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Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: Role in non–small cell lung cancer tumor proliferation 

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Presentation on theme: "Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: Role in non–small cell lung cancer tumor proliferation "— Presentation transcript:

1 Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: Role in non–small cell lung cancer tumor proliferation  Ori Wald, MD, PhD, Uzi Izhar, MD, Gail Amir, MD, Sophie Kirshberg, BSc, Zippora Shlomai, MSc, Gideon Zamir, MD, Amnon Peled, PhD, Oz M. Shapira, MD  The Journal of Thoracic and Cardiovascular Surgery  Volume 141, Issue 6, Pages (June 2011) DOI: /j.jtcvs Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

2 Figure 1 A, Expressions of CXCL12 and CXCR4 in non–small cell lung cancer tissue samples and plasma polymerase chain reaction assays for CXCL12, CXCR4, and β-actin in 3 non–small cell lung cancer tumors. B, Enzyme-linked immunosorbent assay for CXCL12 concentration in fresh tumor tissue and in the serum of patients operated on for non–small cell lung cancer; 4 cases are shown. C through H, Immunohistochemical staining for CXCL12. C, Tumor-adjacent normal lung tissue. D, CXCL12-positive fibroblasts surrounding CXCL12-negative adenocarcinoma cells. E, CXCL12-positive fibroblasts and vascular structures surrounding CXCL12-negative adenocarcinoma cells. F, Both adenocarcinoma cells and tumor stroma staining positively for CXCL12. G, CXCL12-positive fibroblasts and vascular structures surrounding CXCL12-negative squamous carcinoma cells. H, CXCL12-positive squamous cell carcinoma. I, CXCR4-positive adenocarcinoma. The Journal of Thoracic and Cardiovascular Surgery  , DOI: ( /j.jtcvs ) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

3 Figure 2 Production of non–small cell lung cancer–derived neoplastic and carcinoma-associated fibroblast cell lines. Hematoxylin and eosin staining of cancer epithelial cells (A) and cancer-derived fibroblasts (B). Cancer epithelial cells stained positively for cytokeratin (C) and negatively for fibronectin (E). Carcinoma-associated fibroblasts were cytokeratin negative (D) and fibronectin positive (F). The Journal of Thoracic and Cardiovascular Surgery  , DOI: ( /j.jtcvs ) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

4 Figure 3 Characterization of non–small cell lung cancer–derived neoplastic cell lines. A, Polymerase chain reaction results for CXCL12, CXCR4, and β-actin in the cancer epithelial cell lines L3, L4, and A549. B, ELISA assay for CXCL12 secretion to the medium at 24, 48, and 72 hours after plating of L3, L4, and A549 cells. C, Flow cytometric analysis of CXCR4 expressions by L3, L4, and A549. Representative forward and side scatter dot plot and cell gating of L3 is shown at right. Histogram of control antibody and overlay with anti CXCR4 antibody for L3, L4, and A549 are shown at left. Representative hematoxylin and eosin (D and E) and cytokeratin (F) staining of L4-derived tumors forming in the lungs of NOD-SCID mice after injection of the cells into the tail vein. SSC, Side scatter; FSC, forward scatter; PE, phycoerythrin. The Journal of Thoracic and Cardiovascular Surgery  , DOI: ( /j.jtcvs ) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

5 Figure 4 Characterization of non–small cell lung cancer–derived carcinoma-associated fibroblast cell lines. A, Polymerase chain reaction results for CXCL8, CXCL12, CCL2, and β-actin in 2 carcinoma-associated cell lines, F1 and F2. B, Enzyme-linked immunosorbent assay results for CXCL12 secretion to the medium at 24, 48, and 72 hours after plating of F1 and F2 cells. C, Immunohistochemical staining for CXCR4; black arrows point to CXCR4-positive fibroblast. D, Flow cytometric analysis of CXCR4 expression by carcinoma-associated fibroblast cell lines F1, F2, and F3. Histogram of control antibody and overlay with anti-CXCR4 antibody for F1, F2, and F3 are shown. PE, Phycoerythrin. The Journal of Thoracic and Cardiovascular Surgery  , DOI: ( /j.jtcvs ) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

6 Figure 5 CXCL12-induced non–small cell lung cancer proliferation, extracellular signal–regulated kinase phosphorylation, and CCL20 production. A to C, Colony formation by L3, L4, and A549 cells in response to increasing concentration of CXCL12. D to F, Colony formation by L3, L4, and A549 cells in response to increasing concentration of CXCL12 with and without the addition of the CXCR4 antagonist AMD3100. G to I, Western blot analysis for phosphorylated extracellular signal–regulated kinase (Perk, upper panel) and extracellular signal–regulated kinase (erk, lower panel) after stimulation of L3, L4, and A549 cells with CXCL12. J to L, Enzyme-linked immunosorbent assay results for CCL20 secretion after stimulation with increasing concentrations of CXCL12 for L3, L4, and A549 cell lines. M, Enzyme-linked immunosorbent assay results for CCL20 secretion after CXCL12 stimulation with and with out the addition of anti-CXCR4 antibodies or pertussis toxin for L4 cell line. Asterisk indicates P < .05; double asterisk indicates P < .01. The Journal of Thoracic and Cardiovascular Surgery  , DOI: ( /j.jtcvs ) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

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