Tumour innervation and neurosignalling in prostate cancer

Abstract

Prostate cancer progression has been shown to be dependent on the development of autonomic nerves into the tumour microenvironment. Sympathetic nerves activate adrenergic neurosignalling that is necessary in early stages of tumour progression and for initiating an angiogenic switch, whereas parasympathetic nerves activate cholinergic neurosignalling resulting in tumour dissemination and metastasis. The innervation of prostate cancer seems to be initiated by neurotrophic growth factors, such as the precursor to nerve growth factor secreted by tumour cells, and the contribution of brain-derived neural progenitor cells has also been reported. Current experimental, epidemiological and clinical evidence shows the stimulatory effect of tumour innervation and neurosignalling in prostate cancer. Using nerves and neurosignalling could have value in the management of prostate cancer by predicting aggressive disease, treating localized disease through denervation and relieving cancer-associated pain in bone metastases.

Key points

  • Prostate cancer is infiltrated by autonomic nerves that actively stimulate cancer progression.

  • Autonomic nerves infiltrate the tumour microenvironment in response to tumour-derived neurotrophins and axon guidance molecules.

  • Animal models have demonstrated that adrenergic and cholinergic neurosignalling stimulates prostate cancer progression, angiogenesis, invasion and metastasis. Chemical or surgical denervation, as well as genetic or pharmacological blockade, completely inhibit these effects.

  • Attenuated tumour neurosignalling might be a key factor in the decreased incidence of prostate cancer observed in patients with spinal cord injuries or those taking β-blockers.

  • Nerves and neurotrophic growth factors could be used as biomarkers of clinically aggressive prostate cancer, or as therapeutic targets to prevent cancer progression, dissemination and cancer-induced pain.

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Fig. 1: Innervation and neurosignalling in prostate cancer.

References

  1. 1.

    Kumar, A. & Brockes, J. P. Nerve dependence in tissue, organ, and appendage regeneration. Trends Neurosci. 35, 691–699 (2012).

  2. 2.

    Nedvetsky, P. I. et al. Parasympathetic innervation regulates tubulogenesis in the developing salivary gland. Dev. Cell 30, 449–462 (2014).

  3. 3.

    Bower, D. V. et al. Airway branching has conserved needs for local parasympathetic innervation but not neurotransmission. BMC Biol. 12, 92 (2014).

  4. 4.

    Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006).

  5. 5.

    Brownell, I., Guevara, E., Bai, C. B., Loomis, C. A. & Joyner, A. L. Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells. Cell Stem Cell 8, 552–565 (2011).

  6. 6.

    Maryanovich, M. et al. Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche. Nat. Med. 24, 782–791 (2018).

  7. 7.

    Liebig, C., Ayala, G., Wilks, J. A., Berger, D. H. & Albo, D. Perineural invasion in cancer: a review of the literature. Cancer 115, 3379–3391 (2009).

  8. 8.

    Marchesi, F., Piemonti, L., Mantovani, A. & Allavena, P. Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine Growth Factor Rev. 21, 77–82 (2010).

  9. 9.

    Boilly, B., Faulkner, S., Jobling, P. & Hondermarck, H. Nerve dependence: from regeneration to cancer. Cancer Cell 31, 342–354 (2017).

  10. 10.

    Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).

  11. 11.

    Zhao, C. M. et al. Denervation suppresses gastric tumorigenesis. Sci. Transl. Med. 6, 250ra115 (2014).

  12. 12.

    Hayakawa, Y. et al. Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling. Cancer Cell 31, 21–34 (2017).

  13. 13.

    Saloman, J. L. et al. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc. Natl Acad. Sci. USA 113, 3078–3083 (2016).

  14. 14.

    Renz, B. W. et al. β2 adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell 33, 75–90.e7 (2018).

  15. 15.

    Peterson, S. C. et al. Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches. Cell Stem Cell 16, 400–412 (2015).

  16. 16.

    Decker, A. M. et al. Sympathetic signaling reactivates quiescent disseminated prostate cancer cells in the bone marrow. Mol. Cancer Res. 15, 1644–1655 (2017).

  17. 17.

    Zahalka, A. H. et al. Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science 358, 321–326 (2017).

