men with nonmetastatic castration-resistant prostate cancer. Clin. Cancer Res. 25, 7448–7454 (2019).

    Article  CAS  PubMed  Google Scholar 

  30. Hofman, M. S. et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet 395, 1208–1216 (2020).

    Article  CAS  PubMed  Google Scholar 

  31. Maitland, N. J. Resistance to antiandrogens in prostate cancer: is it inevitable, intrinsic or induced? Cancers 13, 327 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Buxton, A. K., Abbasova, S., Bevan, C. L. & Leach, D. A. Liver microenvironment response to prostate cancer metastasis and hormonal therapy. Cancers 14, 6189 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Berry, W. R., Laszlo, J., Cox, E., Walker, A. & Paulson, D. Prognostic factors in metastatic and hormonally unresponsive carcinoma of the prostate. Cancer 44, 763–775 (1979).

    Article  CAS  PubMed  Google Scholar 

  34. Factors in the prognosis of carcinoma of the prostate: a cooperative study. The Veterans Administration Cooperative Urological Research Group. J. Urol. 100, 59–65 (1968).

    Google Scholar 

  35. Petrylak, D. P., Scher, H. I., Li, Z., Myers, C. E. & Geller, N. L. Prognostic factors for survival of patients with bidimensionally measurable metastatic hormone-refractory prostatic cancer treated with single-agent chemotherapy. Cancer 70, 2870–2878 (1992).

    Article  CAS  PubMed  Google Scholar 

  36. Chi, K. N. et al. A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel. Ann. Oncol. 27, 454–460 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Conteduca, V. et al. Impact of visceral metastases on outcome to abiraterone after docetaxel in castration-resistant prostate cancer patients. Future Oncol. 11, 2881–2891 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Vasil’eva, N. N. & Milievskaia, I. L. [Neurogenic stomach neoplasms induced by nitrosomethylures in Syrian hamsters]. Arkh Patol. 39, 66–71 (1977).

    PubMed  Google Scholar 

  39. Armstrong, A. J. et al. A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin. Cancer Res. 13, 6396–6403 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Loriot, Y. et al. Enzalutamide in castration-resistant prostate cancer patients with visceral disease in the liver and/or lung: outcomes from the randomized controlled phase 3 AFFIRM trial. Cancer 123, 253–262 (2017).

    Article  CAS  PubMed  Google Scholar 

  41. Alumkal, J. J. et al. Effect of visceral disease site on outcomes in patients with metastatic castration-resistant prostate cancer treated with enzalutamide in the PREVAIL trial. Clin. Genitourin. Cancer 15, 610–617 e613 (2017).

    Article  PubMed  Google Scholar 

  42. Beer, T. M. et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med. 371, 424–433 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Baciarello, G. et al. Impact of abiraterone acetate plus prednisone in patients with castration-sensitive prostate cancer and visceral metastases over four years of follow-up: a post-hoc exploratory analysis of the LATITUDE study. Eur. J. Cancer 162, 56–64 (2022).

    Article  CAS  PubMed  Google Scholar 

  44. Satapathy, S., Mittal, B. R. & Sood, A. Visceral metastases as predictors of response and survival outcomes in patients of castration-resistant prostate cancer treated with 177Lu-labeled prostate-specific membrane antigen radioligand therapy: a systematic review and meta-analysis. Clin. Nucl. Med. 45, 935–942 (2020).

    Article  PubMed  Google Scholar 

  45. Armstrong, A. J. et al. Development and validation of a prognostic model for overall survival in chemotherapy-naive men with metastatic castration-resistant prostate cancer. Ann. Oncol. 29, 2200–2207 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Akamatsu, S. et al. Development and validation of a novel prognostic model for predicting overall survival in treatment-naive castration-sensitive metastatic prostate cancer. Eur. Urol. Oncol. 2, 320–328 (2019).

    Article  PubMed  Google Scholar 

  47. Gafita, A. et al. Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study. Lancet Oncol. 22, 1115–1125 (2021).

    Article  CAS  PubMed  Google Scholar 

  48. Labrecque, M. P. et al. Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer. J. Clin. Invest. 129, 4492–4505 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Aggarwal, R. et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J. Clin. Oncol. 36, 2492–2503 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bakht, M. K. et al. Landscape of prostate-specific membrane antigen heterogeneity and regulation in AR-positive and AR-negative metastatic prostate cancer. Nat. Cancer 4, 699–715 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Feng, E. et al. Intrinsic molecular subtypes of metastatic castration-resistant prostate cancer. Clin. Cancer Res. 28, 5396–5404 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Conteduca, V. et al. Clinical features of neuroendocrine prostate cancer. Eur. J. Cancer 121, 7–18 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Thysell, E. et al. Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor. Mol. Oncol. 13, 1763–1777 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ku, S. Y., Gleave, M. E. & Beltran, H. Towards precision oncology in advanced prostate cancer. Nat. Rev. Urol. 16, 645–654 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Paschalis, A. et al. Prostate-specific membrane antigen heterogeneity and DNA repair defects in prostate cancer. Eur. Urol. 76, 469–478 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kumar, A. et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat. Med. 22, 369–378 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Alshalalfa, M. et al. Clinicogenomic characterization of prostate cancer liver metastases. Prostate Cancer Prostatic Dis. 25, 366–369 (2022).

