This review documents our rapidly changing perspectives on the function of fatty acid synthase-catalyzed endogenous fatty acid biogenesis in cancer biology.
Up-regulation of fatty acid synthase gene expression and fatty acid synthase biosynthetic activity are molecular events accompanying the pathogenesis and natural history of cancer disease. First, the increased fatty acid synthase gene expression in precursor, preinvasive and invasive cancer lesions appears to represent an indirect, early epiphenomenon, occurring in response to a microenvironment containing regions of poor oxygenation and high acidity due to, for example, lack of an adequate angiogenesis and/or nutritional supply. Second, aberrant transduction cascades driven by cancer-associated oncogenic changes subvert the downregulatory effects of circulating fatty acids. Third, fatty acid synthase-dependent endogenous fatty acid metabolism actively contributes to cancer evolution by specifically regulating the expression, activity and/or cellular localization of proteins closely related to malignant transformation and/or cancer progression.
Fatty acid synthase-catalyzed endogenous fatty acid metabolism appears to be an obligatory acquisition selecting a biologically aggressive sub-group of cancer cells capable of growth and survival upon stresses such as hypoxia, low pH and/or nutritional deprivation. Considering that an ever-growing body of evidence demonstrates that fatty acid synthase-driven signalling actively regulates key cancer-controlling networks, we may hereafter redefine fatty acid synthase as a metabolic oncogene in human cancer cells.
aFoundation of the Recerca Bio-Medical Institute of Girona Dr Josep Trueta, University Hospital of Girona, Dr Josep Trueta, Girona, Catalonia, Spain
bDepartment of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois, USA
cNorthwestern University Feinberg School of Medicine, Chicago, Illinois, USA
dRobert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
Correspondence to Javier A. Menendez, PhD, Fundació d'Investigació Biomèdica de Girona Dr. Josep Trueta (IdIBGi), Institut Catalá d'Oncologia de Girona (ICO Girona), Hospital Universitari de Girona Dr. Josep Trueta, Avenida de Francia, S/N 17007, Girona, Catalonia, Spain Tel: +34 (972) 225 834 ext. 2579, +34 676970422; fax: +34 (972) 217 344; e-mail: email@example.com; firstname.lastname@example.org
This work was supported in part by the Instituto de Salud Carlos III Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria, Spain (grant CP05-00090) to JAM and by the NIH grant awarded to RL (grant 5R01CA116623).