  18. 18.

    Mauffrey, P. et al. Progenitors from the central nervous system drive neurogenesis in cancer. Nature 569, 672–678 (2019).

  19. 19.

    Pundavela, J. et al. ProNGF correlates with Gleason score and is a potential driver of nerve infiltration in prostate cancer. Am. J. Pathol. 184, 3156–3162 (2014).

  20. 20.

    Brundl, J. et al. Computerized quantification and planimetry of prostatic capsular nerves in relation to adjacent prostate cancer foci. Eur. Urol. 65, 802–808 (2014).

  21. 21.

    Ayala, G. E. et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin. Cancer Res. 14, 7593–7603 (2008).

  22. 22.

    Ayala, G. E. et al. In vitro dorsal root ganglia and human prostate cell line interaction: redefining perineural invasion in prostate cancer. Prostate 49, 213–223 (2001).

  23. 23.

    Dolle, L., El Yazidi-Belkoura, I., Adriaenssens, E., Nurcombe, V. & Hondermarck, H. Nerve growth factor overexpression and autocrine loop in breast cancer cells. Oncogene 22, 5592–5601 (2003).

  24. 24.

    Hondermarck, H. Neurotrophins and their receptors in breast cancer. Cytokine Growth Factor Rev. 23, 357–365 (2012).

  25. 25.

    Pundavela, J. et al. Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer. Mol. Oncol. 9, 1626–1635 (2015).

  26. 26.

    Dobrenis, K., Gauthier, L. R., Barroca, V. & Magnon, C. Granulocyte colony-stimulating factor off-target effect on nerve outgrowth promotes prostate cancer development. Int. J. Cancer 136, 982–988 (2015).

  27. 27.

    Zhang, S. et al. Chemokine CXCL12 and its receptor CXCR4 expression are associated with perineural invasion of prostate cancer. J. Exp. Clin. Cancer Res. 27, 62 (2008).

  28. 28.

    He, S. et al. The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion. Mol. Cancer Res. 13, 380–390 (2015).

  29. 29.

    Imitola, J. et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1α/CXC chemokine receptor 4 pathway. Proc. Natl Acad. Sci. USA 101, 18117–18122 (2004).

  30. 30.

    Belmadani, A. et al. The chemokine stromal cell-derived factor-1 regulates the migration of sensory neuron progenitors. J. Neurosci. 25, 3995–4003 (2005).

  31. 31.

    Harnden, P. et al. The prognostic significance of perineural invasion in prostatic cancer biopsies: a systematic review. Cancer 109, 13–24 (2007).

  32. 32.

    Turner, R. M. 2nd et al. Biopsy perineural invasion in prostate cancer patients who are candidates for active surveillance by strict and expanded criteria. Urology 102, 173–177 (2017).

  33. 33.

    Zareba, P. et al. Perineural invasion and risk of lethal prostate cancer. Cancer Epidemiol. Biomarkers Prev. 26, 719–726 (2017).

  34. 34.

    Saeter, T. et al. The relationship between perineural invasion, tumor grade, reactive stroma and prostate cancer-specific mortality: a clinicopathologic study on a population-based cohort. Prostate 76, 207–214 (2016).

  35. 35.

    Moreira, D. M., Fleshner, N. E. & Freedland, S. J. Baseline perineural invasion is associated with shorter time to progression in men with prostate cancer undergoing active surveillance: results from the REDEEM study. J. Urol. 194, 1258–1263 (2015).

  36. 36.

    Loeb, S., Epstein, J. I., Humphreys, E. B. & Walsh, P. C. Does perineural invasion on prostate biopsy predict adverse prostatectomy outcomes? BJU Int. 105, 1510–1513 (2010).

  37. 37.

    Cohn, J. A. et al. The prognostic significance of perineural invasion and race in men considering active surveillance. BJU Int. 114, 75–80 (2014).

  38. 38.

    Ciftci, S. et al. Perineural invasion in prostate biopsy specimens is associated with increased bone metastasis in prostate cancer. Prostate 75, 1783–1789 (2015).

  39. 39.