    Article  CAS  PubMed  Google Scholar 

  58. Samarzija, I. Site-specific and common prostate cancer metastasis genes as suggested by meta-analysis of gene expression data. Life 11, 636 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Faltermeier, C. M. et al. Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. Proc. Natl Acad. Sci. USA 113, E172–E181 (2016).

    Article  CAS  PubMed  Google Scholar 

  60. Lee, J. W. et al. Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature 567, 249–252 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Eveno, C. et al. Proof of prometastatic niche induction by hepatic stellate cells. J. Surg. Res. 194, 496–504 (2015).

    Article  PubMed  Google Scholar 

  62. Kopp, W. [Morphometric distribution of HLA-DR-coded immunocytes in gingiva biopsy specimens with periodontal disease]. Dtsch. Zahnarztl. Z. 45, 93–97 (1990).

    CAS  PubMed  Google Scholar 

  63. Kondo, T. et al. The impact of hepatic fibrosis on the incidence of liver metastasis from colorectal cancer. Br. J. Cancer 115, 34–39 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ohlund, D., Elyada, E. & Tuveson, D. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211, 1503–1523 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Costa-Silva, B. et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hintz, H. M. et al. Imaging fibroblast activation protein alpha improves diagnosis of metastatic prostate cancer with positron emission tomography. Clin. Cancer Res. 26, 4882–4891 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. James, N. D. et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N. Engl. J. Med. 377, 338–351 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Colomba, E. et al. Liver tests increase on abiraterone acetate in men with metastatic prostate cancer: natural history, management and outcome. Eur. J. Cancer 129, 117–122 (2020).

    Article  CAS  PubMed  Google Scholar 

  69. Yun, G. Y. et al. Atypical onset of bicalutamide-induced liver injury. World J. Gastroenterol. 22, 4062–4065 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kim, O. H. et al. Fluid shear stress facilitates prostate cancer metastasis through Piezo1-Src-YAP axis. Life Sci. 308, 120936 (2022).

    Article  CAS  PubMed  Google Scholar 

  71. Akoto, T. & Saini, S. Role of exosomes in prostate cancer metastasis. Int. J. Mol. Sci. 22, 3528 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Vagner, T. et al. Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma. J. Extracell. Vesicles 7, 1505403 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Teng, Y. et al. MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression. Nat. Commun. 8, 14448 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Li, S. et al. Tumour-derived exosomes in liver metastasis: a Pandora’s box. Cell Prolif. 56, e13452 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li, C. et al. hnRNPA2B1-mediated extracellular vesicles sorting of miR-122-5p potentially promotes lung cancer progression. Int. Mol. J. Sci. 22, 12866 (2021).

    Article  CAS  Google Scholar 

  77. Zhang, C. et al. Cancer-derived exosomal HSPC111 promotes colorectal cancer liver metastasis by reprogramming lipid metabolism in cancer-associated fibroblasts. Cell Death Dis. 13, 57 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zeng, Z. et al. Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat. Commun. 9, 5395 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kim, J. et al. Three-dimensional human liver-chip emulating premetastatic niche formation by breast cancer-derived extracellular vesicles. ACS Nano 14, 14971–14988 (2020).

    Article  CAS  PubMed  Google Scholar 

  80. Novizio, N. et al. ANXA1 contained in EVs regulates macrophage polarization in tumor microenvironment and promotes pancreatic cancer progression and metastasis. Int. J. Mol. Sci. 22, 11018 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Baig, M. S. et al. Tumor-derived exosomes in the regulation of macrophage polarization. Inflamm. Res. 69, 435–451 (2020).

    Article  CAS  PubMed  Google Scholar 

  82. Chang, Y. T. et al. Pancreatic cancer-derived small extracellular vesical Ezrin regulates macrophage polarization and promotes metastasis. Am. J. Cancer Res. 10, 12–37 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yin, X. et al. MiR-26b-5p in small extracellular vesicles derived from dying tumor cells after irradiation enhances the metastasis promoting microenvironment in esophageal squamous cell carcinoma. Cancer Lett. 541, 215746 (2022).

    Article  CAS  PubMed  Google Scholar 

  84. Sun, H. et al. Hypoxia-inducible exosomes facilitate liver-tropic premetastatic niche in colorectal cancer. Hepatology 74, 2633–2651 (2021).

    Article  CAS  PubMed  Google Scholar 

  85. Kmiec, Z. Cooperation of liver cells in health and disease. Adv. Anat. Embryol. Cell Biol. 161, 1–151 (2001). III-XIII.

    Google Scholar 

  86. Matsumura, H. et al. Kupffer cells decrease metastasis of colon cancer cells to the liver in the early stage. Int. J. Oncol. 45, 2303–2310 (2014).

    Article  PubMed  Google Scholar 

  87. Condamine, T. & Gabrilovich, D. I. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 32, 19–25 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Zhao, W. et al. Hepatic stellate cells promote tumor progression by enhancement of immunosuppressive cells in an orthotopic liver tumor mouse model. Lab. Invest. 94, 182–191 (2014).

