A wide variety of tumours and their precursor lesions undergo exacerbated de novo biogenesis of fatty acids (FAs) irrespective of the levels of circulating lipids. Neoplastic lipogenesis is reflected by significantly increased activity and coordinate expression of several lipogenic enzymes in tumour cells. Upregulation of fatty acid synthase (FASN), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in FA synthesis, represents a nearly-universal phenotypic alteration in most human malignancies.
Although the same disturbances in signalling pathways responsible for oncogenic transformation can contribute to increased lipogenesis in tumours, FASN hyperactivity and overexpression is not only a secondary phenomenon that results from the induction of other pathways during carcinogenesis. Rather, it is directly selected for because it provides a growth and/or survival advantage achieved through multiple mechanisms.
Early upregulation of FASN in precursor lesions might represent an obligatory metabolic acquisition in response to the microenvironment of pre-invasive lesions (that is, poor oxygenation and high acidity, and/or lack of nutrients), which continue to occur in invasive and/or metastatic stages. The functional and temporal linkage of the 'glycolytic-switch' and the FASN-related lipogenic phenotype may represent co-evolved essential components of the malignant phenotype and, therefore, hallmarks of invasive cancers.
Both the persistent prevalence of the exacerbated de novo FA biosynthesis in primary and metastatic malignancy and the existence of bi-directional linkages of FASN with cancer-controlling networks (such as oestrogen receptor and ERBB2), strongly suggest that FASN can work as a previously unrecognized metabolic intermediate of oncogenesis linking energy, anabolism and malignant transformation.
As exacerbated lipogenesis emerges early in carcinogenesis, it might represent an exploitable target in cancer prevention by retarding the progression of pre-malignant lesions. At later stages, a more complete understanding of the molecular and physiological consequences of its specific inhibition might lead to targeted therapies for the treatment of advanced or metastatic carcinomas.
There is a renewed interest in the ultimate role of fatty acid synthase (FASN) — a key lipogenic enzyme catalysing the terminal steps in the de novo biogenesis of fatty acids — in cancer pathogenesis. Tumour-associated FASN, by conferring growth and survival advantages rather than functioning as an anabolic energy-storage pathway, appears to necessarily accompany the natural history of most human cancers. A recent identification of cross-talk between FASN and well-established cancer-controlling networks begins to delineate the oncogenic nature of FASN-driven lipogenesis. FASN, a nearly-universal druggable target in many human carcinomas and their precursor lesions, offers new therapeutic opportunities for metabolically treating and preventing cancer.
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We truly regret that we could not cite the work of many of our colleagues owing to space limitation. The authors are supported by funding from Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria (FIS), Spain, grants CP05-00090, PI06-0778 and RD06-0020-0028) and grant BCTR0600,894 from the Susan G. Komen Breast Cancer Foundation to J.A.M. And the Extramural Funding Program of the US National Institutes of Health, RO1CA116,623, and the Breast Cancer Auxillary Program of the Evanston Northwestern Healthacare, to R.L.
The authors declare no competing financial interests.
The process by which fats, in the form of acyl coenzyme A (CoA) molecules, are broken down in the mitochondria to generate acetyl-CoA, the entry molecule for the Krebs cycle (also known as the citric acid cycle).
- Genome copy number abnormalities
Gains and losses of DNA sequences throughout the genome that associate with cancer development. Measurement of copy number variations at multiple loci simultaneously provides an important tool for studying cancer.
A protein possessing more than one catalytic function contributed by distinct parts of a polypeptide chain (domains), by distinct subunits, or both.
- Paget's disease of the vulva
A usually non-invasive adenocarcinoma of the skin on the vulva. It may be a primary lesion but in a small percentage of women an invasive cancer of the vulva is found below the area of Paget's.
- Prostatic intraepithelial neoplasia (PIN) lesions
The high-grade form of PIN has been postulated to be the precursor of invasive carcinoma of the prostate. Low-grade PIN corresponds to 'very mild' to 'mild' dysplasia.
- Sterol regulatory element binding protein-1c (SREBP1c)
A basic helix-loop-helix leucine zipper transcription factor that activates genes involved in the synthesis of cholesterol and fatty acids, including fatty acid synthase.
- Gene-set enrichment analysis
A microarray data analysis method that uses predefined gene sets and ranks of genes to identify significant biological changes when gene expression changes in a given microarray data set are minimal or moderate.
- Ductal carcinoma in situ (DCIS)
The earliest form of breast cancer, known as stage 0 (non-invasive) cancer, which stays inside the milk duct of the breast in which it started. It is not known how to predict which DCIS lesions will become invasive.
- Lobular carcinoma in situ (LCIS)
An overgrowth of cells in the lobules of the breast. These cells are not likely to turn into an invasive cancer, but having them means a higher risk of getting breast cancer.
- Lipid raft aggregates
Plasma membrane domains enriched with glycosphingolipids and cholesterol that are implicated in key biological processes including signal transduction, intracellular trafficking, cell polarization and cell migration. Rafts might function as platforms regulating receptor tyrosine kinase signalling pathways.
- Hypoxia-inducible factor-1α (HIF1α)
Part of a dimeric transcription factor formed of α and β subunits that is involved in the hypoxia-sensitive regulation of numerous genes, including glycolytic enzymes, glucose transporters and angiogenic factors.
An autochthonous mouse model of prostate cancer. Various stages of progressive prostate disease can be observed in TRAMP mice, with focal adenocarcinomas developing between 10 and 20 weeks of age with 100% frequency.
This transgenic mouse model overexpresses the non-transforming rat homologue of ERBB2 (Neu) cDNA under control of the mouse mammary tumour virus (MMTV) promoter in a mammary-specific fashion and develops spontaneous focal NEU-expressing tumours.
- Endoplasmic reticulum (ER) stress
The inability of the ER to fold proteins properly. Accumulation of unfolded proteins initiates a stress response called the unfolded protein response (UPR), a set of pathways that decreases protein synthesis. Failure of the UPR to correct ER stress results in apoptosis.
A cell survival mechanism that is activated in response to starvation and can lead to cell death. Subcellular membranes undergo dramatic morphological changes and portions of cytoplasm are degraded.
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Menendez, J., Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7, 763–777 (2007). https://doi.org/10.1038/nrc2222
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