Common treatments for androgen-dependent prostate cancer include prostatectomy, radiation, and hormone therapy to block androgen function. Unfortunately, many patients develop metastatic androgen-independent, or “castration-resistant,” cancer. The immune system and inflammatory responses have been implicated in tumorigenesis and metastasis; therefore, Ammirante et al. examined the role of inflammatory signaling and the immune system in the development of castration-resistant prostate cancer in mice. They found that, in a mouse model of prostate cancer, knocking out the gene encoding IKK-β, which is a kinase involved in the activation of the proinflammatory transcription factor NF-κB, in prostate epithelial cells had no effect on the initial development of androgen-dependent tumors or on the subsequent appearance of castration-resistant cancer. In contrast, selective knockout of NF-κB signaling in bone marrow–derived cells (immune cells) delayed the development of castration-resistant cancer in the mouse prostate cancer model. Although all types of immune cells were found in the regressing tumors in castrated mice, only treatments or genetic experiments that blocked infiltration of B cells delayed development of castration-resistant cancer. Immune cells, including B cells, were found in all human prostate cancer samples analyzed but were not present in samples of normal prostate or benign hyperplasia prostate. Inhibition of B cell recruitment to the tumors with an antibody that blocks the chemoattractant cytokine CXCL213 reduced the abundance of lymphotoxin-β (a member of the tumor necrosis family), and blockade of the receptor for lymphotoxin-β or silencing of its receptor in prostate cancer cells delayed development of castration-resistant cancer. Thus, it appears that the inflammatory response initiated by the dying cancer cells may contribute to therapy failure by recruiting immune cells that release factors that promote survival of androgen-resistant tumor cells.
M. Ammirante, J.-L. Luo, S. Grivennikov, S. Nedospasov, M. Karin, B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464, 302–305 (2010). [PubMed]