Promotion of prostatic metastatic migration towards human bone marrow stoma by Omega 6 and its inhibition by Omega 3 PUFAs

Abstract

Epidemiological studies have shown not only a relationship between the intake of dietary lipids and an increased risk of developing metastatic prostate cancer, but also the type of lipid intake that influences the risk of metastatic prostate cancer. The Omega-6 polyunsaturated fatty acid, Arachidonic acid, has been shown to enhance the proliferation of malignant prostate epithelial cells and increase the risk of advanced prostate cancer. However, its role in potentiating the migration of cancer cells is unknown. Here we show that arachidonic acid at concentrations p5 mM is a potent stimulator of malignant epithelial cellular invasion, which is able to restore invasion toward hydrocortisone-deprived adipocyte-free human bone marrow stroma completely. This observed invasion is mediated by the arachidonic acid metabolite prostaglandin E 2 and is inhibited by the Omega-3 poly-unsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid at a ratio of 1 : 2 Omega-3 : Omega-6, and by the COX-2 inhibitor NS-398. These results identify a mechanism by which arachidonic acid may potentiate the risk of metastatic migration and secondary implantation in vivo, a risk which can be reduced with the uptake of Omega-3 poly-unsaturated fatty acids.

Influence of omega-6 PUFA arachidonic acid and bone marrow adipocytes on metastatic spread from prostate cancer

“…Bone marrow stroma control and AA, previously shown to induce maximum PC-3 invasion (Brown et al, 2006), induced significant invasion through Matrigel ( Figure 1A). Common dietary oils failed to induce significant invasion compared with controls.…”

“…As migrating CaP cells within the BMS take up lipids (Brown et al, 2006) we utilised mBM-Ad pulsed with D 8 -AA to determine whether these cancer cells take up lipids released from the mBM-Ad into the BMS environment or whether the process is mediated through direct interaction with the adipocytes themselves. A white light micrograph (Figure 3) shows a mBM-Ad overlaid with the FTIR spectral maps correlating to the vibrational spectral characteristics u(C -D) and u( ¼ C-D) of D 8 -AA and demonstrates clearly that D 8 -AA lies within the adipocyte.…”

“…Arachidonic acid itself is a potent stimulator of malignant prostate epithelial cell (PEC) invasion, and is able to recover invasion towards adipocyte-free human bone marrow stroma (BMS) by the AA metabolite PGE 2 . This stimulatory effect is abrogated by the addition of long chain marine o-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Brown et al, 2006). It has also been hypothesised that AA acts as a secondary messenger involving an autocrine loop-maintaining EGFR activation (Angelucci et al, 2008).…”

“…It is hypothesised that they have a role in haematopoiesis (Gimble et al, 1992) or act as energy stores supporting oxidative metabolism of resorbing osteoclasts (Dodds et al, 1994) and are fundamental to BMS formation and its long-term maintenance (Gartner and Kaplan, 1980). In long-term human BMS/CaP models malignant cells migrate towards BM-Ad and take up lipids from adipocytes or the surrounding microenvironment (Brown et al, 2006). Separate studies by Tokuda et al (2003) and Gazi et al (2007) found that PC-3 cells interacted directly with adipocytes and using Fourier Transform Infrared spectroscopy (FTIR) to follow deuterated palmitic acid, Gazi et al (2007) confirmed the direct uptake of lipid by CaP cells from BM-Ad.…”

Hepatitis B virus X protein promotes liver cell proliferation via a positive cascade loop involving arachidonic acid metabolism and p-ERK1/2

“…Exogenous AA and its lipid metabolites have been shown to induce ERK activation [40]. Several studies have demonstrated that specific inhibitors of COX and LOX reduce the incidence of development and metastasis of breast cancer tumors in animal models [41][42][43][44] and in humans [43]. Furthermore, COX-2 inhibitors can inhibit the growth of HBx-positive HCC cells [45].…”