B-cell-derived lymphotoxin promotes castration-resistant prostate cancer

Abstract

Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration resistant (CR) metastatic carcinoma 1 . Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent (AD) CaP, metastatic CR-CaP is a major complication with high mortality 2 . Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop CR-CaP within 12-18 months 2 . Despite extensive studies, the mechanisms underlying CR-CaP emergence remain poorly understood and their elucidation is critical for development of improved therapies. Curiously, CR-CaP remains androgen receptor (AR) dependent and potent AR antagonists induce tumor regression in castrated mice 3 . The role of inflammation in CR-CaP has not been addressed, although it was reported that intrinsic NF-κB activation supports its growth 4 . Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer 5 . Whereas acute inflammation is critical for host defense, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IκB kinase (IKK) β and its target NF-κB have important tumor promoting functions within malignant cells and inflammatory cells 6 . The latter, including macrophages and lymphocytes, are important elements of the tumor microenvironment 7-9 , but the mechanisms underlying their recruitment remain obscure, although thought to depend on chemokine and cytokine production 10 . We found that CaP progression is associated with inflammatory infiltration and activation of IKKα, which stimulates metastasis by an NF-κB-independent, cell autonomous, mechanism 11 . We now show that androgen ablation causes infiltration of regressing AD tumors with leukocytes, including B cells, in which IKKβ activation results in production of cytokines that activate IKKα and STAT3 in CaP cells to enhance hormone-free survival.To determine whether IKKβ-driven NF-κB participates in development of CR-CaP, we conditionally deleted the Ikkβ gene in prostate epithelial cells of TRAMP mice, in which CaP is induced by prostate specific expression of SV40 T antigen 12 . Counter to previous expectations 4 , IKKβ ablation in prostate epithelial cells had no effect on genesis and progression of AD-CaP (Fig. S1) or development of CR-CaP after castration (Fig. S2). To facilitate mechanistic analysis of CR-CaP development we used subcutaneous (SC) allografts of the mouse AD-CaP cell line myc-CaP, which is derived from the FVB genetic

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

“…5 In addition to its cytoplasmic functions where it controls the activation of both classical and alternative NF-κB pathways, 6,[9][10][11][12] IKKα can function as a nuclear protein kinase, [33][34][35] and nuclear IKKα plays important roles in prostate cancer progression and metastasis. 13,14 In the present study we have shown that IKKα controls the biogenesis of a group of miRNA, including miR-196a. Phosphorylation of IKKα at 23 T site promotes the association of IKKα with pri-miRNAs, where MiR-196a has two forms: miR-196a1 and miR-196a2.…”

“…Recently, we found that IKKα can be translocated into the nucleus and nuclear IKKα plays important roles in prostate cancer progression and metastasis. 13,14 MicroRNAs (miRNAs) regulate gene expression through suppression of translation and decay of target mRNAs, and are involved in diverse physiological and pathological processes. The primary transcripts of miRNA (pri-miRNA) are cleaved into precursor miRNA (pre-miRNA) by nuclear Drosha, and further processed to mature miRNAs by cytoplasmic Dicer1 in mammalian miRNA biogenesis.…”

Cancer‐promoting tumor‐associated macrophages: New vistas and open questions

“…In a transplanted mammary carcinoma, complement was shown to be involved in myelomonocytic cell recruitment [34], although the mechanisms responsible for complement activation in tumors remain to be defined. It should be noted that B cells can use tools other than antibodies to skew macrophage function and promote tumor progression, including IL-10 and lymphotoxin (LT) [35][36][37][38], and B regulatory cells may be well suited for this [38]. Thus, the mechanisms of co-opting the function of myelomonocytic cells in tumors can differ considerably, although M2-like skewing is a recurrent common denominator.…”

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

“…A study by Ammirante et al (2010) deals with progression of prostate cancer (CaP), mainly focusing on the mechanisms underlying the recurrence of castration-resistant (CR) metastatic carcinomas. In addition to the previously described TRAMP model, subcutaneous allografts of mouse androgen-dependent AD-CaP cell line myc-CaP, were used to facilitate better mechanistic analysis of CR-CaP development.…”