    Liu, H. et al. Prognostic significance of six clinicopathological features for biochemical recurrence after radical prostatectomy: a systematic review and meta-analysis. Oncotarget 9, 32238–32249 (2018).

  40. 40.

    Zhang, L. J. et al. Perineural invasion as an independent predictor of biochemical recurrence in prostate cancer following radical prostatectomy or radiotherapy: a systematic review and meta-analysis. BMC Urol. 18, 5 (2018).

  41. 41.

    DeLancey, J. O. et al. Evidence of perineural invasion on prostate biopsy specimen and survival after radical prostatectomy. Urology 81, 354–357 (2013).

  42. 42.

    Peng, L. C. et al. Effects of perineural invasion on biochemical recurrence and prostate cancer-specific survival in patients treated with definitive external beam radiotherapy. Urol. Oncol. 36, 309.e7–309.e14 (2018).

  43. 43.

    Ahmad, A. S. et al. Should reporting of peri-neural invasion and extra prostatic extension be mandatory in prostate cancer biopsies? Correlation with outcome in biopsy cases treated conservatively. Oncotarget 9, 20555–20562 (2018).

  44. 44.

    Sun, G. et al. The impact of multifocal perineural invasion on biochemical recurrence and timing of adjuvant androgen-deprivation therapy in high-risk prostate cancer following radical prostatectomy. Prostate 77, 1279–1287 (2017).

  45. 45.

    Lubig, S. et al. Quantitative perineural invasion is a prognostic marker in prostate cancer. Pathology 50, 298–304 (2018).

  46. 46.

    Hassan, M. O. & Maksem, J. The prostatic perineural space and its relation to tumor spread: an ultrastructural study. Am. J. Surg. Pathol. 4, 143–148 (1980).

  47. 47.

    Rodin, A. E., Larson, D. L. & Roberts, D. K. Nature of the perineural space invaded by prostatic carcinoma. Cancer 20, 1772–1779 (1967).

  48. 48.

    Amit, M., Na'ara, S. & Gil, Z. Mechanisms of cancer dissemination along nerves. Nat. Rev. Cancer 16, 399–408 (2016).

  49. 49.

    Coarfa, C. et al. Influence of the neural microenvironment on prostate cancer. Prostate 78, 128–139 (2018).

  50. 50.

    Rutledge, A., Jobling, P., Walker, M. M., Denham, J. W. & Hondermarck, H. Spinal cord injuries and nerve dependence in prostate cancer. Trends Cancer 3, 812–815 (2017).

  51. 51.

    McVary, K. T., McKenna, K. E. & Lee, C. Prostate innervation. Prostate Suppl. 8, 2–13 (1998).

  52. 52.

    Wang, J.-M., McKenna, K. E., McVary, K. T. & Lee, C. Requirement of innervation for maintenance of structural and functional integrity in the rat prostate. Biol. Reprod. 44, 1171–1176 (1991).

  53. 53.

    Doggweiler, R., Zermann, D. H., Ishigooka, M. & Schmidt, R. A. Botox-induced prostatic involution. Prostate 37, 44–50 (1998).

  54. 54.

    Frisbie, J. H. & Binard, J. Low prevalence of prostatic cancer among myelopathy patients. J. Am. Paraplegia Soc. 17, 148–149 (1994).

  55. 55.

    Frisbie, J. H. Cancer of the prostate in myelopathy patients: lower risk with higher levels of paralysis. J. Spinal Cord Med. 24, 92–94 discussion 95 (2001).

  56. 56.

    Patel, N., Ngo, K., Hastings, J., Ketchum, N. & Sepahpanah, F. Prevalence of prostate cancer in patients with chronic spinal cord injury. PM R 3, 633–636 (2011).

  57. 57.

    Lee, W. Y. et al. Risk of prostate and bladder cancers in patients with spinal cord injury: a population-based cohort study. Urol. Oncol. 32, e51–e57 (2014).

  58. 58.

    Barbonetti, A. et al. Risk of prostate cancer in men with spinal cord injury: a systematic review and meta-analysis. Asian J. Androl. 20, 555–560 (2018).

  59. 59.

    Bartoletti, R. et al. Prostate growth and prevalence of prostate diseases in early onset spinal cord injuries. Eur. Urol. 56, 142–148 (2009).

