11ß-HSD1 inhibition does not affect murine tumour angiogenesis but may exert a selective effect on tumour growth by modulating inflammation and fibrosis.

Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. Inhibition of the glucocorticoid-activating enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) reduces tissue-specific glucocorticoid action and promotes angiogenesis in murine models of myocardial infarction. Angiogenesis is important in the growth of some solid tumours. This study used murine models of squamous cell carcinoma (SCC) and pancreatic ductal adenocarcinoma (PDAC) to test the hypothesis that 11ß-HSD1 inhibition promotes angiogenesis and subsequent tumour growth. SCC or PDAC cells were injected into female FVB/N or C57BL6/J mice fed either standard diet, or diet containing the 11ß-HSD1 inhibitor UE2316. SCC tumours grew more rapidly in UE2316-treated mice, reaching a larger (P<0.01) final volume (0.158 ± 0.037 cm3) than in control mice (0.051 ± 0.007 cm3). However, PDAC tumour growth was unaffected. Immunofluorescent analysis of SCC tumours did not show differences in vessel density (CD31/alpha-smooth muscle actin) or cell proliferation (Ki67) after 11ß-HSD1 inhibition, and immunohistochemistry of SCC tumours did not show changes in inflammatory cell (CD3- or F4/80-positive) infiltration. In culture, the growth/viability (assessed by live cell imaging) of SCC cells was not affected by UE2316 or corticosterone. Second Harmonic Generation microscopy showed that UE2316 reduced Type I collagen (P<0.001), whilst RNA-sequencing revealed that multiple factors involved in the innate immune/inflammatory response were reduced in UE2316-treated SCC tumours. 11ß-HSD1 inhibition increases SCC tumour growth, likely via suppression of inflammatory/immune cell signalling and extracellular matrix deposition, but does not promote tumour angiogenesis or growth of all solid tumours.

Social justice now for an equitable tomorrow: Reflections from the Consortium of Universities for Global Health Conference 2022.

PLOS Medicine editors Beryne Odeny and Callam Davidson report from the Consortium of Universities for Global Health conference.

Enhanced Angiogenesis by 11ßHSD1 Blockage Is Insufficient to Improve Reperfusion Following Hindlimb Ischaemia.

Background: Critical limb ischaemia (CLI), which is estimated to affect 2 million people in the United States, reduces quality of life, is associated with high morbidity and mortality, and has limited treatment options. Direct stimulation of angiogenesis using proangiogenic growth factors has been investigated as a therapeutic strategy to improve reperfusion in the ischaemic leg. Despite positive outcomes in animal studies, there has been little success in clinical translation. This investigation addressed the hypothesis that angiogenesis could be stimulated indirectly in the ischaemic hindlimb by blocking 11ß-hydroxysteroid dehydrogenase 1 (11ßHSD1)-mediated reactivation of anti-angiogenic glucocorticoids. Method and Results: Corticosterone suppressed ex vivo angiogenesis in the mouse aortic ring assay. 11ßHSD1 deletion (Hsd11b1Del1/Del1) or pharmacological inhibition (with 300 nM UE2316) which block the reactivation of glucocorticoid (i.e., the conversion of 11-dehydrocorticosterone (11DHC) to bioactive corticosterone) significantly reduced 11DHC-induced suppression of angiogenesis. In a sponge implantation model, 11ßHSD1 deletion, but not pharmacological inhibition, enhanced inflammation-induced angiogenesis. By contrast, in the mouse hindlimb ischaemia model, post-ischaemic reperfusion and vascular density were not affected by either deletion or pharmacological inhibition of 11ßHSD1 in young or aged mice. 3D vascular imaging suggested that hind limb reperfusion in the 1st week following induction of ischaemia may be driven by the rapid expansion of collateral arteries rather than by angiogenesis. Conclusion: 11ßHSD1-mediated glucocorticoid reactivation suppressed angiogenesis ex vivo and in vivo. However, regulation of angiogenesis alone was insufficient to promote reperfusion in hindlimb ischaemia. Future investigation of post-ischaemic reperfusion should include other aspects of systemic vascular remodeling including arteriogenesis and collateral formation.