Review: Ketogenic diet in the treatment of cancer – Where do we stand? 評論：生酮飲食治療癌症-我們的立場是什麼？

4.5. Ketogenic diet targets angiogenesis, vascularization and the tumor environment

Various interactions of cancer cells with their environment contribute to tumor progression and metastasis. Tumor cells are capable of creating a suitable microenvironment for their development and invasion by enhancing vascularization, repressing the immune response, and inducting inflammation.

A high level of angiogenesis is a key risk factor for progression in cancer. Therefore, anti-neovascularization strategies are considered one option for combating cancer [147]. In mouse models of brain cancer, neuroblastoma, gastric cancer, and liver cancer, a calorie-restricted or ad libitum KD either alone or in combination with chemotherapy reduced the level of vascularization and resulted in a reduction of intra-tumoral hemorrhage [46], [51], [58], [106], [148], [149]. Even though these studies suggest that KDs are anti-angiogenic, the mechanism behind them has not been fully characterized. During tumor progression, many angiogenic activators support the process of angiogenesis, such as vascular endothelial growth factors (VEGFs), interleukin 8 (IL-8), tumor necrosis factor α (TNF-α) and hypoxia-inducible factors (HIFs) [147]. In mouse glioma models, a KD or caloric restriction induced the reduction of the tumor microvasculature, accompanied by significant reduction of HIF-1α and VEGF receptor 2 levels [149].

Rapidly proliferating cancer cells often experience an imbalance between high oxygen demand and inadequate oxygen supply, resulting in a hypoxic environment. HIFs and carbonic anhydrase IX (CA IX) are commonly used markers of hypoxia that regulate cellular hypoxic responses [150], [151]. In a glioma mouse model, an ad libitum KD led to significantly reduced HIF-1α and CA IX levels in the tumor [149].

Inflammation and innate immunity are markedly associated with tumorigenesis [152]. Studies in mouse models of glioma and pancreatic cancer have shown that KDs improve the immune response against cancer progression [108], [153]. Moreover, a variety of in vitro and in vivo studies provides evidence that the KD and ketone bodies (especially BHB) have an anti-inflammatory effect via suppression of the NLRP3 inflammasome and reduction of inflammatory factors like TNF-α, IL-1, -6 and -18 and prostaglandin E2 [7], [98], [154], [155], [156], [157], [158], [159], [160]. In a colon cancer mouse model, a KD suppressed the elevation of plasma IL-6 and subsequent progression of inflammation [154]. NLRP3 is a multi-protein complex that controls the activation of caspase-1 and the release of the pro-inflammatory cytokines IL-1β and IL-18 in macrophages. Youm and colleagues found that BHB, but not AcAc, inhibits NLRP3 inflammasome assembly [7]. In an in vitro study, BHB suppressed the migration of glioma cells by inhibition of the NLRP3 inflammasome [158]. Further evidence comes from numerous other diseases and disease models highlighting the effect of BHB on NLRP3 [156], [157].