    Article  CAS  PubMed  Google Scholar 

  89. Bu, P. et al. Aldolase B-mediated fructose metabolism drives metabolic reprogramming of colon cancer liver metastasis. Cell Metab. 27, 1249–1262 e1244 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Spratt, D. E. et al. Utility of FDG-PET in clinical neuroendocrine prostate cancer. Prostate 74, 1153–1159 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Yates, C. C., Shepard, C. R., Stolz, D. B. & Wells, A. Co-culturing human prostate carcinoma cells with hepatocytes leads to increased expression of E-cadherin. Br. J. Cancer 96, 1246–1252 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wells, A., Yates, C. & Shepard, C. R. E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin. Exp. Metastasis 25, 621–628 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ma, B. & Wells, A. The mitogen-activated protein (MAP) kinases p38 and extracellular signal-regulated kinase (ERK) are involved in hepatocyte-mediated phenotypic switching in prostate cancer cells. J. Biol. Chem. 289, 11153–11161 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ma, B. et al. Liver protects metastatic prostate cancer from induced death by activating E-cadherin signaling. Hepatology 64, 1725–1742 (2016).

    Article  CAS  PubMed  Google Scholar 

  95. Ma, B., Khazali, A., Shao, H., Jiang, Y. & Wells, A. Expression of E-cadherin and specific CXCR3 isoforms impact each other in prostate cancer. Cell Commun. Signal. 17, 164 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lin, H. Y. et al. Matriptase-2/NR4A3 axis switches TGF-β action toward suppression of prostate cancer cell invasion, tumor growth, and metastasis. Oncogene 41, 2833–2845 (2022).

    Article  CAS  PubMed  Google Scholar 

  97. Wu, Q., Dhir, R. & Wells, A. Altered CXCR3 isoform expression regulates prostate cancer cell migration and invasion. Mol. Cancer 11, 3 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zhu, W. B., Zhao, Z. F. & Zhou, X. AMD3100 inhibits epithelial-mesenchymal transition, cell invasion, and metastasis in the liver and the lung through blocking the SDF-1ɑ/CXCR4 signaling pathway in prostate cancer. J. Cell Physiol. 234, 11746–11759 (2019).

    Article  CAS  PubMed  Google Scholar 

  99. Steele, R., Mott, J. L. & Ray, R. B. MBP-1 upregulates miR-29b that represses Mcl-1, collagens, and matrix-metalloproteinase-2 in prostate cancer cells. Genes. Cancer 1, 381–387 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ru, P. et al. miRNA-29b suppresses prostate cancer metastasis by regulating epithelial-mesenchymal transition signaling. Mol. Cancer Ther. 11, 1166–1173 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Liu, C. et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat. Med. 17, 211–215 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).

    Article  CAS  PubMed  Google Scholar 

  103. Gao, Y. et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat. Immunol. 18, 1004–1015 (2017).

    Article  CAS  PubMed  Google Scholar 

  104. Correia, A. L. et al. Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy. Nature 594, 566–571 (2021).

    Article  CAS  PubMed  Google Scholar 

  105. Ducimetiere, L. et al. Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis. Proc. Natl Acad. Sci. USA 118, e2026271118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Donkor, M. K. et al. T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-β1 cytokine. Immunity 35, 123–134 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Yu, J. et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat. Med. 27, 152–164 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ham, B. et al. TNF receptor-2 facilitates an immunosuppressive microenvironment in the liver to promote the colonization and growth of hepatic metastases. Cancer Res. 75, 5235–5247 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Yang, S. et al. Integrated multi-omics landscape of liver metastases. Gastroenterology 164, 407–423 e417 (2023).

    Article  CAS  PubMed  Google Scholar 

  110. Wu, J. B. et al. MAOA-dependent activation of Shh-IL6-RANKL signaling network promotes prostate cancer metastasis by engaging tumor-stromal cell interactions. Cancer Cell 31, 368–382 (2017).

    Article  CAS  PubMed  Google Scholar 

  111. Wegiel, B. et al. Multiple cellular mechanisms related to cyclin A1 in prostate cancer invasion and metastasis. J. Natl Cancer Inst. 100, 1022–1036 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Klezovitch, O. et al. Hepsin promotes prostate cancer progression and metastasis. Cancer Cell 6, 185–195 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Hsin, F., Hsu, Y. C., Tsai, Y. F., Lin, S. W. & Liu, H. M. The transmembrane serine protease hepsin suppresses type I interferon induction by cleaving STING. Sci. Signal 14, eabb4752 (2021).

    Article  CAS  PubMed  Google Scholar 

  114. Su, W. et al. The polycomb repressor complex 1 drives double-negative prostate cancer metastasis by coordinating stemness and immune suppression. Cancer Cell 36, 139–155 e110 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sailer, V. et al. Experimental in vitro, ex vivo and in vivo models in prostate cancer research. Nat. Rev. Urol. 20, 158–178 (2023).

    Article  PubMed  Google Scholar 

  116. Gao, D. et al. Organoid cultures derived from patients with advanced prostate cancer. Cell 159, 176–187 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Pauli, C. et al. Personalized in vitro and in vivo cancer models to guide precision medicine. Cancer Discov. 7, 462–477 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Hsiao, A. Y. et al. Microfluidic system for formation of PC-3 prostate cancer co-culture spheroids. Biomaterials 30, 3020–3027 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Bock, N. et al. In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer. Sci. Adv. 7, eabg2564 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lau, W. M. et al. Identification of prospective factors promoting osteotropism in breast cancer: a potential role for CITED2. Int. J. Cancer 126, 876–884 (2010).

    Article  CAS  PubMed  Google Scholar 

  121. Qi, X. et al. An oncogenic hepatocyte-induced orthotopic mouse model of hepatocellular cancer arising in the setting of hepatic inflammation and fibrosis. J. Vis. Exp. https://doi.org/10.3791/59368 (2019).

