Prostate cancer (CaP) progresses from
prostatic intraepithelial neoplasia through locally invasive
adenocarcinoma to
castration-resistant metastatic
carcinoma. 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.
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. 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. The role of
inflammation in
castration-resistant CaP has not been addressed, although it was reported that intrinsic
NF-kappaB activation supports its growth.
Inflammation is a localized protective reaction to injury or
infection, but it also has a pathogenic role in many diseases, including
cancer. Whereas acute
inflammation is critical for host defence, chronic
inflammation contributes to
tumorigenesis and metastatic progression. The
inflammation-responsive
IkappaB kinase (
IKK)-beta and its target
NF-kappaB have important tumour-promoting functions within malignant cells and inflammatory cells. The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment, but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on
chemokine and
cytokine production. We found that CaP progression is associated with inflammatory infiltration and activation of
IKK-alpha, which stimulates
metastasis by an
NF-kappaB-independent, cell autonomous mechanism. Here we show that
androgen ablation causes infiltration of regressing
androgen-dependent tumours with leukocytes, including B cells, in which
IKK-beta activation results in production of
cytokines that activate
IKK-alpha and STAT3 in CaP cells to enhance
hormone-free survival.