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

Davidson, C. T.; Miller, E.; Muir, M.; Dawson, J. C.; Lee, M.; Aitken, S.; Serrels, A.; Webster, S. P.; Homer, N. Z. M.; Andrew, R.; Brunton, V. G.; Hadoke, P. W. F.; Walker, B. R.

doi:10.1101/2021.08.04.455121

bioRxiv · 10.1101/2021.08.04.455121

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

Davidson, C. T.·Miller, E.·Muir, M.·Dawson, J. C.·Lee, M.·Aitken, S.·Serrels, A.·Webster, S. P.·Homer, N. Z. M.·Andrew, R.·Brunton, V. G.·Hadoke, P. W. F.·Walker, B. R.

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Abstract

Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. Inhibition of the glucocorticoid-activating enzyme 11{beta}-hydroxysteroid dehydrogenase type 1 (11{beta}-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 11{beta}-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 11{beta}-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 11{beta}-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. 11{beta}-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.

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Davidson, C. T., Miller, E., Muir, M., Dawson, J. C., Lee, M., Aitken, S., Serrels, A., Webster, S. P., Homer, N. Z. M., Andrew, R., Brunton, V. G., Hadoke, P. W. F., Walker, B. R.. 2021-08-04. 11β-HSD1 inhibition does not affect murine tumour angiogenesis but may exert a selective effect on tumour growth by modulating inflammation and fibrosis. https://doi.org/10.1101/2021.08.04.455121

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