Caprylic acid (C8:0) promotes bone metastasis of prostate cancer by dysregulated adipo‐osteogenic balance in bone marrow

Abstract

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Adipocyte-Cancer Cell Interactions in the Bone Microenvironment

“…Another study found that this cytokine upregulated the expression of COX-2, as was also observed with caprylic acid treatment ( 33 ), and macrophage chemoattractant protein (MCP-1) in bone marrow adipocytes ( 31 ). This COX-2 upregulation was further linked to an increase in the production of prostaglandin-2 (PGE-2) by bone marrow adipocytes which was proposed to reciprocally act on PCa to activate pro-survival pathways ( 31 , 33 ). Interestingly, PCa cells co-cultured with bone marrow adipocytes exhibited a reduced sensitivity to docetaxel, a drug used to treat metastatic PCa ( 31 ).…”

“…Two recent preclinical trials have emphasized the association between an increased number bone marrow adipocytes, volume of BMAT and the progression of PCa cells in the bone marrow niche ( 32 , 33 ). High fat diet, caprylic acid treatment and androgen depletion (castration) enhanced the BMSC-to-adipocyte transition in vitro and in mouse models ( 32 , 33 ). Androgen deprivation therapy (ADT) is a common treatment for prostate cancer.…”

“…While it is unclear as to whether the relationship of the elevated caprylic acid levels in patients was causative or correlational with PCa bone metastasis, in vivo treatment of BMSCs with caprylic acid increased the adipocyte differentiation and the protein expression of PPARγ, while subsequently reducing the number of osteoblasts. Treatment of bone marrow adipocytes with caprylic acid also induced higher expression of cyclooxygenase 2 (COX-2) ( 33 ), which has been implicated in several pro-tumor pathways ( 39 ). Thus, elevated levels of caprylic acid may support PCa bone metastasis through the promotion of adipogenesis over osteoblastogenesis.…”

“…Less well defined is the contribution of adipocyte secreted factors to the pro-tumor microenvironment within bone marrow. Both bone marrow adipocyte-derived lipids ( 38 ) and certain adipokines ( 42 ) have been shown to have several pro-tumor actions with respect to PCa cells including stimulating cell cycle progression, proliferation ( 32 ), migration, invasion ( 30 , 33 ), abnormal morphology ( 43 ) and promoting oxidative stress ( 30 ). For example, in a 3D in vitro co-culture model of bone marrow adipocytes and PCa cells, inhibitors of fatty acid-binding protein 4 and adipocyte triglyceride lipase, used in combination, reduced the invasiveness of PCa cells ( 43 ).…”

Distinct Metabolism of Bone Marrow Adipocytes and their Role in Bone Metastasis

“…Nevertheless, it remains unclear whether BMAs can dedifferentiate into the same tumor-aiding phenotype as found in other adipose tissues. Regarding overall lipid metabolism, researchers have shown that caprylic acid (C8:0) was increased in prostate cancer patients with diagnosed bone metastases ( 95 ). These results open a novel research avenue to study the various fatty acid-influenced molecular actions in the BMA-tumor cell interplays.…”