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ABSTRACT
Introduction
Brain metastasis is a highly traumatic event in the progression of malignant tumors, often symbolizing higher mortality. Metabolic alterations are hallmarks of cancer, and the mask of lipid metabolic program rearrangement in cancer progression is gradually being unraveled.
Areas covered
In this work, we reviewed clinical and fundamental studies related to lipid expression and activity changes in brain metastases originating from lung, breast, and cutaneous melanomas, respectively. Novel roles of lipid metabolic reprogramming in the development of brain metastasis from malignant tumors were identified and its potential as a therapeutic target was evaluated. Published literature and clinical studies in databases consisting of PubMed, Embase, Scopus and www.ClinicalTrials.gov from 1990 to 2022 were searched.
Expert opinion
Lipid metabolic reprogramming in brain metastasis is involved in de novo lipid synthesis within low lipid availability environments, regulation of lipid uptake and storage, metabolic interactions between brain tumors and the brain microenvironment, and membrane lipid remodeling, in addition to being a second messenger for signal transduction. Although some lipid metabolism modulators work efficiently in preclinical models, there is still a long way to go from laboratory to clinic. This area of research holds assurance for the organ-targeted treatment of brain metastases through drug-regulated metabolic targets and dietary interventions.
GRAPHICAL ABSTRACT
Article highlights
Lipid metabolic reprogramming in brain metastasis is involved in de novo lipid synthesis within low-lipid availability environments, regulation of lipid uptake and storage, metabolic interactions between brain tumors and the brain microenvironment, and membrane lipid remodeling, in addition to being a second messenger for signal transduction.
The brain’s low-lipid availability microenvironment selects ‘seed’ cells that can synthesize fatty acids on their own.
De novo lipogenesis primarily affects the survival of cancer cells in the brain microenvironment but has a limited role in brain micro-metastasis formation.
In addition to affecting membrane properties, the remodeling of membrane lipids affects the homeostasis of other metabolite classes and is associated with oxidative stress and ferroptosis.
Preclinical studies targeting lipid metabolism have shown promising results in brain metastasis, offering novel therapeutic opportunities for brain metastasis.
Abbreviations
| CNS | = | central nervous system |
| MRI | = | magnetic resonance imaging |
| NSCLC | = | non-small cell lung cancer |
| FA | = | fatty acid |
| DNL | = | de novo lipogenesis |
| ACSS2 | = | cytoplasmic acetyl-CoA synthetase 2 |
| TCA | = | tricarboxylic acid |
| PUFAs | = | polyunsaturated fatty acids |
| DHA | = | docosahexaenoic acid |
| BBB | = | blood-brain barrier |
| PDX | = | patient-derived xenograft |
| PM | = | Plasma membrane |
| LPCAT1 | = | lysophosphatidylcholine acyltransferases 1 |
| LPC | = | lysophosphatidylcholine |
| PC | = | phosphatidylcholine |
| EGFR | = | epidermal growth factor receptor |
| PI3K | = | phosphoinositide 3-kinase |
| AKT | = | protein kinase B |
| TAG | = | triacylglycerols |
| mTORC | = | mammalian target of rapamycin complex |
| Her2 | = | human epidermal growth factor receptor 2 |
| SREBP1 | = | sterol regulatory-element binding proteins 1 |
| FASN | = | fatty acid synthase |
| SCD1 | = | stearoyl coenzyme a desaturase 1 |
| ACLY | = | ATP citrate lyase |
| TNBC | = | triple-negative breast cancer |
| NADPH | = | nicotinamide adenine dinucleotide phosphate hydrogen |
| CSF | = | cerebrospinal fluid |
| MFP | = | mammary fat pad |
| MUFAs | = | monounsaturated fatty acids |
| ACC | = | acetyl-CoA carboxylase |
| FABP7 | = | fatty acid binding protein 7 |
| BLBP | = | brain lipid binding protein |
| LDs | = | lipid droplets |
| OXPHOS | = | oxidative phosphorylation |
| CD36 | = | cluster of differentiation 36 |
| FABP6 | = | fatty acid binding protein 6 |
| PPARγ | = | Peroxisome Proliferator-Activated receptor γ |
| CM | = | conditioned medium |
| AA | = | arachidonic acid |
| PCDH7 | = | protocadherin 7 |
| PLCβ | = | phospholipase Cβ |
| CaMKII | = | calmodulin-dependent protein kinase II |
| PIP2 | = | phosphatidylinositol 4,5-bisphosphate |
| IP3 | = | inositol 1,4,5-trisphosphate |
| DAG | = | 1,2-diacylglycerol |
| ER | = | endoplasmic reticulum |
| PKC | = | protein kinase C |
| FAO | = | fatty acid oxidation |
| EMT | = | epithelial-mesenchymal transition |
| PET | = | positron emission tomography |
| PPMP | = | L-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol |
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.