Presence of cancer-associated fibroblasts inversely correlates with Schwannian stroma in neuroblastoma tumors

Rana Zeine, Helen R. Salwen, Radhika Peddinti, Yufeng Tian, Lisa Guerrero, Qiwei Yang, Alexandre Chlenski, Susan L. Cohn

Research output: Contribution to journalArticle

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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 α-smooth muscle actin (α-SMA) and were distinguished from pericytes by staining negatively for high-molecular-weight caldesmon. α-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 (P0.001). 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 (P0.001). In the xenografts with infiltrating Schwann cells (n10), the number of cancer-associated fibroblasts per mm 2 was approximately sevenfold less than in the control xenografts without stromal Schwann cells (n9) (mean of 5130 vs 368105, respectively; P0.001). 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.

Original languageEnglish (US)
Pages (from-to)950-958
Number of pages9
JournalModern Pathology
Volume22
Issue number7
DOIs
StatePublished - Jul 1 2009

Fingerprint

Neuroblastoma
Schwann Cells
Neoplasms
Stromal Cells
Heterografts
Cancer-Associated Fibroblasts
Calmodulin-Binding Proteins
Pericytes
Myofibroblasts
Smooth Muscle
Actins
Fibroblasts
Cell Count
Molecular Weight
Staining and Labeling
Carcinoma

Keywords

  • Cancer-associated fibroblast
  • Neuroblastoma
  • Schwannian stroma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Zeine, R., Salwen, H. R., Peddinti, R., Tian, Y., Guerrero, L., Yang, Q., ... Cohn, S. L. (2009). Presence of cancer-associated fibroblasts inversely correlates with Schwannian stroma in neuroblastoma tumors. Modern Pathology, 22(7), 950-958. https://doi.org/10.1038/modpathol.2009.52

Presence of cancer-associated fibroblasts inversely correlates with Schwannian stroma in neuroblastoma tumors. / Zeine, Rana; Salwen, Helen R.; Peddinti, Radhika; Tian, Yufeng; Guerrero, Lisa; Yang, Qiwei; Chlenski, Alexandre; Cohn, Susan L.

In: Modern Pathology, Vol. 22, No. 7, 01.07.2009, p. 950-958.

Research output: Contribution to journalArticle

Zeine, R, Salwen, HR, Peddinti, R, Tian, Y, Guerrero, L, Yang, Q, Chlenski, A & Cohn, SL 2009, 'Presence of cancer-associated fibroblasts inversely correlates with Schwannian stroma in neuroblastoma tumors', Modern Pathology, vol. 22, no. 7, pp. 950-958. https://doi.org/10.1038/modpathol.2009.52
Zeine, Rana ; Salwen, Helen R. ; Peddinti, Radhika ; Tian, Yufeng ; Guerrero, Lisa ; Yang, Qiwei ; Chlenski, Alexandre ; Cohn, Susan L. / Presence of cancer-associated fibroblasts inversely correlates with Schwannian stroma in neuroblastoma tumors. In: Modern Pathology. 2009 ; Vol. 22, No. 7. pp. 950-958.
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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 α-smooth muscle actin (α-SMA) and were distinguished from pericytes by staining negatively for high-molecular-weight caldesmon. α-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 (P0.001). 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 (P0.001). In the xenografts with infiltrating Schwann cells (n10), the number of cancer-associated fibroblasts per mm 2 was approximately sevenfold less than in the control xenografts without stromal Schwann cells (n9) (mean of 5130 vs 368105, respectively; P0.001). 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.",
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