Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids.

Oncogenic transformation is associated with profound changes in cellular metabolism, but whether tracking these can improve disease stratification or influence therapy decision-making is largely unknown. Using the iKnife to sample the aerosol of cauterized specimens, we demonstrate a new mode of real-time diagnosis, coupling metabolic phenotype to mutant PIK3CA genotype. Oncogenic PIK3CA results in an increase in arachidonic acid and a concomitant overproduction of eicosanoids, acting to promote cell proliferation beyond a cell-autonomous manner. Mechanistically, mutant PIK3CA drives a multimodal signaling network involving mTORC2-PKCζ-mediated activation of the calcium-dependent phospholipase A2 (cPLA2). Notably, inhibiting cPLA2 synergizes with fatty acid-free diet to restore immunogenicity and selectively reduce mutant PIK3CA-induced tumorigenicity. Besides highlighting the potential for metabolic phenotyping in stratified medicine, this study reveals an important role for activated PI3K signaling in regulating arachidonic acid metabolism, uncovering a targetable metabolic vulnerability that largely depends on dietary fat restriction. VIDEO ABSTRACT.

DNA Damage, Repair, and Cancer Metabolism.

Although there has been a renewed interest in the field of cancer metabolism in the last decade, the link between metabolism and DNA damage/DNA repair in cancer has yet to be appreciably explored. In this review, we examine the evidence connecting DNA damage and repair mechanisms with cell metabolism through three principal links. (1) Regulation of methyl- and acetyl-group donors through different metabolic pathways can impact DNA folding and remodeling, an essential part of accurate double strand break repair. (2) Glutamine, aspartate, and other nutrients are essential for de novo nucleotide synthesis, which dictates the availability of the nucleotide pool, and thereby influences DNA repair and replication. (3) Reactive oxygen species, which can increase oxidative DNA damage and hence the load of the DNA-repair machinery, are regulated through different metabolic pathways. Interestingly, while metabolism affects DNA repair, DNA damage can also induce metabolic rewiring. Activation of the DNA damage response (DDR) triggers an increase in nucleotide synthesis and anabolic glucose metabolism, while also reducing glutamine anaplerosis. Furthermore, mutations in genes involved in the DDR and DNA repair also lead to metabolic rewiring. Links between cancer metabolism and DNA damage/DNA repair are increasingly apparent, yielding opportunities to investigate the mechanistic basis behind potential metabolic vulnerabilities of a substantial fraction of tumors.

Isoflurane, a commonly used volatile anesthetic, enhances renal cancer growth and malignant potential via the hypoxia-inducible factor cellular signaling pathway in vitro.

BACKGROUND: Growing evidence indicates that perioperative factors, including choice of anesthetic, affect cancer recurrence after surgery although little is known about the effect of anesthetics on cancer cells themselves. Certain anesthetics are known to affect hypoxia cell signaling mechanisms in healthy cells by up-regulating hypoxia-inducible factors (HIFs). HIFs are also heavily implicated in tumorigenesis and high levels correlate with poor prognosis. METHODS: Renal cell carcinoma (RCC4) cells were exposed to isoflurane for 2 h at various concentrations (0.5-2%). HIF-1α, HIF-2α, phospho-Akt, and vascular endothelial growth factor A levels were measured by immunoblotting at various time points (0-24 h). Cell migration was measured across various components of extracellular matrix, and immunocytochemistry was used to analyze proliferation rate and cytoskeletal changes. RESULTS: Isoflurane up-regulated levels of HIF-1α and HIF-2α and intensified expression of vascular endothelial growth factor A. Exposed cultures contained significantly more cells (1.81 ± 0.25 vs. 1.00 of control; P = 0.03) and actively proliferating cells (89.4 ± 2.80 vs. 64.74 ± 7.09% of control; P = 0.016) than controls. These effects were abrogated when cells were pretreated with the Akt inhibitor, LY294002. Exposed cells also exhibited greater migration on tissue culture-coated (F = 16.89; P = 0.0008), collagen-coated (F = 20.99; P = 0.0003), and fibronectin-coated wells (F = 8.21; P = 0.011) as along with dramatic cytoskeletal rearrangement, with changes to both filamentous actin and α-tubulin. CONCLUSIONS: These results provide evidence that a frequently used anesthetic can exert a protumorigenic effect on a human cancer cell line. This may represent an important contributory factor to high recurrence rates observed after surgery.

Cancer recurrence after surgery: direct and indirect effects of anesthetic agents.

Surgery is of paramount importance in the management of solid tumors as definitive resection can be totally curative. Nonetheless, metastatic recurrence after surgery remains a major cause of morbidity and mortality. Interest in the impact of the perioperative period on cancer recurrence is now growing rapidly, with recent research suggesting that some anesthetics or anesthetic techniques may influence the pathophysiology of postoperative metastatic spread. Our review examines the most widely postulated mechanisms for this, including the impact of anesthesia on neuroendocrine and immune function. We also consider evidence for a direct impact on tumor cell signaling pathways based on findings from organ protection research. These studies have demonstrated that certain volatile anaesthetics confer cytoprotective properties to exposed cells and lead to significant upregulation of Hypoxia Inducible Factor-1α (HIF-1α). This ubiquitous transcription factor exerts many effects in cancer: its activity has been linked with more aggressive phenotypes and poorer clinical prognosis. It is proposed that such an upregulation of HIFs in tumor cells by these anesthetics may contribute to a tumor's recurrence by stimulating cytoprotective or protumorigenic behavior in residual cells. Conversely, other anesthetic agents appear to downregulate HIFs or cause negligible effect and thus may prove more suitable for use in cancer surgery. As anesthetic drugs are given at a point of potentially high vulnerability in terms of dissemination and establishment of metastases, there is an urgent need to determine the most appropriate anesthetic strategy for surgical oncology so that the optimal techniques are used to maximize long-term survival.