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

• Published in: Nature (London) 2010-03, Vol.464 (7286), p.302-305
• Main Authors: Ammirante, Massimo, Luo, Jun-Li, Grivennikov, Sergei, Nedospasov, Sergei, Karin, Michael
• Format: Article
• Language: English
• Subjects: 631/250/127/1220; 631/250/1619/40; 692/699/67/589/466; 692/700/565/238; Androgens - metabolism; Animals; Apoptosis; B-Lymphocytes - metabolism; Bone marrow; Development and progression; Gene expression; Health aspects; Hormones, Sex; Humanities and Social Sciences; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Infiltration; letter; Lymphocytes; Lymphotoxin-alpha - metabolism; Male; Metastasis; Mice; multidisciplinary; Orchiectomy; Physiological aspects; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - physiopathology; Rodents; Science; Science (multidisciplinary); Survival Analysis; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08782

Lymphotoxin's role in prostate cancer progression In the early stages of prostate cancer, cancerous cell growth is dependent on androgens, hence the success of prostatectomy, radiation and androgen-ablating drug therapies. With time, the cancer often develops into an androgen-insensitive, therapy-resistant form with high mortality rates. Work in mouse models of prostate cancer raises the possibility that androgen-ablating therapies may indirectly promote the development of metastatic secondary tumours. Ammirante et al . report that in mice with transgene-induced spontaneous prostate cancer, B-cell infiltration, a component of the natural inflammatory response, activates lymphotoxin release, which stimulates metastasis. In the second model, involving subcutaneous transplantation of an androgen-dependent prostate cancer cell line, it is shown that regression of androgen-deprived primary tumours results in an inflammatory response — and lymphotoxin production. Interfering with the lymphotoxin pathway may therefore offer therapeutic strategies for androgen-independent prostate cancer. In a mouse model of prostate cancer it is shown that infiltrating B cells promote tumorigenesis by secreting lymphotoxin. Lymphotoxin accelerates the emergence of castration-resistant prostate tumours in this model. Interfering with this pathway may offer therapeutic strategies for androgen-independent prostate cancer. Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma 1 . Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant 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 castration-resistant CaP within 12–18 months 2 . Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice 3 . The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-κB activation supports its growth 4 . Inflamm