PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy

PTEN loss is prognostic for patient relapse post-radiotherapy in prostate cancer (CaP). Infiltration of tumor-associated macrophages (TAMs) is associated with reduced disease-free survival following radical prostatectomy. However, the association between PTEN loss, TAM infiltration and radiotherapy response of CaP cells remains to be evaluated. Immunohistochemical and molecular analysis of surgically-resected Gleason 7 tumors confirmed that PTEN loss correlated with increased CXCL8 expression and macrophage infiltration. However PTEN status had no discernable correlation with expression of other inflammatory markers by CaP cells, including TNF-α. In vitro, exposure to conditioned media harvested from irradiated PTEN null CaP cells induced chemotaxis of macrophage-like THP-1 cells, a response partially attenuated by CXCL8 inhibition. Co-culture with THP-1 cells resulted in a modest reduction in the radio-sensitivity of DU145 cells. Cytokine profiling revealed constitutive secretion of TNF-α from CaP cells irrespective of PTEN status and IR-induced TNF-α secretion from THP-1 cells. THP-1-derived TNF-α increased NFκB pro-survival activity and elevated expression of anti-apoptotic proteins including cellular inhibitor of apoptosis protein-1 (cIAP-1) in CaP cells, which could be attenuated by pre-treatment with a TNF-α neutralizing antibody. Treatment with a novel IAP antagonist, AT-IAP, decreased basal and TNF-α-induced cIAP-1 expression in CaP cells, switched TNF-α signaling from pro-survival to pro-apoptotic and increased radiation sensitivity of CaP cells in co-culture with THP-1 cells. We conclude that targeting cIAP-1 can overcome apoptosis resistance of CaP cells and is an ideal approach to exploit high TNF-α signals within the TAM-rich microenvironment of PTEN-deficient CaP cells to enhance response to radiotherapy.

Pupillary and visual thresholds in young children as an index of population vitamin A status

A prototype scotopic sensitivity machine was used to evaluate pupillary and visual thresholds for 295 Indonesian children aged 1-5 y, most of whom were initially vitamin A-deficient. Subjects were tested 6 and 9 mo after receiving a high dose of vitamin A. A group of 136 older children was tested at 6 mo after dosing; all subjects underwent testing at 9 mo. After testing at 9 mo, children randomly received either a second high dose of vitamin A or placebo and were tested a final time 2 wk later. Children with abnormal pupillary thresholds had significantly higher relative dose responses (RDRs) (P < 0.01) and significantly lower serum retinol values (P = 0.05) than did normal children. The mean pupillary threshold rose (eg, retinal sensitivity fell) as vitamin A status deteriorated between 6 and 9 mo after initial dosing, and was significantly different from a group of normal American children tested previously (P < 0.001). After placebo-controlled dosing, the decline in pupillary and visual thresholds (rise in retinal sensitivity) was significant for children receiving vitamin A but not for children receiving placebo.