title: Matricellular protein SPARCL1 regulates tumor microenvironment-dependent endothelial cell heterogeneity in colorectal carcinoma.
abstract: Different tumor microenvironments (TMEs) induce stromal cell plasticity that affects tumorigenesis. The impact of TME-dependent heterogeneity of tumor endothelial cells (TECs) on tumorigenesis is unclear. Here, we isolated pure TECs from human colorectal carcinomas (CRCs) that exhibited TMEs with either improved (Th1-TME CRCs) or worse clinical prognosis (control-TME CRCs). Transcriptome analyses identified markedly different gene clusters that reflected the tumorigenic and angiogenic activities of the respective TMEs. The gene encoding the matricellular protein SPARCL1 was most strongly upregulated in Th1-TME TECs. It was also highly expressed in ECs in healthy colon tissues and Th1-TME CRCs but low in control-TME CRCs. In vitro, SPARCL1 expression was induced in confluent, quiescent ECs and functionally contributed to EC quiescence by inhibiting proliferation, migration, and sprouting, whereas siRNA-mediated knockdown increased sprouting. In human CRC tissues and mouse models, vessels with SPARCL1 expression were larger and more densely covered by mural cells. SPARCL1 secretion from quiescent ECs inhibited mural cell migration, which likely led to stabilized mural cell coverage of mature vessels. Together, these findings demonstrate TME-dependent intertumoral TEC heterogeneity in CRC. They further indicate that TEC heterogeneity is regulated by SPARCL1, which promotes the cell quiescence and vessel homeostasis contributing to the favorable prognoses associated with Th1-TME CRCs.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Naschberger
authors.forename: Andrea
authors.initials: A
authors.lastname: Liebl
authors.forename: Vera S
authors.initials: VS
authors.lastname: Schellerer
authors.forename: Manuela
authors.initials: M
authors.lastname: Schütz
authors.forename: Nathalie
authors.initials: N
authors.lastname: Britzen-Laurent
authors.forename: Patrick
authors.initials: P
authors.lastname: Kölbel
authors.forename: Ute
authors.initials: U
authors.lastname: Schaal
authors.forename: Lisa
authors.initials: L
authors.lastname: Haep
authors.forename: Daniela
authors.initials: D
authors.lastname: Regensburger
authors.forename: Thomas
authors.initials: T
authors.lastname: Wittmann
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.forename: Tilman T
authors.initials: TT
authors.lastname: Rau
authors.forename: Barbara
authors.initials: B
authors.lastname: Dietel
authors.forename: Valérie S
authors.initials: VS
authors.lastname: Méniel
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
authors.forename: Susanne
authors.initials: S
authors.lastname: Merkel
authors.forename: Roland S
authors.initials: RS
authors.lastname: Croner
authors.forename: Werner
authors.initials: W
authors.lastname: Hohenberger
authors.forename: Michael
authors.initials: M
authors.lastname: Stürzl
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D009363:Neoplasm Proteins; C503126:SPARCL1 protein, human; C503127:Sparcl1 protein, mouse