title: CSF1 expression in nongynecological leiomyosarcoma is associated with increased tumor angiogenesis.
abstract: Leiomyosarcoma (LMS) is a malignant tumor of smooth muscle cells for which few effective therapies exist. A subset of LMS cases express macrophage colony-stimulating factor (CSF1) and the resultant tumor-associated macrophage (TAM) infiltration predicts poor clinical outcome. Further, TAMs have been shown to increase tumor angiogenesis. Here, we analyzed 149 LMS cases by immunohistochemistry for vascular marker CD34 and show that high microvessel density (MVD) in nongynecological LMS cases significantly predicts poor patient outcome. The majority of high MVD cases were also CSF1-positive, and when combining high MVD with CSF1 expression, an even stronger prognostic correlation with patient outcome was obtained. Gene expression profiling revealed that MVD has a stronger correlation with CSF1 expression than with expression of vascular endothelial growth factor isoforms, which have traditionally been used as markers of angiogenesis and as anti-angiogenic therapeutic targets. Finally, patterns of CSF1 expression and TAM recruitment remained consistent between primary tumors and their metastases, and between primary tumors and those grown as xenografts in mice, highlighting the stability of these features to the biology of LMS tumors. Together, these findings suggest an important role for CSF1 and the resulting TAM infiltration in the pathological neovascularization of LMS tumors and provide a rationale for CSF1-targeted therapies in LMS.
authors.affiliation: Department of Pathology, Stanford University Medical Center, Stanford, California, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Espinosa
authors.forename: Badreddin
authors.initials: B
authors.lastname: Edris
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Cheng
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.forename: Kelli D
authors.initials: KD
authors.lastname: Montgomery
authors.forename: Sushama
authors.initials: S
authors.lastname: Varma
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Marinelli
authors.forename: Robert B
authors.initials: RB
authors.lastname: West
authors.forename: Torsten
authors.initials: T
authors.lastname: Nielsen
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007890:Leiomyosarcoma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D055806:Microvessels / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D016173:Macrophage Colony-Stimulating Factor