JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells
Menée in vitro et in vivo, cette étude suggère l'intérêt d'un traitement ciblé sur STAT3, une protéine essentielle à la survie des cellules cancéreuses les plus primitives, pour les patients atteints d'un cancer de la prostate de stade avancé
IL-6 overexpression and constitutive STAT3 activation occur in many cancers including prostate cancer. However, their contribution to prostate stem and progenitor cells has not been explored. In this study, we show that stem-like cells from prostate cancer patients secrete higher levels of IL-6 than their counterparts in non-neoplastic prostate. Tumor grade did not influence the levels of expression or secretion. Stem-like and progenitor cells expressed the IL-6 receptor gp80 with concomitant expression of pSTAT3. Blockade of activated STAT3, by either anti-IL-6 antibody siltuximab (CNTO 328) or LLL12, a specific ρSTAT3 inhibitor, suppressed the clonogenicity of the stem-like cells in patients with high grade disease. In a murine xenograft model utilized to determine the in vivo effects of ρSTAT3 suppression, LLL12 treatment effectively abolished outgrowth of a patient-derived castrate-resistant tumor. Our results indicate that the most primitive cells in prostate cancer require ρSTAT3 for survival, rationalizing STAT3 as a therapeutic target to treat advanced prostate cancer.