TY - JOUR
T1 - Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis
AU - Thanki, Ketan K.
AU - Johnson, Paul
AU - Higgins, Edward J.
AU - Maskey, Manjit
AU - Phillips, Ches'Nique N.
AU - Dash, Swetaleena
AU - Almenas, Francisco Arroyo
AU - Govar, Armita Abdollahi
AU - Tian, Bing
AU - Villéger, Romain
AU - Beswick, Ellen
AU - Wang, Rui
AU - Szabo, Csaba
AU - Chao, Celia
AU - Pinchuk, Irina V.
AU - Hellmich, Mark R.
AU - Módis, Katalin
N1 - Funding Information:
Drs. Thanki and Johnson were supported by the T32 training grant from the National Institutes of Health / NIDDK ( DK007639 ), Bethesda, USA. Drs. Hellmich and Szabo were or currently are funded by the Cancer Prevention & Research Institute of Texas (CPRIT) , DP150074 , Texas, USA, The National Institutes of Health / NCI ( R01CA175803 ), Bethesda, USA, and the Swiss Krebsliga ( KLS-4504-08-2018 ). Dr. Modis is currently funded by the Department of Defense , Career Development Award ( W81XWH2010641 ) and the American Cancer Society , Research Scholar Grant ( RSG-21-027-01-CSM ).
Funding Information:
The BM functions as a reservoir of stem and progenitor cells, including mesenchymal stem cells, hematopoietic stem cells, and endothelial progenitor cells, limiting inflammation at the site of injury and initiating the cellular processes of proliferation, migration, and differentiation critical to restoring tissue integrity and homeostasis [44,46]. A recent study using Helicobacter hepaticus induced colitis demonstrated that chronic oral administration of the H2S donor DATS reduced colon inflammation by limiting the recruitment of granulocytic myeloid-derived suppressor cells [58]. Also, H2S showed to promote the resolution of inflammation by inducing neutrophil apoptosis [59] and driving the differentiation of macrophages towards the anti-inflammatory “M2” phenotype [60]. In addition, our key finding that tumor growth was inhibited in the WT chimeric mice, could be partially explained by the lack of CSE-expressing endothelial progenitor cells (EPCs) from the CSE KO BM inhibiting tumor angiogenesis, a critical step in tumor development and progression. Supporting this interpretation, Lui and colleagues have shown that siRNA-mediated downregulation of CSE in BM-derived EPCs inhibited angiogenesis and wound healing in an animal model of type 2 diabetes [61]. Proof of this mechanism in the AOM/DSS model of CAC will require selectively downregulating CSE in BM-derived EPCs.Drs. Thanki and Johnson were supported by the T32 training grant from the National Institutes of Health/NIDDK (DK007639), Bethesda, USA. Drs. Hellmich and Szabo were or currently are funded by the Cancer Prevention & Research Institute of Texas (CPRIT), DP150074, Texas, USA, The National Institutes of Health/NCI (R01CA175803), Bethesda, USA, and the Swiss Krebsliga (KLS-4504-08-2018). Dr. Modis is currently funded by the Department of Defense, Career Development Award (W81XWH2010641) and the American Cancer Society, Research Scholar Grant (RSG-21-027-01-CSM).
Publisher Copyright:
© 2022
PY - 2022/9
Y1 - 2022/9
N2 - Ulcerative colitis (UC) is characterized by widespread relapsing inflammation of the colonic mucosa. Colitis-associated cancer (CAC) is one of the most serious complications of a prolonged history of UC. Hydrogen sulfide (H2S) has emerged as an important physiological mediator of gastrointestinal homeostasis, limiting mucosal inflammation and promoting tissue healing in response to injury. Inhibition of cystathionine-γ-lyase (CSE)-dependent H2S production in animal models of UC has been shown to exacerbate colitis and delay tissue repair. It is unknown whether CSE plays a role in CAC, or the downregulation of CSE expression and/or activity promotes CAC development. In humans, we observed a significant decrease in CSE expression in colonic biopsies from patients with UC. Using the dextran sodium sulfate (DSS) model of epithelium injury-induced colitis and global CSE KO mouse strain, we demonstrated that CSE is critical in limiting mucosal inflammation and stimulating epithelial cell proliferation in response to injury. In vitro studies showed that CSE activity stimulates epithelial cell proliferation, basal and cytokine-stimulated cell migration, as well as cytokine regulation of transepithelial permeability. In the azoxymethane (AOM)/DSS model of CAC, the loss of CSE expression accelerated both the development and progression of CAC. The increased tumor multiplicity and severity of CAC observed in CSE-KO mice were associated with reduced levels of mucosal IL-10 expression and increased levels of IL-6. Restoring CSE expression in bone marrow (BM) cells of CSE-KO mice through reciprocal BM transplantation raised mucosal IL-10 expression, decreased IL-6 level, and reduced the number of aberrant crypt foci and tumors in AOM/DSS-treated mice. These studies demonstrate that CSE expression in BM cells plays a critical role in suppressing CAC in mice. Furthermore, the data suggest that the inhibitory effects of CSE on the development of CAC are due, in part, to the modulation of mucosal pro-and anti-inflammatory cytokine expression.
AB - Ulcerative colitis (UC) is characterized by widespread relapsing inflammation of the colonic mucosa. Colitis-associated cancer (CAC) is one of the most serious complications of a prolonged history of UC. Hydrogen sulfide (H2S) has emerged as an important physiological mediator of gastrointestinal homeostasis, limiting mucosal inflammation and promoting tissue healing in response to injury. Inhibition of cystathionine-γ-lyase (CSE)-dependent H2S production in animal models of UC has been shown to exacerbate colitis and delay tissue repair. It is unknown whether CSE plays a role in CAC, or the downregulation of CSE expression and/or activity promotes CAC development. In humans, we observed a significant decrease in CSE expression in colonic biopsies from patients with UC. Using the dextran sodium sulfate (DSS) model of epithelium injury-induced colitis and global CSE KO mouse strain, we demonstrated that CSE is critical in limiting mucosal inflammation and stimulating epithelial cell proliferation in response to injury. In vitro studies showed that CSE activity stimulates epithelial cell proliferation, basal and cytokine-stimulated cell migration, as well as cytokine regulation of transepithelial permeability. In the azoxymethane (AOM)/DSS model of CAC, the loss of CSE expression accelerated both the development and progression of CAC. The increased tumor multiplicity and severity of CAC observed in CSE-KO mice were associated with reduced levels of mucosal IL-10 expression and increased levels of IL-6. Restoring CSE expression in bone marrow (BM) cells of CSE-KO mice through reciprocal BM transplantation raised mucosal IL-10 expression, decreased IL-6 level, and reduced the number of aberrant crypt foci and tumors in AOM/DSS-treated mice. These studies demonstrate that CSE expression in BM cells plays a critical role in suppressing CAC in mice. Furthermore, the data suggest that the inhibitory effects of CSE on the development of CAC are due, in part, to the modulation of mucosal pro-and anti-inflammatory cytokine expression.
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U2 - 10.1016/j.redox.2022.102417
DO - 10.1016/j.redox.2022.102417
M3 - Article
C2 - 35933902
AN - SCOPUS:85136115621
SN - 2213-2317
VL - 55
JO - Redox Biology
JF - Redox Biology
M1 - 102417
ER -