  122. Liu, K. et al. A novel mouse model for liver metastasis of prostate cancer reveals dynamic tumour-immune cell communication. Cell Prolif. 54, e13056 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Acevedo, V. D. et al. Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer Cell 12, 559–571 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Cho, H. et al. RapidCaP, a novel GEM model for metastatic prostate cancer analysis and therapy, reveals myc as a driver of Pten-mutant metastasis. Cancer Discov. 4, 318–333 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Taranda, J. et al. Combined whole-organ imaging at single-cell resolution and immunohistochemical analysis of prostate cancer and its liver and brain metastases. Cell Rep. 37, 110027 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zaporowska-Stachowiak, I. et al. Managing metastatic bone pain: new perspectives, different solutions. Biomed. Pharmacother. 93, 1277–1284 (2017).

    Article  CAS  PubMed  Google Scholar 

  127. Alderton, G. K. Metastasis: directions to metastatic sites. Nat. Rev. Cancer 15, 696–697 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Xu, N. et al. Risk factors of developing visceral metastases at diagnosis in prostate cancer patients. Transl. Cancer Res. 8, 928–938 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Steffens, J., Friedmann, W. & Lobeck, H. Immunohistochemical diagnosis of the metastasizing prostatic carcinoma. Eur. Urol. 11, 91–94 (1985).

    Article  CAS  PubMed  Google Scholar 

  130. Whitney, C. A. et al. In men with castration-resistant prostate cancer, visceral metastases predict shorter overall survival: what predicts visceral metastases? Results from the SEARCH database. Eur. Urol. Focus. 3, 480–486 (2017).

    Article  PubMed  Google Scholar 

  131. Minami, Y. & Kudo, M. Hepatic malignancies: correlation between sonographic findings and pathological features. World J. Radiol. 2, 249–256 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Sahani, D. V., Bajwa, M. A., Andrabi, Y., Bajpai, S. & Cusack, J. C. Current status of imaging and emerging techniques to evaluate liver metastases from colorectal carcinoma. Ann. Surg. 259, 861–872 (2014).

    Article  PubMed  Google Scholar 

  133. Tanaka, T. et al. Current imaging techniques for and imaging spectrum of prostate cancer recurrence and metastasis: a pictorial review. Radiographics 40, 709–726 (2020).

    Article  PubMed  Google Scholar 

  134. Namasivayam, S., Martin, D. R. & Saini, S. Imaging of liver metastases: MRI. Cancer Imaging 7, 2–9 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Niekel, M. C., Bipat, S. & Stoker, J. Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment. Radiology 257, 674–684 (2010).

    Article  PubMed  Google Scholar 

  136. Floriani, I. et al. Performance of imaging modalities in diagnosis of liver metastases from colorectal cancer: a systematic review and meta-analysis. J. Magn. Reson. Imaging 31, 19–31 (2010).

    Article  PubMed  Google Scholar 

  137. Brimo, F. & Epstein, J. I. Immunohistochemical pitfalls in prostate pathology. Hum. Pathol. 43, 313–324 (2012).

    Article  CAS  PubMed  Google Scholar 

  138. de Galiza Barbosa, F. et al. Nonprostatic diseases on PSMA PET imaging: a spectrum of benign and malignant findings. Cancer Imaging 20, 23 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Jadvar, H. Molecular imaging of prostate cancer: PET radiotracers.AJR Am. J. Roentgenol. 199, 278–291 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Jadvar, H. Positron emission tomography in prostate cancer: summary of systematic reviews and meta-analysis. Tomography 1, 18–22 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Vaz, C. V. et al. Androgens enhance the glycolytic metabolism and lactate export in prostate cancer cells by modulating the expression of GLUT1, GLUT3, PFK, LDH and MCT4 genes. J. Cancer Res. Clin. Oncol. 142, 5–16 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Jadvar, H. Molecular imaging of prostate cancer with 18F-fluorodeoxyglucose PET. Nat. Rev. Urol. 6, 317–323 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Umbehr, M. H., Muntener, M., Hany, T., Sulser, T. & Bachmann, L. M. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and meta-analysis. Eur. Urol. 64, 106–117 (2013).

    Article  PubMed  Google Scholar 

  144. Garcia, J. R. et al. [Low diagnostic yield of the 11C-choline PET/CT in the detection of liver metastasis from prostate cancer]. Rev. Esp. Med. Nucl. Imagen Mol. 33, 56–57 (2014).

    CAS  PubMed  Google Scholar 

  145. Ghedini, P. et al. Liver metastases from prostate cancer at 11C-Choline PET/CT: a multicenter, retrospective analysis. Eur. J. Nucl. Med. Mol. Imaging 45, 751–758 (2018).

    Article  CAS  PubMed  Google Scholar 

  146. Bianchi, D., Rizzo, A., Bonacina, M., Zaniboni, A. & Savelli, G. Penile metastasis from prostate cancer detected by 18F-fluorocholine PET/CT. Clin. Nucl. Med. 46, e38–e39 (2021).

    Article  PubMed  Google Scholar 

  147. Dejust, S., Messaoud, L., Jallerat, P., Marical, V. & Morland, D. Hepatic metastases from prostatic adenocarcinoma without elevated 18F-choline activity. Clin. Nucl. Med. 43, 780–781 (2018).

