Clinical and functional characterization of CXCR1/CXCR2 biology in the relapse and radiotherapy resistance of primary PTEN-deficient prostate carcinoma
| Autor: | Kevin M. Prise, Chris Armstrong, David Waugh, Robert G. Bristow, Oksana Lyubomska, Suneil Jain, Chee Wee Ong, Karl T. Butterworth, Pamela J. Maxwell, Silvia Berlingeri, Jonathan A. Coulter, Steven Walker, Ian G. Mills, Melissa J. LaBonte, Rebecca Gallagher, Joe M O'Sullivan |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Biochemical recurrence Manchester Cancer Research Centre medicine.medical_treatment ResearchInstitutes_Networks_Beacons/mcrc Cell Standard Article Biology medicine.disease Radiation therapy 03 medical and health sciences Prostate cancer 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure SDG 3 - Good Health and Well-being In vivo 030220 oncology & carcinogenesis Gene expression Cancer research medicine biology.protein PTEN CXC chemokine receptors |
| Zdroj: | Nar Cancer Armstrong, C W D, Coulter, J A, Ong, C W, Maxwell, P J, Walker, S, Butterworth, K T, Lyubomska, O, Berlingeri, S, Gallagher, R, O'Sullivan, J M, Jain, S, Mills, I G, Prise, K M, Bristow, R G, LaBonte, M J & Waugh, D J J 2020, ' Clinical and functional characterization of CXCR1/CXCR2 biology in the relapse and radiotherapy resistance of primary PTEN-deficient prostate carcinoma ', Familial Cancer, vol. 2, no. 3, pp. zcaa012 . https://doi.org/10.1093/narcan/zcaa012 Armstrong, C, Ong, C W, Maxwell, P, O'Sullivan, J, Prise, K, Butterworth, K, Coulter, J, Walker, S, Oksana, L, Gallagher, R, Jain, S, Bristow, R G, Mills, I, Waugh, D & LaBonte Wilson, M 2020, ' Clinical and functional characterization of CXCR1/CXCR2 biology in the relapse and radiotherapy resistance of primary PTEN-deficient prostate carcinoma ', NAR Cancer, vol. 2, no. 3, zcaa012 . https://doi.org/10.1093/narcan/zcaa012 |
| DOI: | 10.1093/narcan/zcaa012 |
| Popis: | Functional impairment of the tumour suppressor PTEN is common in primary prostate cancer and has been linked to relapse post-radiotherapy (post-RT). Pre-clinical modelling supports elevated CXC chemokine signalling as a critical mediator of PTEN-depleted disease progression and therapeutic resistance. We assessed the correlation of PTEN deficiency with CXC chemokine signalling and its association with clinical outcomes. Gene expression analysis characterized a PTENLOW/CXCR1HIGH/CXCR2HIGH cluster of tumours that associates with earlier time to biochemical recurrence [hazard ratio (HR) 5.87 and 2.65, respectively] and development of systemic metastasis (HR 3.51). In vitro, CXCL signalling was further amplified following exposure of PTEN-deficient prostate cancer cell lines to ionizing radiation (IR). Inhibition of CXCR1/2 signalling in PTEN-depleted cell-based models increased IR sensitivity. In vivo, administration of a CXCR1/2-targeted pepducin (x1/2pal-i3), or CXCR2-specific antagonist (AZD5069), in combination with IR to PTEN-deficient xenografts attenuated tumour growth and progression compared to control or IR alone. Post-mortem analysis confirmed that x1/2pal-i3 administration attenuated IR-induced CXCL signalling and anti-apoptotic protein expression. Interventions targeting CXC chemokine signalling may provide an effective strategy to combine with RT in locally advanced prostate cancer patients with known presence of PTEN-deficient foci. |
| Databáze: | OpenAIRE |
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