Arachidonic acid modulates the crosstalk between prostate carcinoma and bone stromal cells

Abstract

Diets high in n-6 fatty acids are associated with an increased risk of bone metastasis from prostate carces (PCa). The molecular mechanism underlying this phenomenon is largely unknown. Arachidonic acid (AA) and its precursor linoleic acid can be metabolized to produce pro-inflammatory cytokines that act as autocrine and paracrine regulators of cancer behavior. We and other authors have previously reported that factors released by PCa cells excite an aberrant response in bone marrow stromal cells (BMSCs). We planned to study how AA may modulate in vitro the interaction between PCa cells and human BMSCs. First, we observed that AA is a potent mitogenic factor for PCa cells through the production of both 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) metabolites. While 5-LOX controls cell survival through the regulation of the Bcl-2/Bax ratio, COX-2 activity stimulates the release of transforming growth factor-a (TGF-a) and pro-inflammatory cytokines. The blockade of COX-2 activity through a specific inhibitor is sufficient to repress AA-induced gene transcription. The over-expression of transforming growth factor -a (TGF-a), tumour necrosis factor-a (TNF-a) and interleukin-1 b (IL-1b) by AA-primed PCa cells resulted particularly effective in modifying cell behavior of cultured human BMSCs. In fact, we observed an increment in the cell number of BMSCs, due prevalently to the action of TGF-a, the number of osteoblasts, and the production of receptor activator for nuclear factor k B ligand (RANKL), events mainly controlled by inflammatory cytokines. These findings provide a possible molecular mechanism by which dietary n-6 fatty acids accumulating in bone marrow may influence the formation of PCaderived metastatic lesions and indicate new molecular targets for the therapy of metastatic PCa.

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

“…The reduced invasion towards LA compared with AA may be because of the cells' requirement to convert LA into AA and to metabolize AA to induce invasion. It has been postulated (Angelucci et al, 2008) that proliferation and migration is controlled by an autocrine loop maintaining EGFR signalling which, in turn, is controlled by AA-induced TGF-a. This suggests for LA to stimulate invasion, it must be first metabolised to AA, which is then metabolised by 5-LOX and COX-2 to induce EGFR-mediated signalling of invasion.…”

“…Oleic acid has been shown to activate EGFR signalling in both endothelial (Vacaresse et al, 1999) and breast cancer cell lines (Soto-Guzman et al, 2008). Angelucci et al (2008) has previously reported that AA stimulates the EGFR pathway leading to increased cellular invasion. This suggests that within our in vitro model, where oleic acid is the predominant lipid within the system, oleic acid may act in a similar way to AA and induces invasion via the EGFR signalling pathway.…”

“…Thus, AA not only induces greater adipogenesis than other PUFAs, it's processing by the adipocyte also leads to super-added chemoattractive stimulation. This may be because of the production of metabolites and initiation of additional pathways that are themselves potent stimulators of invasion (Hassan and Carraway, 2006;Angelucci et al, 2008).…”

“…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).…”

Orthopaedic Research in Italy: State of the Art

“…The study of the interactions of MSC with cancer cells could lead to novel therapeutic approaches (168). To date, only few researches are involved in studying the role of MSC in the development of bone metastases (169). Though angiogenesis has been largely investigated in primitive tumours and visceral metastases, only few researches specifically addressing its role in the development of bone metastases.…”