title: Natriuretic peptide receptor A signaling regulates stem cell recruitment and angiogenesis: a model to study linkage between inflammation and tumorigenesis.
abstract: Natriuretic peptide receptor A (NPRA), the signaling receptor for the cardiac hormone, atrial natriuretic peptide (ANP), is expressed abundantly in inflamed/injured tissues and tumors. NPRA deficiency substantially decreases tissue inflammation and inhibits tumor growth. However, the precise mechanism of NPRA function and whether it links inflammation and tumorigenesis remains unknown. Since both injury repair and tumor growth require stem cell recruitment and angiogenesis, we examined the role of NPRA signaling in tumor angiogenesis as a model of tissue injury repair in this study. In in vitro cultures, aortas from NPRA-KO mice show significantly lower angiogenic response compared to wild-type counterparts. The NPRA antagonist that decreases NPRA expression, inhibits lipopolysaccharide-induced angiogenesis. The reduction in angiogenesis correlates with decreased expression of vascular endothelial growth factor and chemokine (C-X-C motif) receptor 4 (CXCR4) implicating a cell recruitment defect. To test whether NPRA regulates migration of cells to tumors, mesenchymal stem cells (MSCs) were administered i.v., and the results showed that MSCs fail to migrate to the tumor microenvironment in NPRA-KO mice. However, coimplanting tumor cells with MSCs increases angiogenesis and tumorigenesis in NPRA-KO mice, in part by promoting expression of CXCR4 and its ligand, stromal cell-derived factor 1α. Taken together, these results demonstrate that NPRA signaling regulates stem cell recruitment and angiogenesis leading to tumor growth. Thus, NPRA signaling provides a key linkage between inflammation and tumorigenesis, and NPRA may be a target for drug development against cancers and tissue injury repair.
authors.affiliation: Department of Molecular Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Jaya
authors.initials: J
authors.lastname: Mallela
authors.forename: Sowndharya
authors.initials: S
authors.lastname: Ravi
authors.forename: Frantz
authors.initials: F
authors.lastname: Jean Louis
authors.forename: Bianca
authors.initials: B
authors.lastname: Mulaney
authors.forename: Michael
authors.initials: M
authors.lastname: Cheung
authors.forename: Ujjwala
authors.initials: U
authors.lastname: Sree Garapati
authors.forename: Vignesh
authors.initials: V
authors.lastname: Chinnasamy
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.forename: Srinivas
authors.initials: S
authors.lastname: Nagaraj
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Mohapatra
authors.forename: Subhra
authors.initials: S
authors.lastname: Mohapatra
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A