Abstract
BACKGROUND: When single-agent androgen deprivation therapy (ADT) is administered for locally advanced prostate cancer, men usually relapse within 1-2 years with more malignant castrate-resistant disease. The reason for this is currently unknown. We now hypothesise that an initial treatment response that increases tumour hypoxia drives selection of more malignant tumours.
METHODS: The LNCaP prostate tumour xenografts were analysed for physiological (oxygen and vasculature) and genetic (PCR array) changes during longitudinal treatment with ADT (bicalutamide, 6 or 2 mg kg⁻¹ daily for 28 days).
RESULTS: Bicalutamide caused an immediate (within 24 h) dose-dependent fall in oxygenation in LNCaP-luc prostate tumours with a nadir of ≤ 0.1% oxygen within 3-7 days; this was attributed to a significant loss of tumour microvessels (window chamber study). The hypoxic nadir persisted for 10-14 days. During the next 7 days, tumours regrew, oxygenation improved and the vasculature recovered; this was inhibited by the VEGF inhibitor B20.4.1.1. Gene expression over 28 days showed marked fluctuations consistent with the physiological changes. Accompanying the angiogenic burst (day 21) was a particularly striking increase in expression of genes associated with epithelial-to-mesenchymal transition (EMT). In particular, insulin-like growth factor 1 (IGF-1) showed increases in mRNA and protein expression.
CONCLUSIONS: Hypoxic stress caused by ADT promotes EMT, providing a mechanism for the cause of malignant progression in prostate cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 659-68 |
| Number of pages | 10 |
| Journal | British Journal of Cancer |
| Volume | 114 |
| Issue number | 6 |
| Early online date | 08 Mar 2016 |
| DOIs | |
| Publication status | Early online date - 08 Mar 2016 |
| Externally published | Yes |
Keywords
- Androgen Antagonists/pharmacology
- Anilides/pharmacology
- Animals
- Cell Growth Processes
- Cell Hypoxia/drug effects
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Epithelial-Mesenchymal Transition/drug effects
- Humans
- Lung Neoplasms/drug therapy
- Male
- Mice
- Mice, Inbred BALB C
- Mice, SCID
- Neovascularization, Pathologic/drug therapy
- Nitriles/pharmacology
- Oxygen/metabolism
- Prostatic Neoplasms/blood supply
- Tosyl Compounds/pharmacology
- Xenograft Model Antitumor Assays
Access to Document
- Androgen deprivation in LNCaP prostate tumour xenografts induces vascular changes and hypoxic stress, resulting in promotion of epithelial-to-mesenchymal transition
Copyright 2019 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.