The effect of cytokines on neuroendocrine differentiation in prostate cancer

Prostate cancer is an androgen dependent cancer that can initially be effectively treated with androgen deprivation therapy (ADT). However, during the treatment process, most prostate cancer patients eventually develop drug resistance and gradually progress to castration resistant prostate cancer. Among them, neuroendocrine prostate cancer (NEPC) is the most difficult to treat and different from de-novo NEPC and small cell cancer of prostate. With the decrease of androgen levels in cancer cells after castration treatment, the differentiation of cells with neuroendocrine phenotype increases, promoting cancer cell growth in the form of paracrine secretion. The factors that affect this mechanism include loss of RB1 (Retinoblastoma 1) and TP53 (Tumor Protein 53) gene expression, changes in epigenetic factors, and swelling changes in tumor microenvironment, etc. Within the tumor microenvironment, cytokines such as interleukin-6 and interferon have the greatest impact. The author of this article aims to explore new strategies for delaying the progression of NEPC by elucidating the latest research progress on the mechanism of cytokines in neuroendocrine differentiation of prostate cancer.

Prostate cancer; Neuroendocrine differentiation; Cytokine

[1] Aurilio G, Cimadamore A, Mazzucchelli R, Lopez-Beltran A, Verri E, Scarpelli M, et al. Androgen receptor signaling pathway in prostate cancer: from genetics to clinical applications. Cells. 2020; 9: 2653.

[2] Merseburger AS, Alcaraz A, von Klot CA. Androgen deprivation therapy as backbone therapy in the management of prostate cancer. OncoTargets and Therapy. 2016; 9: 7263–7274.

[3] Niu Y, Guo C, Wen S, Tian J, Luo J, Wang K, et al. ADT with antiandrogens in prostate cancer induces adverse effect of increasing resistance, neuroendocrine differentiation and tumor metastasis. The Cancer Letter. 2018; 439: 47–55.

[4] Sagnak L, Topaloglu H, Ozok U, Ersoy H. Prognostic significance of neuroendocrine differentiation in prostate adenocarcinoma. Clinical Genitourinary Cancer. 2011; 9: 73–80.

[5] Chen R, Dong X, Gleave M. Molecular model for neuroendocrine prostate cancer progression. BJU International. 2018; 122: 560–570.

[6] Yamada Y, Beltran H. Clinical and biological features of neuroendocrine prostate cancer. Current Oncology Reports. 2021; 23: 15.

[7] Mehraj U, Ganai RA, Macha MA, Hamid A, Zargar MA, Bhat AA, et al. The tumor microenvironment as driver of stemness and therapeutic resistance in breast cancer: new challenges and therapeutic opportunities. Cellular Oncology. 2021; 44: 1209–1229.

[8] Zhou H, He Q, Li C, Alsharafi BLM, Deng L, Long Z, et al. Focus on the tumor microenvironment: a seedbed for neuroendocrine prostate cancer. Frontiers in Cell and Developmental Biology. 2022; 10: 955669.

[9] Liu Q, Yu S, Li A, Xu H, Han X, Wu K. Targeting interlukin-6 to relieve immunosuppression in tumor microenvironment. Tumor Biology. 2017; 39: 1010428317712445.

[10] Natani S, Dhople VM, Parveen A, Sruthi KK, Khilar P, Bhukya S, et al. AMPK/SIRT1 signaling through p38MAPK mediates Interleukin-6 induced neuroendocrine differentiation of LNCaP prostate cancer cells. Molecular Cell Research. 2021; 1868: 119085.

[11] Yu SH, Maynard JP, Vaghasia AM, De Marzo AM, Drake CG, Sfanos KS. A role for paracrine interleukin-6 signaling in the tumor microenvironment in prostate tumor growth. Prostate. 2019; 79: 215–222.

[12] Ji Y, Liu B, Chen L, Li A, Shen K, Su R, et al. Repurposing ketotifen as a therapeutic strategy for neuroendocrine prostate cancer by targeting the IL-6/STAT3 pathway. Cellular Oncology. 2023; 46: 1445–1456.

[13] Zhu Y, Liu C, Cui Y, Nadiminty N, Lou W, Gao AC. Interleukin-6 induces neuroendocrine differentiation (NED) through suppression of RE-1 silencing transcription factor (REST). Prostate. 2014; 74: 1086–1094.

[14] Chang PC, Wang TY, Chang YT, Chu CY, Lee CL, Hsu HW, et al. Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells. PLOS ONE. 2014; 9: e88556.

[15] Lehrer S, Diamond EJ, Mamkine B, Stone NN, Stock RG. Serum interleukin-8 is elevated in men with prostate cancer and bone metastases. Technology in Cancer Research & Treatment. 2004; 3: 411.

[16] Patel BJ, Pantuck AJ, Zisman A, Tsui KH, Paik SH, Caliliw R, et al. CL1-GFP: an androgen independent metastatic tumor model for prostate cancer. Journal of Urology. 2000; 164: 1420–1425.

