## 3 Molecular Mechanisms of Omega-3 Fatty Acids in Cancer
### n-3 PUFA Inhibits Angiogenesis  
The vascular homeostasis is maintained by a balance between pro- and anti-angiogenic factors. The process where new blood vessels are formed is called angiogenesis, and happens when the pro-angiogenic signals are predominant [66].  
For a tumor to proliferate uncontrollably and transition from a dormant state to an invasive one, it must acquire the ability to stimulate angiogenesis, thereby ensuring a sufficient blood supply to meet its escalating metabolic demands. This phenomenon, commonly referred to as the \"angiogenic switch\", involves the heightened activation of pro-angiogenic signaling pathways [67].  
Since its identification as a viable target for cancer therapy, numerous angiogenic treatments have been formulated, primarily focusing on anti-VEGF modalities. However, their efficacy remains limited and unclear, failing to significantly enhance life expectancy and even demonstrating a propensity to promote metastasis, particularly evidenced in preclinical investigations. This phenomenon may be attributed to the varied mechanismsthrough which tumors develop resistance to such therapies, including compensatory processes, co-option of adjacent normal vasculature or induction of pro-angiogenic factors due to the hypoxic conditions induced by anti-angiogenic interventions. Given this context, it has been advocated that novel anti-angiogenic cancer therapies should target alternative angiogenic pathways and serve as adjuncts to other molecular targets rather than focusing solely on angiogenesis inhibition [67; 68].  
n-3 PUFA have been implicated in the inhibition of angiogenesis by virtue of their lipid metabolites, which compete with alternative substrates to yield metabolites of lesser harmfulness or potential benefit. For example, the enzyme COX-2 can utilize AA to generate PGE2 and, alternatively, can employ EPA as a less favorable substrate, resulting in the formation of PGE3 [69]. While PGE2 is widely known for inducing angiogenesis and inflammation as well as promoting tumor growth and metastasis, PGE3 has shown to have significantly reduced detrimental effects and has even shown to inhibit proliferation and invasion in cancer cell lines [58; 70; 71; 72] including melanoma [73].  
Furthermore, [PERSON] et al. demonstrated that DHA can be converted into hydroxyl DHA, whose lipid metabolites exhibit anti-angiogenic properties [74]. However, [PERSON] et al. found that 4-hydroxy-docosahexaenoic acid, a product of DHA metabolism by 5-lipoxygenase (5-LOX), was crucial for these effects, rather than its metabolism by COX-2. [75].  
5-LOX is also responsible for metabolizing AA, generating 5-Hydroxyeicosatetraenoic acid (HETE), which has been demonstrated to induce inflammation and angiogenesis and promote tumor progression. Furthermore, 15-Lipoxygenase can metabolize both EPA and DHA to produce HETE and 17-hydroxy-docosahexaenoic acid (17-HDHA), respectively. These metabolites have been shown to reduce the activity of 5-LOX, thereby mitigating inflammation and angiogenesis. Additionally, 17-HDHA has demonstrated other anti-inflammatory mechanisms by downregulating pro-inflammatory cytokines and modulating the immune response [69].  
Notably, within both anti-angiogenic and anti-inflammatory mechanisms, there exist counterparts among n-6 and n-3 PUFAs, with n-3 derivatives being linked to anti-inflammatory, anti-angiogenic and anti-tumor proliferation effects. [PERSON] et al. investigated this phenomenon and underscored the significance of maintaining a low tissue n-6/n-3 PUFA ratio as a novel strategy for cancer treatment [76].