  60. 60.

    Benaim, E. A., Montoya, J. D., Saboorian, M. H., Litwiller, S. & Roehrborn, C. G. Characterization of prostate size, PSA and endocrine profiles in patients with spinal cord injuries. Prostate Cancer Prostatic Dis. 1, 250–255 (1998).

  61. 61.

    Pannek, J., Bartel, P., Gocking, K. & Frotzler, A. Prostate volume in male patients with spinal cord injury: a question of nerves? BJU Int. 112, 495–500 (2013).

  62. 62.

    Frisbie, J. H., Kumar, S., Aguilera, E. J. & Yalla, S. Prostate atrophy and spinal cord lesions. Spinal Cord 44, 24–27 (2006).

  63. 63.

    Hammerer, P. G., McNeal, J. E. & Stamey, T. A. Correlation between serum prostate specific antigen levels and the volume of the individual glandular zones of the human prostate. J. Urol. 153, 111–114 (1995).

  64. 64.

    Clark, M. J. et al. Testosterone replacement therapy and motor function in men with spinal cord injury: a retrospective analysis. Am. J. Phys. Med. Rehabil. 87, 281–284 (2008).

  65. 65.

    Schopp, L. H. et al. Testosterone levels among men with spinal cord injury admitted to inpatient rehabilitation. Am. J. Phys. Med. Rehabil. 85, 678–684 quiz 685-687 (2006).

  66. 66.

    Huang, H. F. et al. The effects of spinal cord injury on the status of messenger ribonucleic acid for TRPM 2 and androgen receptor in the prostate of the rat. J. Androl. 18, 250–256 (1997).

  67. 67.

    Barron, T. I., Connolly, R. M., Sharp, L., Bennett, K. & Visvanathan, K. Beta blockers and breast cancer mortality: a population-based study. J. Clin. Oncol. 29, 2635–2644 (2011).

  68. 68.

    Melhem-Bertrandt, A. et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J. Clin. Oncol. 29, 2645–2652 (2011).

  69. 69.

    Watkins, J. L. et al. Clinical impact of selective and nonselective beta-blockers on survival in patients with ovarian cancer. Cancer 121, 3444–3451 (2015).

  70. 70.

    Hwa, Y. L. et al. Beta-blockers improve survival outcomes in patients with multiple myeloma: a retrospective evaluation. Am. J. Hematol. 92, 50–55 (2017).

  71. 71.

    Cardwell, C. R., Coleman, H. G., Murray, L. J., O’Sullivan, J. M. & Powe, D. G. Beta-blocker usage and prostate cancer survival: a nested case-control study in the UK Clinical Practice Research Datalink cohort. Cancer Epidemiol. 38, 279–285 (2014).

  72. 72.

    Assayag, J., Pollak, M. N. & Azoulay, L. Post-diagnostic use of beta-blockers and the risk of death in patients with prostate cancer. Eur. J. Cancer 50, 2838–2845 (2014).

  73. 73.

    Grytli, H. H., Fagerland, M. W., Fossa, S. D., Tasken, K. A. & Haheim, L. L. Use of beta-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy. Prostate 73, 250–260 (2013).

  74. 74.

    Grytli, H. H., Fagerland, M. W., Fossa, S. D. & Tasken, K. A. Association between use of beta-blockers and prostate cancer-specific survival: a cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. Eur. Urol. 65, 635–641 (2014).

  75. 75.

    Lu, H. et al. Impact of beta-blockers on prostate cancer mortality: a meta-analysis of 16,825 patients. Onco Targets Ther. 8, 985–990 (2015).

  76. 76.

    Weberpals, J. et al. Immortal time bias in pharmacoepidemiological studies on cancer patient survival: empirical illustration for beta-blocker use in four cancers with different prognosis. Eur. J. Epidemiol. 32, 1019–1031 (2017).

  77. 77.

    Weberpals, J., Jansen, L., Carr, P. R., Hoffmeister, M. & Brenner, H. Beta blockers and cancer prognosis – The role of immortal time bias: a systematic review and meta-analysis. Cancer Treat. Rev. 47, 1–11 (2016).

  78. 78.

