Abstract
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.
Highlights
Radiotherapy (RT) constitutes a major treatment modality used in patients presenting with localized prostate cancer (CaP) [1]
We have previously proposed that augmentation of CXCL8 signaling is a crucial mediator of PTEN-depleted tumorigenesis in CaP [5]
Validation experiments confirmed separation of these distinct PTEN populations using RT-PCR analysis of mRNA expression (p < 0.001; Figure 1A). Cytokine profiling of these samples confirmed that low PTEN mRNA expression was correlative with increased CXCL8 mRNA (Spearman correlation: −0.5088; p = 0.0261) (Figure 1B)
Summary
Radiotherapy (RT) constitutes a major treatment modality used in patients presenting with localized prostate cancer (CaP) [1]. Loss of the haplo-insufficient tumor suppressor PTEN has recently been identified as a prognostic factor for patient relapse following RT [4]. Knowledge of microenvironmentmediated radioresistance in CaP is poorly characterized www.impactjournals.com/oncotarget but given the strong association of inflammation with the disease, there is a high potential that the immune cell infiltrate may modulate the overall tumor response to RT in early-stage disease. Tumor-associated macrophages (TAM) have been identified as a significant component of the inflammatory cell infiltrate in CaP and may influence disease progression through their ability to release soluble signaling factors within the tumor boundaries [9, 10]. TAM infiltration has previously been correlated with disease free survival (DFS) following radical prostatectomy (RP) (11–13). No such studies have been reported regarding RT response
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