Aromatic Hydrocarbon Receptor Suppresses Prostate Cancer Bone Metastasis Cells-Induced Vasculogenesis of Endothelial Progenitor Cells under Hypoxia

Background/Aims: Hypoxia leads to the development of neovascularization in solid tumor by regulating VEGF expression. Aromatic hydrocarbon receptor (AHR), a receptor for dioxin-like compounds, functions as a transcription factor through dimerization with hypoxia-inducible factors 1β (HIF-1β) and inhibits the secretion of vascular endothelial growth factor (VEGF). The purpose of this study was to explore whether AHR can suppress hypoxia-induced VEGF production in prostate bone metastasis cells and repress neovascularization in endothelial progenitor cells (EPCs), and, if so, through what mechanisms. Methods: PC-3 or LNCaP cells induced angiogenesis was detected by Matrigel-based tube formation assay, mRNA expression levels was measured by qRT-PCR, VEGF secretion level was determined by ELISA assay, respectively. Results: AHR activation inhibits hypoxia-induced adhesiveness and vasculogenesis of EPCs induced by PC-3 or LNCaP cells under hypoxia. Moreover, AHR activation suppressed hypoxia-induced VEGF production in PC-3 and LNCaP cells (48 ± 14% in PC-3, p = 0.000; 41 ± 14% in LNCaP, p = 0.000) by attenuating HIF-1α and HIF-1β level that in turn diminished the angiogenic ability of EPCs in vitro. Furthermore, we found the mRNA level of hypoxia-inducible factors 1α (HIF-1α) (1.54 ± 0.13 fold in PC-3, p = 0.002, 1.62 ± 0.12 fold in LNCaP, p = 0.001) and HIF-1β (1.67 ± 0.23 fold in PC-3, p = 0.007; 1.75 ± 0.26 fold in LNCaP, p=0.008) were upregulated in prostate cancer bone metastasis PC-3 and LNCaP cell lines in response to hypoxia, and revealed that the regulation of VEGF by HIF-1α and HIF-1β was possibly mediated by the activation of phosphatidylinositol 3-kinase pathway. Conclusion: By providing a mechanistic insight into the modulation of neovascularization by AHR ligand, we suggest that AHR ligand has a strong potential of being a new therapeutic agent with applications in the field of bone metastatic prostate cancer

Biomechanical analysis of a newly developed shape memory alloy hook in a transforaminal lumbar interbody fusion (TLIF) in vitro model.

The objective of this biomechanical study was to evaluate the stability provided by a newly developed shape memory alloy hook (SMAH) in a cadaveric transforaminal lumbar interbody fusion (TLIF) model.Six human cadaveric spines (L1-S2) were tested in an in vitro flexibility experiment by applying pure moments of ±8 Nm in flexion/extension, left/right lateral bending, and left/right axial rotation. After intact testing, a TLIF was performed at L4-5. Each specimen was tested for the following constructs: unilateral SMAH (USMAH); bilateral SMAH (BSMAH); unilateral pedicle screws and rods (UPS); and bilateral pedicle screws and rods (BPS). The L3-L4, L4-L5, and L5-S1 range of motion (ROM) were recorded by a Motion Analysis System.Compared to the other constructs, the BPS provided the most stability. The UPS significantly reduced the ROM in extension/flexion and lateral bending; the BSMAH significantly reduced the ROM in extension/flexion, lateral bending, and axial rotation; and the USMAH significantly reduced the ROM in flexion and left lateral bending compared with the intact spine (p<0.05). The USMAH slightly reduced the ROM in extension, right lateral bending and axial rotation (p>0.05). Stability provided by the USMAH compared with the UPS was not significantly different. ROMs of adjacent segments increased in all fixed constructs (p>0.05).Bilateral SMAH fixation can achieve immediate stability after L4-5 TLIF in vitro. Further studies are required to determine whether the SMAH can achieve fusion in vivo and alleviate adjacent segment degeneration

Range of motion at L3-4.

<p>Abbreviations: F, flexion; E, extension; LLB, left lateral bending; RLB, right lateral bending; LR, left rotation; RR, right rotation. USMAH, unilateral shape memory alloy hook; BSMAH, bilateral shape memory alloy hook; UPS, unilateral pedicle screws and rods; BPS, bilateral pedicle screws and rods.</p

45 mm Shape memory Alloy Hook (SMAH).

<p>Left, prototype; right, unfolded in ice and water mixture.</p

Range of motion at L5-S1.

<p>Abbreviations: F, flexion; E, extension; LLB, left lateral bending; RLB, right lateral bending; LR, left rotation; RR, right rotation. USMAH, unilateral shape memory alloy hook; BSMAH, bilateral shape memory alloy hook; UPS, unilateral pedicle screws and rods; BPS, bilateral pedicle screws and rods.</p

Range of motion at L4-5.

<p>Abbreviations: F, flexion; E, extension; LLB, left lateral bending; RLB, right lateral bending; LR, left rotation; RR, right rotation. USMAH, unilateral shape memory alloy hook; BSMAH, bilateral shape memory alloy hook; UPS, unilateral pedicle screws and rods; BPS, bilateral pedicle screws and rods. * significant difference vs. the intact spine (p<0.05). # significant difference vs. the BPS construct (p<0.05). + significant difference vs. the BSMAH construct (p<0.05).</p

Surgical constructs.

<p>1. Transforaminal lumbar interbody fusion (TLIF) with unilateral shape memory alloy hook (USMAH) at L4-5; 2. TLIF with bilateral shape memory alloy hook (BSMAH) at L4-5; 3. TLIF with unilateral pedicle screws and rods (UPS) at L4-5; 4. TLIF with bilateral pedicle screws and rods (BPS) at L4-5.</p