title: Hematopoietic stem cell-derived cancer-associated fibroblasts are novel contributors to the pro-tumorigenic microenvironment.
abstract: Targeting the tumor microenvironment is critical toward improving the effectiveness of cancer therapeutics. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types of the tumor microenvironment, playing an important role in tumor progression. Multiple origins for CAFs have been proposed including resident fibroblasts, adipocytes, and bone marrow. Our laboratory previously identified a novel hematopoietic stem cell (HSC) origin for CAFs; however, the functional roles of HSC-derived CAFs (HSC-CAFs) in tumor progression have not yet been examined. To test the hypothesis that HSC-CAFs promote tumor progression through contribution to extracellular matrix (ECM) and paracrine production of pro-angiogenic factors, we developed a method to isolate HSC-CAFs. HSC-CAFs were profiled on the basis of their expression of hematopoietic and fibroblastic markers in two murine tumor models. Profiling revealed production of factors associated with ECM deposition and remodeling. Functional in vivo studies showed that co-injection of HSC-CAFs with tumor cells resulted in increased tumor growth rate and significantly larger tumors than tumor cells alone. Immunohistochemical studies revealed increased blood vessel density with co-injection, demonstrating a role for HSC-CAFs in tumor vascularization. Mechanistic in vitro studies indicated that HSC-CAFs play a role in producing vascular endothelial growth factor A and transforming growth factor-β1 in endothelial tube formation and patterning. In vitro and in vivo findings suggest that HSC-CAFs are a critical component of the tumor microenvironment and suggest that targeting the novel HSC-CAF may be a promising therapeutic strategy.
authors.affiliation: Research Services, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Lindsay T
authors.initials: LT
authors.lastname: McDonald
authors.affiliation: Research Services, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Dayvia L
authors.initials: DL
authors.lastname: Russell
authors.affiliation: Research Services, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Kelly
authors.affiliation: Research Services, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: College of Graduate Studies, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Anjan
authors.initials: A
authors.lastname: Motamarry
authors.affiliation: Department of Surgery, Division of Cardiothoracic Research, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Risha K
authors.initials: RK
authors.lastname: Patel
authors.affiliation: Research Services, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA; Department of Surgery, Division of Cardiothoracic Research, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
authors.affiliation: Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Watson
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Turner
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Watson
authors.affiliation: Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Soloff
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Findlay
authors.affiliation: Research Services, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA. Electronic address: laruerc@musc.edu.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: LaRue
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000473:pathology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment / Q000502:physiology*; D014471:Umbilical Veins