Publications

Objective— The endogenous role of the VEGF family member vascular endothelial growth factor-B (VEGF-B) in pathological angiogenesis remains unclear. Methods and Results— We studied the role of VEGF-B in various models of pathological angiogenesis using mice lacking VEGF-B (VEGF-B −/− ) or overexpressing VEGF-B 167 . After occlusion of the left coronary artery, VEGF-B deficiency impaired vessel growth in the ischemic myocardium whereas, in wild-type mice, VEGF-B 167 overexpression enhanced revascularization of the infarct and ischemic border zone. By contrast, VEGF-B deficiency did not affect vessel growth in the wounded skin, hypoxic lung, ischemic retina, or ischemic limb. Moreover, VEGF-B 167 overexpression failed to enhance vascular growth in the skin or ischemic limb. Conclusion— VEGF-B appears to have a relatively restricted angiogenic activity in the ischemic heart. These insights might offer novel therapeutic opportunities.

Aggregation by design Amyloid aggregation is driven by short sequences within proteins that self-assemble into characteristic amyloid structures. About 30 human proteins are implicated in amyloid-associated diseases, but many more contain short sequences that are potentially amyloidogenic. Gallardo et al. designed a peptide based on an amyloidogenic sequence in the vascular endothelial growth factor receptor VEGFR2. The peptide induced VEGFR2 to form aggregates with features characteristic of amyloids. Amyloids were toxic only in cells that required VEGFR2 activity, suggesting that the toxicity was due to loss of function of VEGFR2, rather than to inherent toxicity of the aggregates. The peptide inhibited VEGFR2-dependent tumor growth in a mouse tumor model. Science , this issue p. 10.1126/science.aah4949

Abstract Intrinsic and adaptive resistance hampers the success of antiangiogenic therapies (AAT), especially in breast cancer where this treatment modality has proven largely ineffective. Therefore, novel strategies to improve the efficacy of AAT are warranted. Solid tumors such as breast cancer are characterized by a high infiltration of myeloid-derived suppressor cells (MDSC), which are key drivers of resistance to AAT. Therefore, we hypothesized that all-trans retinoic acid (ATRA), which induces differentiation of MDSC into mature cells, could improve the therapeutic effect of AAT. ATRA increased the efficacy of anti–VEGFR2 antibodies alone and in combination with chemotherapy in preclinical breast cancer models. ATRA reverted the anti–VEGFR2-induced accumulation of intratumoral MDSC, alleviated hypoxia, and counteracted the disorganization of tumor microvessels. Mechanistic studies indicate that ATRA treatment blocked the AAT-induced expansion of MDSC secreting high levels of vessel-destabilizing S100A8. Thus, concomitant treatment with ATRA holds the potential to improve AAT in breast cancer and possibly other tumor types. Significance: Increasing the therapeutic efficiency of antiangiogenic drugs by reducing resistance-conferring myeloid-derived suppressor cells might improve breast cancer treatment. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/12/3220/F1.large.jpg. Cancer Res; 78(12); 3220–32. ©2018 AACR.

peer reviewed

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<p>PDF - 49K, Description of additional methods and procedures used in the study. Also includes supplementary references.</p>

Androgens control spermatogenesis, but germ cells themselves do not express a functional androgen receptor (AR). Androgen regulation is thought to be mediated by Sertoli and peritubular myoid cells, but their relative roles and the mechanisms involved remain largely unknown. Using Cre/ loxP technology, we have generated mice with a ubiquitous knockout of the AR as well as mice with a selective AR knockout in Sertoli cells (SC) only. Mice with a floxed exon 2 of the AR gene were crossed with mice expressing Cre recombinase ubiquitously or selectively in SC (under control of the anti-Müllerian hormone gene promoter). AR knockout males displayed a complete androgen insensitivity phenotype. Testes were located abdominally, and germ cell development was severely disrupted. In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract. Expression of the homeobox gene Pem , which is androgen-regulated in SC, was severely decreased. Testis weight was reduced to 28% of that in WT littermates. Stereological analysis indicated that the number of SC was unchanged, whereas numbers of spermatocytes, round spermatids, and elongated spermatids were reduced to 64%, 3%, and 0% respectively of WT. These changes were associated with increased germ cell apoptosis and grossly reduced expression of genes specific for late spermatocyte or spermatid development. It is concluded that cell-autonomous action of the AR in SC is an absolute requirement for androgen maintenance of complete spermatogenesis, and that spermatocyte/spermatid development/survival critically depends on androgens.

Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.

Abstract To overcome the resistance to VEGF-inhibitor treatment, additional anti-angiogenic agents need to be valorized. Placental growth factor (PlGF), a VEGF homologue, stimulates endothelial, tumor and inflammatory cells. Studies in independently generated PlGF−/− mice by us and Regeneron identified a role for PlGF in inflammatory, ischemic and malignant disease, while the anti-PlGF mAb 5D11D4 blocks growth of implanted tumors. Several clinical studies also show that PlGF levels correlate with poor prognosis in diverse types of cancer, while the humanized anti-human PlGF mAb TB403 has been succesfully tested in a phase I trial in out-treated cancer patients. However, genetic evidence for a disease-candidate role of PlGF or an effect of the anti-PlGF mAb 5D11D4 in spontaneous cancer models has been lacking so far. Here, we show that loss of PlGF inhibited a carcinogen-induced skin tumor model papilloma formation and angiogenesis. Furthermore, silencing of PlGF in a transgenic hepatocellular carcinoma (HCC) model reduced tumor size and incidence. In a carcinogen-induced HCC model, most WT but only a minority of PlGF−/− mice died, while fewer tumor nodules developed in PlGF−/− mice. When WT mice with established HCC were treated with 5D11D4, more control IgG than 5D11D4 treated mice died. PlGF blockage inhibited the characteristic arterialization response in these tumors and blocked vessel abnormalization in HCC leading to reduced levels of hypoxia, known to stimulate HCC growth, however, without affecting microvascular density. These findings indicate that the anti-cancer activity of PlGF-blockage is not reflected by a change in vessel density alone. In the Rip1Tag2 model, no differences between WT and PlGF−/− mice or 5D11D4-treated mice in tumor burden or incidence were found, indicating that 5D11D4 does not have off-target effects. Resistance of this model is likely due to the lack of infiltration by Gr1+ neutrophils by PlGF blockage. These findings and previously published results of a Phase I trial with TB403 warrant furter analysis of anti-PlGF strategies for (non)-oncology indications. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-362.

High-fat diet obesity is linked to increased lung injury and bronchoalveolar lavage fluid (BALF) fatty acids in a hyperoxic ARDS model. In the present study, obesity not only upregulated intracellular lipids and effectors of fatty acid mitochondrial import but also was associated with downregulated fatty acid oxidation and reduced ATP production in alveolar epithelial type 2 cells after injury. Hyperoxic AEC2 from obese mice had reduced phospholipids, and obese mice had increased BALF surface tension after injury.

Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of OXPHOS during quiescence, beyond ATP production, is not well understood. Using mouse models of inducible OXPHOS deficiency in all cell types or specifically in the vascular endothelium that negligibly relies on OXPHOS-derived ATP, we show that selectively during quiescence OXPHOS provides oxidative stress resistance by supporting macroautophagy/autophagy. Mechanistically, OXPHOS constitutively generates low levels of endogenous ROS that induce autophagy via attenuation of ATG4B activity, which provides protection from ROS insult. Physiologically, the OXPHOS-autophagy system (i) protects healthy tissue from toxicity of ROS-based anticancer therapy, and (ii) provides ROS resistance in the endothelium, ameliorating systemic LPS-induced inflammation as well as inflammatory bowel disease. Hence, cells acquired mitochondria during evolution to profit from oxidative metabolism, but also built in an autophagy-based ROS-induced protective mechanism to guard against oxidative stress associated with OXPHOS function during quiescence.<b>Abbreviations</b>: AMPK: AMP-activated protein kinase; AOX: alternative oxidase; Baf A: bafilomycin A₁; CI, respiratory complexes I; DCF-DA: 2',7'-dichlordihydrofluorescein diacetate; DHE: dihydroethidium; DSS: dextran sodium sulfate; ΔΨmi: mitochondrial inner membrane potential; EdU: 5-ethynyl-2'-deoxyuridine; ETC: electron transport chain; FA: formaldehyde; HUVEC; human umbilical cord endothelial cells; IBD: inflammatory bowel disease; LC3B: microtubule associated protein 1 light chain 3 beta; LPS: lipopolysaccharide; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; mtDNA: mitochondrial DNA; NAC: N-acetyl cysteine; OXPHOS: oxidative phosphorylation; PCs: proliferating cells; PE: phosphatidylethanolamine; PEITC: phenethyl isothiocyanate; QCs: quiescent cells; ROS: reactive oxygen species; PLA2: phospholipase A2, WB: western blot.