    Batty, G. D., Russ, T. C., Stamatakis, E. & Kivimaki, M. Psychological distress in relation to site specific cancer mortality: pooling of unpublished data from 16 prospective cohort studies. BMJ 356, j108 (2017).

  79. 79.

    Prasad, S. M. et al. Effect of depression on diagnosis, treatment, and mortality of men with clinically localized prostate cancer. J. Clin. Oncol. 32, 2471–2478 (2014).

  80. 80.

    Zhu, J. et al. First-onset mental disorders after cancer diagnosis and cancer-specific mortality: a nationwide cohort study. Ann. Oncol. 28, 1964–1969 (2017).

  81. 81.

    Hassan, S. et al. Behavioral stress accelerates prostate cancer development in mice. J. Clin. Invest. 123, 874–886 (2013).

  82. 82.

    Cheng, Y. et al. Depression promotes prostate cancer invasion and metastasis via a sympathetic-cAMP-FAK signaling pathway. Oncogene 37, 2953–2966 (2018).

  83. 83.

    Cheng, Y. et al. Depression-induced neuropeptide Y secretion promotes prostate cancer growth by recruiting myeloid cells. Clin. Cancer Res. 25, 2621–2632 (2019).

  84. 84.

    US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02944201 (2019).

  85. 85.

    US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03152786 (2019).

  86. 86.

    Pasquier, E. et al. Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment. Oncotarget 2, 797–809 (2011).

  87. 87.

    Pasquier, E. et al. β-Blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma. Br. J. Cancer 108, 2485–2494 (2013).

  88. 88.

    Tannock, I. F. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351, 1502–1512 (2004).

  89. 89.

    Sweeney, C. J. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N. Engl. J. Med. 373, 737–746 (2015).

  90. 90.

    James, N. D. et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 387, 1163–1177 (2016).

  91. 91.

    US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT01520441 (2015).

  92. 92.

    Reeves, F. A. et al. Prostatic nerve subtypes independently predict biochemical recurrence in prostate cancer. J. Clin. Neurosci. 63, 213–219 (2019).

  93. 93.

    Bothwell, M. NGF, BDNF, NT3, and NT4. Handb. Exp. Pharmacol. 220, 3–15 (2014).

  94. 94.

    Dalal, R. & Djakiew, D. Molecular characterization of neurotrophin expression and the corresponding tropomyosin receptor kinases (trks) in epithelial and stromal cells of the human prostate. Mol. Cell. Endocrinol. 134, 15–22 (1997).

  95. 95.

    Weeraratna, A. T., Arnold, J. T., George, D. J., DeMarzo, A. & Isaacs, J. T. Rational basis for Trk inhibition therapy for prostate cancer. Prostate 45, 140–148 (2000).

  96. 96.

    Djakiew, D. Dysregulated expression of growth factors and their receptors in the development of prostate cancer. Prostate 42, 150–160 (2000).

  97. 97.

    Perez, M., Regan, T., Pflug, B., Lynch, J. & Djakiew, D. Loss of low-affinity nerve growth factor receptor during malignant transformation of the human prostate. Prostate 30, 274–279 (1997).

  98. 98.

    Liss, M. A. et al. Urinary nerve growth factor as an oncologic biomarker for prostate cancer aggressiveness. Urol Oncol 32, 714–719 (2014).

  99. 99.

    Ban, K., Feng, S., Shao, L. & Ittmann, M. RET signaling in prostate cancer. Clin. Cancer Res. 23, 4885–4896 (2017).

  100. 100.

    Dang, T. & Liou, G. Y. Macrophage cytokines enhance cell proliferation of normal prostate epithelial cells through activation of ERK and Akt. Sci Rep 8, 7718 (2018).

  101. 101.

    Baspinar, S., Bircan, S., Ciris, M., Karahan, N. & Bozkurt, K. K. Expression of NGF, GDNF and MMP-9 in prostate carcinoma. Pathol. Res. Pract. 213, 483–489 (2017).

  102. 102.

    Dakhova, O., Rowley, D. & Ittmann, M. Genes upregulated in prostate cancer reactive stroma promote prostate cancer progression in vivo. Clin. Cancer Res. 20, 100–109 (2014).

