title: Presence of cancer-associated fibroblasts inversely correlates with Schwannian stroma in neuroblastoma tumors.
abstract: Stromal cells have a central function in the regulation of tumor angiogenesis. Recent studies have shown that stromal myofibroblasts (cancer-associated fibroblasts) actively promote tumor growth and enhance tumor angiogenesis in many types of adult carcinomas. To evaluate the function cancer-associated fibroblasts have in neuroblastoma angiogenesis and investigate their relationship to stromal Schwann cells, we quantified cancer-associated fibroblasts in 60 primary neuroblastoma tumors and in a novel neuroblastoma xenograft model in which murine Schwann cells were induced to infiltrate into the tumor stroma. Tumor sections were examined for presence of microvascular proliferation, a hallmark of tumor angiogenesis. Cancer-associated fibroblasts were characterized by positive immunostaining for alpha-smooth muscle actin (alpha-SMA) and were distinguished from pericytes by staining negatively for high-molecular-weight caldesmon. alpha-SMA-positive cells were quantified and their number was defined as high when >1.0% of the area was positive. Associations between high cancer-associated fibroblast number, microvascular proliferation and established prognosticators were analyzed. High numbers of cancer-associated fibroblasts were associated with Schwannian stroma-poor histopathology and microvascular proliferation. Thirty-seven (80%) of the 46 Schwannian stroma-poor tumors had high numbers of cancer-associated fibroblasts in the tumor stroma compared to only 2 (14%) of the 14 Schwannian stroma-rich/dominant tumors (P<0.001). Thirty-three (89%) of 37 tumors with microvascular proliferation had high numbers of cancer-associated fibroblasts compared to 9 (40%) of 22 tumors without microvascular proliferation (P<0.001). In the xenografts with infiltrating Schwann cells (n=10), the number of cancer-associated fibroblasts per mm(2) was approximately sevenfold less than in the control xenografts without stromal Schwann cells (n=9) (mean of 51+/-30 vs 368+/-105, respectively; P<0.001). Thus, cancer-associated fibroblasts were inversely associated with presence of Schwann cells, suggesting that Schwann cells may prevent the activation of fibroblasts. A deeper understanding of the function cancer-associated fibroblasts have in neuroblastoma angiogenesis may guide future development of stroma-directed therapeutic strategies.
authors.affiliation: Department of Pathology, Northwestern University, Chicago, IL, USA.
authors.forename: Rana
authors.initials: R
authors.lastname: Zeine
authors.forename: Helen R
authors.initials: HR
authors.lastname: Salwen
authors.forename: Radhika
authors.initials: R
authors.lastname: Peddinti
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Tian
authors.forename: Lisa
authors.initials: L
authors.lastname: Guerrero
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Yang
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chlenski
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cohn
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology*; D009447:Neuroblastoma / Q000098:blood supply / Q000401:mortality / Q000473:pathology*; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D012583:Schwann Cells / Q000473:pathology*; D012584:Sciatic Nerve / Q000473:pathology / Q000601:surgery; D017154:Stromal Cells / Q000473:pathology*
chemical_list: D000199:Actins; D015415:Biomarkers; D002148:Calmodulin-Binding Proteins