    Article  PubMed  Google Scholar 

  148. Onner, H., Ozer, H., Celik, A. V., Yilmaz, F. & Kara Gedik, G. Isolated liver metastasis detected by 68Ga-PSMA PET/CT in newly diagnosed prostate cancer. Clin. Nucl. Med. 48, 259–260 (2023).

    Article  PubMed  Google Scholar 

  149. De Man, K. et al. 18F-PSMA-11 versus 68Ga-PSMA-11 positron emission tomography/computed tomography for staging and biochemical recurrence of prostate cancer: a prospective double-blind randomised cross-over trial. Eur. Urol. 82, 501–509 (2022).

    Article  PubMed  Google Scholar 

  150. Seniaray, N., Verma, R., Belho, E., Malik, D. & Mahajan, H. Diffuse pulmonary metastases from prostate cancer on 68Ga PSMA PET/CT. Clin. Nucl. Med. 44, 898–900 (2019).

    Article  PubMed  Google Scholar 

  151. Soydal, C., Ozkan, E., Yerlikaya, H., Utkan, G. & Kucuk, O. N. Widespread metastatic prostate carcinoma shown by 68Ga-PSMA PET/CT. Clin. Nucl. Med. 41, e294–e295 (2016).

    Article  PubMed  Google Scholar 

  152. Chan, M., Hsiao, E. & Turner, J. Cerebellar metastases from prostate cancer on 68Ga-PSMA PET/CT. Clin. Nucl. Med. 42, 193–194 (2017).

    Article  PubMed  Google Scholar 

  153. Seifert, R. et al. Second version of the prostate cancer molecular imaging standardized evaluation framework including response evaluation for clinical trials (PROMISE V2). Eur. Urol. 83, 405–412 (2023).

    Article  CAS  PubMed  Google Scholar 

  154. Watt, F. et al. A tissue-specific enhancer of the prostate-specific membrane antigen gene, FOLH1. Genomics 73, 243–254 (2001).

    Article  CAS  PubMed  Google Scholar 

  155. Noss, K. R., Wolfe, S. A. & Grimes, S. R. Upregulation of prostate specific membrane antigen/folate hydrolase transcription by an enhancer. Gene 285, 247–256 (2002).

    Article  CAS  PubMed  Google Scholar 

  156. Beltran, H. et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat. Med. 22, 298–305 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Bakht, M. K. et al. Neuroendocrine differentiation of prostate cancer leads to PSMA suppression. Endocr. Relat. Cancer 26, 131–146 (2018).

    Article  PubMed  Google Scholar 

  158. Thang, S. P. et al. Poor outcomes for patients with metastatic castration-resistant prostate cancer with low prostate-specific membrane antigen (PSMA) expression deemed ineligible for 177Lu-labelled PSMA radioligand therapy. Eur. Urol. Oncol. 2, 670–676 (2019).

    Article  PubMed  Google Scholar 

  159. Evans, M. J. et al. Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen. Proc. Natl Acad. Sci. USA 108, 9578–9582 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Shetty, D., Patel, D., Le, K., Bui, C. & Mansberg, R. Pitfalls in gallium-68 PSMA PET/CT interpretation-A pictorial review. Tomography 4, 182–193 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Ladron-de-Guevara, D., Canelo, A., Piottante, A. & Regonesi, C. False-positive 18F-prostate-specific membrane antigen-1007 PET/CT caused by hepatic multifocal inflammatory foci. Clin. Nucl. Med. 46, e80–e83 (2021).

    Article  PubMed  Google Scholar 

  162. Kesch, C. et al. High fibroblast-activation-protein expression in castration-resistant prostate cancer supports the use of FAPI-molecular theranostics. Eur. J. Nucl. Med. Mol. Imaging 49, 385–389 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Kessel, K. et al. Prostate-specific membrane antigen and fibroblast activation protein distribution in prostate cancer: preliminary data on immunohistochemistry and PET imaging. Ann. Nucl. Med. 36, 293–301 (2022).

    Article  CAS  PubMed  Google Scholar 

  164. Bluemel, C. et al. 68Ga-PSMA-PET/CT in patients with biochemical prostate cancer recurrence and negative 18F-Choline-PET/CT. Clin. Nucl. Med. 41, 515–521 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Bakht, M. K. et al. Differential expression of glucose transporters and hexokinases in prostate cancer with a neuroendocrine gene signature: a mechanistic perspective for 18F-FDG imaging of PSMA-suppressed tumors. J. Nucl. Med. 61, 904–910 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Jadvar, H. The VISION forward: recognition and implication of PSMA-/18F-FDG+ mCRPC. J. Nucl. Med. 63, 812–815 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ignatiadis, M., Sledge, G. W. & Jeffrey, S. S. Liquid biopsy enters the clinic - implementation issues and future challenges. Nat. Rev. Clin. Oncol. 18, 297–312 (2021).

    Article  PubMed  Google Scholar 

  168. Xu, L. et al. The novel association of circulating tumor cells and circulating megakaryocytes with prostate cancer prognosis. Clin. Cancer Res. 23, 5112–5122 (2017).

    Article  CAS  PubMed  Google Scholar 

  169. Aceto, N. et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110–1122 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Hille, C. & Pantel, K. Prostate cancer: circulating tumour cells in prostate cancer. Nat. Rev. Urol. 15, 265–266 (2018).

