Hypoxia selects for androgen independent LNCaP cells with a more malignant geno‐ and phenotype

Abstract

Hypoxia confers resistance to common cancer therapies, however, it has also has been shown to result in genetic alterations which may allow a survival advantage and increase the tumorigenic properties of cancer cells. Additionally, it may exert a selection pressure, allowing expansion of tumor cells with a more aggressive phenotype. To further assess the role of hypoxia in malignant progression in prostate cancer we exposed human androgen dependent prostate cancer cells (LNCaP) to cycles of chronic hypoxia and isolated a subline, LNCaP‐H1. This article describes the partial characterization of this cell line. The LNCaP‐H1 subline showed altered growth characteristics and exhibited androgen independent growth both in vitro and in vivo. Furthermore, these cells were resistant to mitochondrial‐mediated apoptosis, probably since the endogenous levels of Bax was lower and Bcl‐2 higher than in the parental LNCaP cells. Microarray analysis revealed that a complex array of pathways had differential gene expression between the 2 cell lines, with LNCaP‐H1 cells exhibiting a genetic profile which suggests that they may be more likely metastasize to distant organs, especially bone. This was supported by an in vitro invasion assay, and an in vivo metastasis study. This study shows that hypoxia can select for androgen independent prostate cancer cells which have a survival advantage and are more likely to invade and metastasize. © 2008 Wiley‐Liss, Inc.

Diffusion-weighted magnetic resonance imaging for monitoring prostate cancer progression in patients managed by active surveillance

“…To our knowledge, however, a reduction in vascularity within non-tumour regions of the prostate over time has not been described previously. It may be that this factor is an important driver of disease progression, and this is supported by ex vivo findings of increased hypoxia in more aggressive tumour types [16]. A larger series using dynamic contrastenhanced MRI to compare modelled vascular parameters of perfusion and permeability in patients on active surveillance programmes would be useful.…”

Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response

“…In one study, hypoxia only caused death of tumour cells when oxygen levels were ,0.01% (0.075 mmHg) for more than 24 h. 42 In our studies, a proportion of LNCaP tumour cells survived exposure in vitro to 48 h or longer of 0.1% oxygen. 43 More recently, we have shown that the median oxygen level of bicalutamide-treated LNCaP prostate xenografts remained below 0.1% oxygen for more than 10 days. 44 Overall, survival in this extreme stress will drive selection for malignant phenotypes that are governed by a Darwinian selection process.…”

“…62 Early studies have shown that hypoxia selected for cells with defects in apoptosis. 6 Further reports have confirmed that hypoxia can impose a selection pressure that allows clonal variant expansion in vitro 43,63,64 and in vivo. 55 Studies in our laboratory showed that mice bearing LNCaP xenografts exposed to bicalutamide-induced hypoxia had increased metastasis to the lungs; this correlated with an increase in Bcl2 and reduction in Bax.…”

Dissecting Biology of Solid Tumour: The Microenvironment and Cancer Progression

“…Data from the author's laboratory provides a strong link between intratumor oxygen level and angiogenic responses [12]. Generally, intra-tumor oxygen play a major role in up regulation of pro-angioogenic factor such as VEGF-A -an endothelial cells' specific mitogen [13]. In fact, the transcriptional regulation of VEGF-A is mediated by hypoxia inducible factor 1 alpha (HIF-1α) [14].…”