Clinical Newswire, March 11, 2010 - Androgen ablation, commonly used in the treatment of prostate cancer, may indirectly promote the development of metastatic, therapy-resistant secondary tumors through the triggering of an inflammatory response, according to a paper published in the March 11 issue of Nature. Targeting molecules involved in this process may improve patient prognosis.
Prostate cancer in its early stages depends on androgens for its growth, therefore androgen-ablating therapies can be used effectively and many patients initially respond to such therapies, however the cancer often progresses to a castration-resistant form within 12-18 months. Metastatic castration-resistant prostate cancer is a major complication and has high mortality rates, however the mechanisms underlying its emergence have been poorly understood. This study, by Michael Karin and colleagues, explains a possible mechanism involving the inflammatory response triggered by death of the androgen-deprived primary cancer.
Chronic inflammation has a pathogenic role in many diseases, including cancer, and it contributes to tumorigenesis and metastatic progression. Androgen ablation causes the death of androgen-dependent cells in the primary tumor, but it also causes infiltration of regressing androgen-dependent tumors with leukocytes, including B-cells, which produce lymphotoxin, a cytokine that activates pathways enabling androgen-independent growth, the researchers show.
The researchers also show that in a mouse model, interfering with lymphotoxin production or signaling delays the appearance of androgen-independent prostate cancer by 3-4 weeks, estimating that similar interventions may delay the appearance of such tumors in human patients undergoing androgen ablation therapy by 2.3 to 3.1 years. Importantly, the study results suggest that at least in prostate cancer, the inflammatory response triggered by the dying primary tumor contributes to the failure of anti-cancer therapy.
“Our results predict that individuals who produce high levels of lymphotoxin are more likely to develop castration-resistant prostate cancer and should therefore be the main beneficiaries of anti-lymphotoxin therapy”, the authors conclude.
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