    Article  CAS  PubMed  Google Scholar 

  171. Chen, J. F. et al. Subclassification of prostate cancer circulating tumor cells by nuclear size reveals very small nuclear circulating tumor cells in patients with visceral metastases. Cancer 121, 3240–3251 (2015).

    Article  PubMed  Google Scholar 

  172. Snyder, M. W., Kircher, M., Hill, A. J., Daza, R. M. & Shendure, J. Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin. Cell 164, 57–68 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Mouliere, F. et al. Enhanced detection of circulating tumor DNA by fragment size analysis. Sci. Transl. Med. 10, eaat4921 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Mehra, N. et al. Plasma cell-free DNA concentration and outcomes from taxane therapy in metastatic castration-resistant prostate cancer from two phase III trials (FIRSTANA and PROSELICA). Eur. Urol. 74, 283–291 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Vandekerkhove, G. et al. Circulating tumor DNA abundance and potential utility in de novo metastatic prostate cancer. Eur. Urol. 75, 667–675 (2019).

    Article  CAS  PubMed  Google Scholar 

  176. Wyatt, A. W. et al. Concordance of circulating tumor DNA and matched metastatic tissue biopsy in prostate cancer. J. Natl Cancer Inst. 109, djx118 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Schweizer, M. T. et al. Concordance of DNA repair gene mutations in paired primary prostate cancer samples and metastatic tissue or cell-free DNA. JAMA Oncol. 7, 1–5 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Beltran, H. et al. Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer. J. Clin. Invest. 130, 1653–1668 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Del Re, M. et al. The detection of androgen receptor splice variant 7 in plasma-derived exosomal RNA strongly predicts resistance to hormonal therapy in metastatic prostate cancer patients. Eur. Urol. 71, 680–687 (2017).

    Article  PubMed  Google Scholar 

  180. Zhang, Y. et al. Loss of exosomal miR-146a-5p from cancer-associated fibroblasts after androgen deprivation therapy contributes to prostate cancer metastasis. J. Exp. Clin. Cancer Res. 39, 282 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Bhagirath, D. et al. microRNA-1246 is an exosomal biomarker for aggressive prostate cancer. Cancer Res. 78, 1833–1844 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Davis, I. D. et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N. Engl. J. Med. 381, 121–131 (2019).

    Article  CAS  PubMed  Google Scholar 

  183. Goodman, O. B. Jr et al. Exploratory analysis of the visceral disease subgroup in a phase III study of abiraterone acetate in metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 17, 34–39 (2014).

    Article  CAS  PubMed  Google Scholar 

  184. Berthold, D. R. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J. Clin. Oncol. 26, 242–245 (2008).

    Article  CAS  PubMed  Google Scholar 

  185. de Wit, R. et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N. Engl. J. Med. 381, 2506–2518 (2019).

    Article  PubMed  Google Scholar 

  186. Alabi, B. R., Liu, S. & Stoyanova, T. Current and emerging therapies for neuroendocrine prostate cancer. Pharmacol. Ther. 238, 108255 (2022).

    Article  CAS  PubMed  Google Scholar 

  187. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04709276 (2024).

  188. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05413421 (2024).

  189. Fizazi, K. et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 x 2 factorial design. Lancet 399, 1695–1707 (2022).

    Article  CAS  PubMed  Google Scholar 

  190. Hussain, M. et al. Darolutamide plus androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer by disease volume and risk subgroups in the phase III ARASENS trial. J. Clin. Oncol. 41, 3595–3607 (2023).

    Article  CAS  PubMed  Google Scholar 

  191. Clarke, N. W. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. N. Engl. J. Med. Evid. 1, 9 (2022).

    Google Scholar 

  192. Agarwal, N. et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet 402, 291–303 (2023).

    Article  CAS  PubMed  Google Scholar 

  193. de Bono, J. S. et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 22, 1250–1264 (2021).

    Article  PubMed  Google Scholar 

  194. Chi, K. N. et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann. Oncol. 34, 772–782 (2023).

    Article  CAS  PubMed  Google Scholar 

  195. Abida, W. et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J. Clin. Oncol. 38, 3763–3772 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Petrylak, D. P. et al. Pembrolizumab plus docetaxel for patients with metastatic castration-resistant prostate cancer (mCRPC): randomized, double-blind, phase 3 KEYNOTE-921 study. J. Clin. Oncol. 41, 19–19 (2023).

    Article  Google Scholar 

  197. Hennrich, U. & Eder, M. [177Lu]Lu-PSMA-617 (PluvictoTM): the first FDA-approved radiotherapeutical for treatment of prostate cancer. Pharmaceuticals 15, 1292 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Sartor, O. et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N. Engl. J. Med. 385, 1091–1103 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Pouessel, D. et al. Liver metastases in prostate carcinoma: clinical characteristics and outcome. BJU Int. 99, 807–811 (2007).

    Article  CAS  PubMed  Google Scholar 

  200. Ferdinandus, J. et al. Predictors of response to radioligand therapy of metastatic castrate-resistant prostate cancer with 177Lu-PSMA-617. J. Nucl. Med. 58, 312–319 (2017).

    Article  CAS  PubMed  Google Scholar 

  201. Violet, J. et al. Dosimetry of 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer: correlations between pretherapeutic imaging and whole-body tumor dosimetry with treatment outcomes. J. Nucl. Med. 60, 517–523 (2019).