  103. 103.

    Gillard, M. et al. Elevation of stromal-derived mediators of inflammation promote prostate cancer progression in African-American men. Cancer Res. 78, 6134–6145 (2018).

  104. 104.

    Allen, J. K. et al. Sustained adrenergic signaling promotes intratumoral innervation through BDNF induction. Cancer Res. 78, 3233–3242 (2018).

  105. 105.

    Zhang, D. et al. Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer. Nat. Commun. 7, 10798 (2016).

  106. 106.

    Mauroy, B. et al. The inferior hypogastric plexus (pelvic plexus): its importance in neural preservation techniques. Surg. Radiol. Anat. 25, 6–15 (2003).

  107. 107.

    Lunacek, A., Schwentner, C., Fritsch, H., Bartsch, G. & Strasser, H. Anatomical radical retropubic prostatectomy: ‘curtain dissection’ of the neurovascular bundle. BJU Int. 95, 1226–1231 (2005).

  108. 108.

    Eichelberg, C. et al. Nerve distribution along the prostatic capsule. Eur. Urol. 51, 105–111 (2007).

  109. 109.

    Young, D. L. & Halstead, L. A. Pyridostigmine for reversal of severe sequelae from botulinum toxin injection. J. Voice 28, 830–834 (2014).

  110. 110.

    Silva, J. et al. Intraprostatic botulinum toxin type A injection in patients with benign prostatic enlargement: duration of the effect of a single treatment. BMC Urol. 9, 9 (2009).

  111. 111.

    Griffin, N., Faulkner, S., Jobling, P. & Hondermarck, H. Targeting neurotrophin signaling in cancer: the renaissance. Pharmacol. Res. 135, 12–17 (2018).

  112. 112.

    Amatu, A., Sartore-Bianchi, A. & Siena, S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 1, e000023 (2016).

  113. 113.

    George, D. J., Suzuki, H., Bova, G. S. & Isaacs, J. T. Mutational analysis of the TrkA gene in prostate cancer. Prostate 36, 172–180 (1998).

  114. 114.

    Warrington, R. J. & Lewis, K. E. Natural antibodies against nerve growth factor inhibit in vitro prostate cancer cell metastasis. Cancer Immunol. Immunother. 60, 187–195 (2011).

  115. 115.

    Collins, C. et al. Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint. Cancer Biol. Ther. 6, 1360–1367 (2007).

  116. 116.

    Aubert, L. et al. NGF-induced TrkA/CD44 association is involved in tumor aggressiveness and resistance to lestaurtinib. Oncotarget 6, 9807–9819 (2015).

  117. 117.

    Yakes, F. M. et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther. 10, 2298–2308 (2011).

  118. 118.

    Basch, E. et al. Effects of cabozantinib on pain and narcotic use in patients with castration-resistant prostate cancer: results from a phase 2 nonrandomized expansion cohort. Eur. Urol. 67, 310–318 (2015).

  119. 119.

    Smith, D. C. et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J. Clin. Oncol. 31, 412–419 (2013).

  120. 120.

    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).

  121. 121.

    Basch, E. M. et al. Final analysis of COMET-2: cabozantinib (Cabo) versus mitoxantrone/prednisone (MP) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with moderate to severe pain who were previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E) [abstract]. J. Clin. Oncol. 33, (7 Suppl.) 141 (2015).

  122. 122.

    US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02219711 (2019).

  123. 123.

    Ojemuyiwa, M. A., Madan, R. A. & Dahut, W. L. Tyrosine kinase inhibitors in the treatment of prostate cancer: taking the next step in clinical development. Expert Opin. Emerg. Drugs 19, 459–470 (2014).

  124. 124.

    Gravina, G. L. et al. Increased expression and activity of p75NTR are crucial events in azacitidine-induced cell death in prostate cancer. Oncol. Rep. 36, 125–130 (2016).

  125. 125.

    Anagnostopoulou, V. et al. Differential effects of dehydroepiandrosterone and testosterone in prostate and colon cancer cell apoptosis: the role of nerve growth factor (NGF) receptors. Endocrinology 154, 2446–2456 (2013).

