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

Oncotarget
Chris W D ArmstrongDavid J J Waugh

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 ...Continue Reading

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Citations

Jul 5, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Heedoo LeeYang Jin
May 22, 2018·American Journal of Reproductive Immunology : AJRI·Cole CliffordMadhuri Koti
Jun 24, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Guanglei HuYumin Xia
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Apr 25, 2020·British Journal of Cancer·Thiago VidottoJeremy A Squire
Oct 28, 2020·Cells·Daniel J TurnhamHelen B Pearson

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Methods Mentioned

BETA
flow cytometry
xenograft
FCS
chips
PCR
chip
X-Ray
Assay

Software Mentioned

GraphPad
GenomeStudio Gene Expression Module
Prism
GenomeStudio

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