[17] Lee LF, Louie MC, Desai SJ, Yang J, Chen HW, Evans CP, et al. Interleukin-8 confers androgen-independent growth and migration of LNCaP: differential effects of tyrosine kinases Src and FAK. Oncogene. 2004; 23: 2197–2205.

[18] Huang J, Yao JL, Zhang L, Bourne PA, Quinn AM, di Sant’Agnese PA, et al. Differential expression of interleukin-8 and its receptors in the neuroendocrine and non-neuroendocrine compartments of prostate cancer. The American Journal of Pathology. 2005; 166: 1807–1815.

[19] Rodarte KE, Nir Heyman S, Guo L, Flores L, Savage TK, Villarreal J, et al. Neuroendocrine differentiation in prostate cancer requires ASCL1. American Association for Cancer Research. 2024; 84: 3522–3537.

[20] Zhang XQ, Kondrikov D, Yuan TC, Lin FF, Hansen J, Lin MF. Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion-induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells. Oncogene. 2003; 22: 6704–6716.

[21] Kim J, Jin H, Zhao JC, Yang YA, Li Y, Yang X, et al. FOXA1 inhibits prostate cancer neuroendocrine differentiation. Oncogene. 2017; 36: 4072–4080.

[22] Di Lorenzo G, Tortora G, D’Armiento FP, De Rosa G, Staibano S, Autorino R, et al. Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer. Clinical Cancer Research. 2002; 8: 3438–3444.

[23] Li Y, Chen HQ, Chen MF, Liu HZ, Dai YQ, Lv H, et al. Neuroendocrine differentiation is involved in chemoresistance induced by EGF in prostate cancer cells. Life Sciences. 2009; 84: 882–887.

[24] Cortés MA, Cariaga-Martinez AE, Lobo MV, Martín Orozco RM, Motiño O, Rodríguez-Ubreva FJ, et al. EGF promotes neuroendocrine-like differentiation of prostate cancer cells in the presence of LY294002 through increased ErbB2 expression independent of the phosphatidylinositol 3-kinase-AKT pathway. Carcinogenesis. 2012; 33: 1169–1177.

[25] Wang X, Qin X, Yan M, Shi J, Xu Q, Li Z, et al. Loss of exosomal miR-3188 in cancer-associated fibroblasts contributes to HNC progression. Journal of Experimental & Clinical Cancer Research. 2019; 38: 151.

[26] Prud’homme GJ, Kurt M, Wang Q. Pathobiology of the klotho antiaging protein and therapeutic considerations. Frontiers in Aging. 2022; 3: 931331.

[27] Xu X, Zheng L, Yuan Q, Zhen G, Crane JL, Zhou X, et al. Transforming growth factor-β in stem cells and tissue homeostasis. Bone Research. 2018; 6: 2.

[28] Dicken H, Hensley PJ, Kyprianou N. Prostate tumor neuroendocrine differentiation via EMT: the road less traveled. Asian Journal of Urology. 2019; 6: 82–90.

[29] Sagara H, Okada T, Okumura K, Ogawa H, Ra C, Fukuda T, et al. Activation of TGF-beta/Smad2 signaling is associated with airway remodeling in asthma. Journal of Allergy and Clinical Immunology. 2002; 110: 249–254.

[30] Platz EA, De Marzo AM. Epidemiology of inflammation and prostate cancer. Journal of Urology. 2004; 171: S36–S40.

[31] Untergasser G, Plas E, Pfister G, Heinrich E, Berger P. Interferon-gamma induces neuroendocrine-like differentiation of human prostate basal-epithelial cells. Prostate. 2005; 64: 419–429.

[32] Borkowetz A, Froehner M, Rauner M, Conrad S, Erdmann K, Mayr T, et al. Neuropilin-2 is an independent prognostic factor for shorter cancer-specific survival in patients with acinar adenocarcinoma of the prostate. International Journal of Cancer. 2020; 146: 2619–2627.

[33] Islam R, Mishra J, Polavaram NS, Bhattacharya S, Hong Z, Bodas S, et al. Neuropilin-2 axis in regulating secretory phenotype of neuroendocrine-like prostate cancer cells and its implication in therapy resistance. Cell Reports. 2022; 40: 111097.

[34] Wang J, Li J, Yin L, Pu T, Wei J, Karthikeyan V, et al. Neuropilin-2 promotes lineage plasticity and progression to neuroendocrine prostate cancer. Oncogene. 2022; 41: 4307–4317.

[35] Wang M, Wisniewski CA, Xiong C, Chhoy P, Goel HL, Kumar A, et al. Therapeutic blocking of VEGF binding to neuropilin-2 diminishes PD-L1 expression to activate antitumor immunity in prostate cancer. Science Translational Medicine. 2023; 15: eade5855.