    Article  CAS  PubMed  Google Scholar 

  202. Park, I. K. et al. Effect of equine-assisted activities on cardiac autonomic function in children with cerebral palsy: a pilot randomized-controlled trial. J. Altern. Complement. Med. 27, 96–102 (2021).

    Article  PubMed  Google Scholar 

  203. Kyte, J. A. Cancer vaccination with telomerase peptide GV1001. Expert. Opin. Investig. Drugs 18, 687–694 (2009).

    Article  CAS  PubMed  Google Scholar 

  204. Kim, J. W. et al. Anti-metastatic effect of GV1001 on prostate cancer cells; roles of GnRHR-mediated Gɑs-cAMP pathway and AR-YAP1 axis. Cell Biosci. 11, 191 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Agarwal, N. et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). Lancet Oncol. 23, 899–909 (2022).

    Article  CAS  PubMed  Google Scholar 

  206. Agarwal, N. et al. A phase III, randomized, open-label study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy in patients with metastatic castration-resistant prostate cancer. Future Oncol. 18, 1185–1198 (2022).

    Article  CAS  PubMed  Google Scholar 

  207. Pang, Y. et al. Development of FAPI tetramers to improve tumor uptake and efficacy of FAPI radioligand therapy. J. Nucl. Med. 64, 1449–1455 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Feuerecker, B. et al. Activity and adverse events of actinium-225-PSMA-617 in advanced metastatic castration-resistant prostate cancer after failure of lutetium-177-PSMA. Eur. Urol. 79, 343–350 (2021).

    Article  CAS  PubMed  Google Scholar 

  209. Ballal, S. et al. Long-term survival outcomes of salvage [225Ac]Ac-PSMA-617 targeted alpha therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer: a real-world study. Eur. J. Nucl. Med. Mol. Imaging 50, 3777–3789 (2023).

    Article  CAS  PubMed  Google Scholar 

  210. Sathekge, M. M., Bruchertseifer, F., Vorster, M., Morgenstern, A. & Lawal, I. O. Global experience with PSMA-based alpha therapy in prostate cancer. Eur. J. Nucl. Med. Mol. Imaging 49, 30–46 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Zang, J. et al. First-in-human study of 177Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer. Eur. J. Nucl. Med. Mol. Imaging 46, 148–158 (2019).

    Article  CAS  PubMed  Google Scholar 

  212. Wang, G. et al. A single-arm, low-dose, prospective study of 177Lu-EB-PSMA radioligand therapy in patients with metastatic castration-resistant prostate cancer. J. Nucl. Med. 64, 611–617 (2023).

    Article  CAS  PubMed  Google Scholar 

  213. Ost, P. et al. Metastasis-directed therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature. Eur. Urol. 67, 852–863 (2015).

    Article  PubMed  Google Scholar 

  214. Wang, S. C., McCarthy, L. P. & Mehdi, S. Isolated hepatic metastasis from prostate carcinoma. Urol. Case Rep. 10, 51–53 (2017).

    Article  PubMed  Google Scholar 

  215. Battaglia, A. et al. Metastasectomy for visceral and skeletal oligorecurrent prostate cancer. World J. Urol. 37, 1543–1549 (2019).

    Article  PubMed  Google Scholar 

  216. Zager, J. S. et al. FOCUS phase 3 trial results: percutaneous hepatic perfusion (PHP) with melphalan for patients with ocular melanoma liver metastases (PHP-OCM-301/301A). J. Clin. Oncol. 40, 9510–9510 (2022).

    Article  Google Scholar 

  217. Chalkidou, A. et al. Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study. Lancet Oncol. 22, 98–106 (2021).

    Article  PubMed  Google Scholar 

  218. Wang, H., Li, X., Peng, R., Wang, Y. & Wang, J. Stereotactic ablative radiotherapy for colorectal cancer liver metastasis. Semin. Cancer Biol. 71, 21–32 (2021).

    Article  CAS  PubMed  Google Scholar 

  219. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT02239900 (2024).

  220. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT02710253 (2024).

  221. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT02843165 (2024).

  222. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT02888743 (2024).

  223. Corn, P. G. et al. Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1–2 trial. Lancet Oncol. 20, 1432–1443 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04592237 (2024).

  225. Blum, A., Wang, P. & Zenklusen, J. C. SnapShot: TCGA analyzed tumors. Cell 173, 530 (2018).

    Article  CAS  PubMed  Google Scholar 

  226. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

    Article  PubMed  Google Scholar 

  227. Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Fizazi, K. et al. Health-related quality of life and pain outcomes with [177Lu]Lu-PSMA-617 plus standard of care versus standard of care in patients with metastatic castration-resistant prostate cancer (VISION): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 24, 597–610 (2023).

    Article  CAS  PubMed  Google Scholar 

  229. Chi, K. N. et al. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J. Clin. Oncol. 41, 3339–3351 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Kelly, W. K. et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J. Clin. Oncol. 30, 1534–1540 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Chi, K. N. et al. Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 18, 473–485 (2017).

    Article  CAS  PubMed  Google Scholar 

  232. Saad, F. et al. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. Lancet Oncol. 16, 338–348 (2015).

    Article  CAS  PubMed  Google Scholar 

  233. Oudard, S. et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized phase III trial-FIRSTANA. J. Clin. Oncol. 35, 3189–3197 (2017).

