Vessel sprouting by migrating tip and proliferating stalk endothelial cells (ECs) is controlled by genetic signals (such as Notch), but it is unknown whether metabolism also regulates this process. Here, we show that ECs relied on glycolysis rather than on oxidative phosphorylation for ATP production and that loss of the glycolytic activator PFKFB3 in ECs impaired vessel formation. Mechanistically, PFKFB3 not only regulated EC proliferation but also controlled the formation of filopodia/lamellipodia and directional migration, in part by compartmentalizing with F-actin in motile protrusions. Mosaic in vitro and in vivo sprouting assays further revealed that PFKFB3 overexpression overruled the pro-stalk activity of Notch, whereas PFKFB3 deficiency impaired tip cell formation upon Notch blockade, implying that glycolysis regulates vessel branching.

No abstract

Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry-based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors. Reversal of the lipogenic switch in cancer cells by treatment with the lipogenesis inhibitor soraphen A or by targeting lipogenic enzymes with small interfering RNA leads to a marked decrease in saturated and mono-unsaturated phospholipid species and increases the relative degree of polyunsaturation. Because polyunsaturated acyl chains are more susceptible to peroxidation, inhibition of lipogenesis increases the levels of peroxidation end products and renders cells more susceptible to oxidative stress-induced cell death. As saturated lipids pack more densely, modulation of lipogenesis also alters lateral and transversal membrane dynamics as revealed by diffusion of membrane-targeted green fluorescent protein and by the uptake and response to doxorubicin. These data show that shifting lipid acquisition from lipid uptake toward de novo lipogenesis dramatically changes membrane properties and protects cells from both endogenous and exogenous insults. These findings provide important new insights into the role of de novo lipogenesis in cancer cells, and they provide a rationale for the use of lipogenesis inhibitors as antineoplastic agents and as chemotherapeutic sensitizers. Cancer Res; 70(20); 8117-26. ©2010 AACR.

Page 704, credit for the schematic panels in the model of vessel remodeling during lung maturation (Fig. 2c-e) was omitted. The panels were originally published in Fig. 3 of Burri, P.H. Fetal and postnatal development of the lung. Annu. Rev. Physiol. 46, 617-628 (1984). This reference should be added as reference 44 on p. 710. Elsewhere on the same page, the authors erroneously used the term 'alveoli', which refers to structures that form only after birth, to denote 'saccules', which form during the saccular stage of embryonic development. In the legend of Fig. 2, the description of parts c-e should read: "c-e, Schematic illustration of capillary remodeling in septa. During lung development, capillaries around the airspaces establish a close contact with the overlying cuboidal epithelium (c). Perinatally, secondary septa develop from primary septa, containing a double capillary network (d). In the mature lung, interalveolar septa contain a single capillary layer (e)." In the body of the article, the second through fourth full sentences of the right-hand column should be replaced by the following: "In addition, capillaries in the septa failed to remodel properly in HIF-2α-/-mice. During normal lung development 44 , capillaries, which previously formed a loose network within the mesenchyme, arrange themselves around the airspaces, subsequently establishing in many places a close contact with the overlying cuboidal epithelium (Fig. 2c). During the saccular stage, the capillary networks form a capillary bilayer in the intersacullar septa as the airspaces approach each other (Fig. 2d). In the mature lung, interalveolar septa contain a single capillary layer (Fig. 2e)."

No abstract