Showing papers by "Stanley G. Rockson published in 2020"

Leukotrienes in Tumor-Associated Inflammation.

Abstract: Leukotrienes are biologically active eicosanoid lipid mediators that originate from oxidative metabolism of arachidonic acid Biosynthesis of leukotrienes involves a set of soluble and membrane-bound enzymes that constitute a machinery complex primarily expressed by cells of myeloid origin Leukotrienes and their synthetic enzymes are critical immune modulators for leukocyte migration Increased concentrations of leukotrienes are implicated in a number of inflammatory disorders More recent work indicates that leukotrienes may also interact with a variety of tissue cells, contributing to the low-grade inflammation of cardiovascular, neurodegenerative, and metabolic conditions, as well as that of cancer Leukotriene signaling contributes to the active tumor microenvironment, promoting tumor growth and resistance to immunotherapy This review summarizes recent insights into the intricate roles of leukotrienes in promoting tumor growth and metastasis through shaping the tumor microenvironment The emerging possibilities for pharmacological targeting of leukotriene signaling in tumor metastasis are considered

Platelet factor 4 is a biomarker for lymphatic-promoted disorders

Abstract: Genetic or acquired defects of the lymphatic vasculature often result in disfiguring, disabling, and, occasionally, life-threatening clinical consequences. Advanced forms of lymphedema are readily diagnosed clinically, but more subtle presentations often require invasive imaging or other technologies for a conclusive diagnosis. On the other hand, lipedema, a chronic lymphatic microvascular disease with pathological accumulation of subcutaneous adipose tissue, is often misdiagnosed as obesity or lymphedema; currently there are no biomarkers or imaging criteria available for a conclusive diagnosis. Recent evidence suggests that otherwise-asymptomatic defective lymphatic vasculature likely contributes to an array of other pathologies, including obesity, inflammatory bowel disease, and neurological disorders. Accordingly, identification of biomarkers of lymphatic malfunction will provide a valuable resource for the diagnosis and clinical differentiation of lymphedema, lipedema, obesity, and other potential lymphatic pathologies. In this paper, we profiled and compared blood plasma exosomes isolated from mouse models and from human subjects with and without symptomatic lymphatic pathologies. We identified platelet factor 4 (PF4/CXCL4) as a biomarker that could be used to diagnose lymphatic vasculature dysfunction. Furthermore, we determined that PF4 levels in circulating blood plasma exosomes were also elevated in patients with lipedema, supporting current claims arguing that at least some of the underlying attributes of this disease are also the consequence of lymphatic defects.

Decreased lymphatic HIF-2α accentuates lymphatic remodeling in lymphedema

Abstract: Pathologic lymphatic remodeling in lymphedema evolves during periods of tissue inflammation and hypoxia through poorly defined processes. In human and mouse lymphedema, there is a significant increase of hypoxia inducible factor 1 α (HIF-1α), but a reduction of HIF-2α protein expression in lymphatic endothelial cells (LECs). We questioned whether dysregulated expression of these transcription factors contributes to disease pathogenesis and found that LEC-specific deletion of Hif2α exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif2α caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2α is an important mediator of lymphatic health. HIF-2α promoted protective phosphorylated TIE2 (p-TIE2) signaling in LECs, a process also replicated by upregulating TIE2 signaling through adenovirus-mediated angiopoietin-1 (Angpt1) gene therapy. Our study suggests that HIF-2α normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2α pathways in lymphedema could mitigate long-term pathology and disability.