    Article  CAS  PubMed  Google Scholar 

  234. Vogelzang, N. J. et al. Efficacy and safety of autologous dendritic cell-based immunotherapy, docetaxel, and prednisone vs placebo in patients with metastatic castration-resistant prostate cancer: the VIABLE phase 3 randomized clinical trial. JAMA Oncol. 8, 546–552 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Saad, F. et al. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 22, 1541–1559 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Morris, M. J. et al. Randomized phase III study of enzalutamide compared with enzalutamide plus abiraterone for metastatic castration-resistant prostate cancer (Alliance A031201 Trial). J. Clin. Oncol. 41, 3352–3362 (2023).

    Article  CAS  PubMed  Google Scholar 

  237. Kellokumpu-Lehtinen, P. L. et al. 2-Weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial. Lancet Oncol. 14, 117–124 (2013).

    Article  CAS  PubMed  Google Scholar 

  238. Beer, T. M. et al. Custirsen (OGX-011) combined with cabazitaxel and prednisone versus cabazitaxel and prednisone alone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel (AFFINITY): a randomised, open-label, international, phase 3 trial. Lancet Oncol. 18, 1532–1542 (2017).

    Article  CAS  PubMed  Google Scholar 

  239. Fizazi, K. et al. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J. Clin. Oncol. 33, 723–731 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Eisenberger, M. et al. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m2) and the currently approved dose (25 mg/m2) in postdocetaxel patients with metastatic castration-resistant prostate cancer-PROSELICA. J. Clin. Oncol. 35, 3198–3206 (2017).

    Article  CAS  PubMed  Google Scholar 

  241. Antonarakis, E. S. et al. Pembrolizumab plus olaparib for patients with previously treated and biomarker-unselected metastatic castration-resistant prostate cancer: the randomized, open-label, phase III KEYLYNK-010 trial. J. Clin. Oncol. 41, 3839–3850 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Smith, M. et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J. Clin. Oncol. 34, 3005–3013 (2016).

    Article  CAS  PubMed  Google Scholar 

  243. Gravis, G. et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 14, 149–158 (2013).

    Article  CAS  PubMed  Google Scholar 

  244. Chi, K. N. et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N. Engl. J. Med. 381, 13–24 (2019).

    Article  CAS  PubMed  Google Scholar 

  245. Agarwal, N. et al. Orteronel for metastatic hormone-sensitive prostate cancer: a multicenter, randomized, open-label phase III trial (SWOG-1216). J. Clin. Oncol. 40, 3301–3309 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03179410 (2024).

  247. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03582475 (2024).

  248. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03910660 (2024).

  249. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03896503 (2024).

  250. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04702737 (2024).

  251. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04848337 (2024).

  252. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04926181 (2024).

  253. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05582031 (2024).

  254. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05605522 (2024).

  255. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05652686 (2024).

  256. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05988918 (2024).

  257. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05691465 (2024).

  258. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06094842 (2024).

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Acknowledgements

This study was supported by Oriental Scholar Professorship, Shanghai Municipal Commission of Education, China; National Nature Science Foundation of China (82172621, 81972375); Shanghai Medical Innovation Research Special Project (21Y11904300); Shanghai Shenkang Research Physician Innovation and Transformation Ability Training Project (SHDC2022CRD035); General Program of Beijing Xisike Clinical Oncology Research Foundation (Y-MSDZD2021-0230, Y-2019AZMS-0012); China Urological Oncology Research Foundation, Primary Health Care Foundation, China; Chinese Anti-Cancer Association — Hengrui PARP Inhibitor Cancer Research Foundation; Shanghai Academic/Technology Research Leader (23XD1420600); Fudan University (FDUROP No.22065) and the Medical Science Data Center in Shanghai Medical College of Fudan University. The authors express their gratitude to all the patients and their families who have participated in the Fudan University Shanghai Cancer Center Prostate Cancer Liver Metastasis Registry (FUSCC-PCaLM) since 2020. They thank them for providing them with clinical research samples, imaging data and follow-up treatment information. Their invaluable contributions have greatly contributed to the understanding and exploration of prostate cancer liver metastasis for both clinicians and researchers.

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Author notes

  1. These authors contributed equally: Xudong Ni, Yu Wei.

  2. These authors jointly supervised this work: Dingwei Ye, Yao Zhu.

Authors and Affiliations

  1. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China

    Xudong Ni, Yu Wei, Xiaomeng Li, Jian Pan, Bangwei Fang, Tingwei Zhang, Dingwei Ye & Yao Zhu

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Xudong Ni, Yu Wei, Xiaomeng Li, Jian Pan, Bangwei Fang, Tingwei Zhang, Dingwei Ye & Yao Zhu

  3. Shanghai Genitourinary Cancer Institute, Shanghai, China

    Xudong Ni, Yu Wei, Xiaomeng Li, Jian Pan, Bangwei Fang, Tingwei Zhang, Dingwei Ye & Yao Zhu

  4. Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China

    Ying Lu

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Contributions

Y.Z., X.N., Y.W., X.L., J.P., B.F. and T.Z. researched data for the article. Y.Z., X.L., B.F. and T.Z. contributed substantially to discussion of the content. Y.Z., X.N., Y.W. wrote the article. Y.Z., Y.L. and D.Y. reviewed and/or edited the manuscript before submission.

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Correspondence to Yao Zhu.

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Nature Reviews Urology thanks A. Kishan, A. Briganti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Ni, X., Wei, Y., Li, X. et al. From biology to the clinic — exploring liver metastasis in prostate cancer. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-024-00875-x

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