  126. 126.

    Sanchez, C. et al. Effect of GnRH analogs on the expression of TrkA and p75 neurotrophin receptors in primary cell cultures from human prostate adenocarcinoma. Prostate 65, 195–202 (2005).

  127. 127.

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

  128. 128.

    Cecchini, M. G., Wetterwald, A., Pluijm, G. v. d. & Thalmann, G. N. Molecular and biological mechanisms of bone metastasis. EAU Update Series 3, 214–226 (2005).

  129. 129.

    Eastham, J. A. Bone health in men receiving androgen deprivation therapy for prostate cancer. J. Urol. 177, 17–24 (2007).

  130. 130.

    Denk, F., Bennett, D. L. & McMahon, S. B. Nerve growth factor and pain mechanisms. Annu. Rev. Neurosci. 40, 307–325 (2017).

  131. 131.

    Halvorson, K. G. et al. A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone. Cancer Res. 65, 9426–9435 (2005).

  132. 132.

    Jimenez-Andrade, J. M., Ghilardi, J. R., Castaneda-Corral, G., Kuskowski, M. A. & Mantyh, P. W. Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain. Pain 152, 2564–2574 (2011).

  133. 133.

    McCaffrey, G. et al. NGF blockade at early times during bone cancer development attenuates bone destruction and increases limb use. Cancer Res. 74, 7014–7023 (2014).

  134. 134.

    Buehlmann, D., Ielacqua, G. D., Xandry, J. & Rudin, M. Prospective administration of anti-nerve growth factor treatment effectively suppresses functional connectivity alterations after cancer-induced bone pain in mice. Pain 160, 151–159 (2019).

  135. 135.

    Slatkin, N. et al. Fulranumab as adjunctive therapy for cancer-related pain: a phase 2, randomized, double-blind, placebo-controlled, multicenter study. J. Pain 20, 440–452 (2019).

  136. 136.

    Sopata, M. et al. Efficacy and safety of tanezumab in the treatment of pain from bone metastases. Pain 156, 1703–1713 (2015).

  137. 137.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02609828 (2019).

  138. 138.

    Lee, I. H. et al. Perineural invasion is a marker for pathologically advanced disease in localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 68, 1059–1064 (2007).

  139. 139.

    Bismar, T. A., Lewis, J. S. Jr., Vollmer, R. T. & Humphrey, P. A. Multiple measures of carcinoma extent versus perineural invasion in prostate needle biopsy tissue in prediction of pathologic stage in a screening population. Am. J. Surg. Pathol. 27, 432–440 (2003).

  140. 140.

    Egan, A. J. & Bostwick, D. G. Prediction of extraprostatic extension of prostate cancer based on needle biopsy findings: perineural invasion lacks significance on multivariate analysis. Am. J. Surg. Pathol. 21, 1496–1500 (1997).

  141. 141.

    Aaltomaa, S. et al. Expression of Ki-67, cyclin D1 and apoptosis markers correlated with survival in prostate cancer patients treated by radical prostatectomy. Anticancer Res. 26, 4873–4878 (2006).

  142. 142.

    Lee, J. T. et al. Prediction of perineural invasion and its prognostic value in patients with prostate cancer. Korean J. Urol. 51, 745–751 (2010).

  143. 143.

    van den Ouden, D., Hop, W. C., Kranse, R. & Schroder, F. H. Tumour control according to pathological variables in patients treated by radical prostatectomy for clinically localized carcinoma of the prostate. Br. J. Urol. 79, 203–211 (1997).

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Acknowledgements

The authors wish to acknowledge the financial support of the Cancer Council, New South Wales, Australia and the National Health and Medical Research Council (NHMRC), Australia.

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B.M. researched data for the article, B.M. and H.H. made substantial contributions to discussion of content and wrote the manuscript, and all authors reviewed and edited the manuscript before submission.

Correspondence to Hubert Hondermarck.

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Nature Reviews Urology thanks A. Zahalka and J.-P. Theurillat and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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March, B., Faulkner, S., Jobling, P. et al. Tumour innervation and neurosignalling in prostate cancer. Nat Rev Urol (2020) doi:10.1038/s41585-019-0274-3

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