CANCER-ASSOCIATED FIBROBLASTS COLOCALIZE with MICROVASCULAR PROLIFERATION and
                           THEIR LEVELS INVE...
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Zeine et al. Poster 2009 Tumor Stromal Interactions in Neuroblastoma Cancers

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Tumor-Promoting Fibrovascular Stroma vs. Tumor Inhibitory Schwannian Stroma in Neuroblastoma Tumors

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Zeine et al. Poster 2009 Tumor Stromal Interactions in Neuroblastoma Cancers

  1. 1. CANCER-ASSOCIATED FIBROBLASTS COLOCALIZE with MICROVASCULAR PROLIFERATION and THEIR LEVELS INVERSELY CORRELATE with SCHWANNIAN STROMA in NEUROBLASTOMA Zeine, R., Salwen, HR., Peddinti, R., Tian, Y., Guerrero, L., Yang, Q., Chlens A. and Cohn, SL. ki, Northwestern Univers and University of Chicago, Chicago, IL, United States ity USCAP March 2009 Boston Abstract Materials and Methods Results Summary Abstract Background Objectives Background: Cancer-Associated Fibroblasts (CAFs) promote Number of SS-RICH, No MVP SS-POOR tumor growth, angiogenesis and invasion in certain carcinomas. Clinical Parameter Patients CAFs Associate with MVP Reduced CAFs Engrafted INSIDE Sc. N. hCD We have previously demonstrated inverse correlations between microvascular proliferation (MVP), a hallmark of angiogenesis in AGE at diagnosis 34>1yr, 19<1yr in Human NB Tumors in NB Xenografts PERCENT αSMA+ve Area (mean ±SD) aggressive tumors, and Schwannian Stroma (SS) in DIAGNOSIS GN, GNB, NB 7, 11, 42 5.0 Engrafted Inside Sciatic Nerve αSMA +ve CELLS /mm2 (mean ±SD) neuroblastoma (NB). To investigate the relationship of CAFs to MVP and to SS in NB, we quantified CAF levels in 60 primary STAGE (1+2+3), 4 34, 15 4.5 * 500 MYCN Amplified, Single, u 9, 40, 4 human NB tumors, and in NB xenografts with infiltrating murine 4.0 Schwann cells and reduced vascular density. PROGNOSTIC CATEGORY p<0.001 450 Favorable, Unfavorable, u 28, 23, 2 3.5 400 Design: 46 SS-poor and 14 SS-rich/dominant human NB tumors Pericytes Pericytes RISK GROUP High, Low 15, 25 Pericytes were evaluated. Vascular morphology was examined for 3.0 350 αSMA αSMA presence or absence of MVP. NB (SMS-KCNR) cells were 2.5 300 CAFs CAFs & Pericytes inoculated either inside or outside the sciatic nerve of nude mice, CAFs with vascular density and Schwann cell infiltration levels 2.0 250 previously reported. Quantitative (ACIS II) and semiquantitative scoring were utilized to assess CAF levels as reflected by 1.5 200 p<0.001 percent of αSMA+ve tumor areas. Positive immunostaining for 150 hMW-Caldesmon distinguished pericytes from CAFs. 1.0 Result: In the human NB series, the level of CAFs reflected by 0.5 100 * percent αSMA+ve area were strongly associated with SS-poor 50 0.0 histology (p<0.001) and colocalized with MVP (p<0.001). 0 αSMA In the NB xenografts with infiltrating stromal Schwann cells NB NB GNBI GN Control Engrafted CONTROL Xenograft SS-POOR with MVP SS-POOR (n=10), CAF accumulation was 7-fold less than in controls (n=9) & n=9 Inside Sc. N. with mean αSMA+ve cells/mm2 of 51±30 vs. 368±105, Quantification of αSMA immunostaining GNBN respectively; p<0.001. by Automated Cellular Image Analysis(II) with MVP No MVP n=10 Conclusions (Clarient - Chromavision) (Stained/Total Area) Conclusion: Our findings suggest that CAFs promote Cancer-Associated Fibroblasts (CAFs) Colocalize with Microvascular angiogenesis in NB and that Schwann cells may prevent CAF Cancer-Associated Fibroblast Levels Proliferation which is a Poor Prognostic Indicator in NB Tumors. infiltration. Novel anti-CAF therapeutic strategies may benefit children with aggressive NB. Tumors with Tumors with Tumors with PERCENT CAFs are Precluded from Schwannian Stroma-Rich Regions in NB. Modern Pathology, Zeine et al. 2009 Number ≤1.1% Area 1.1-3.0% Area ≥3.0% Area αSMA+ve t-test of DIAGNOSIS It is Possible to Reduce CAF Accumulation by Increasing the αSMA +ve αSMA +ve αSMA +ve Areas Background TUMORS LOW MEDIUM HIGH Mean ±SD Schwannian Component within the Tumor Microenvironment. We have shown that microvascular 5 Neuroblastoma Undifferentiated 1 (20%) 2 (40%) 2 (40%) 3.40% ±2.19 Our Results are Consistent with Tumor-Inhibitory Roles for Schwannian-Derived Factors, and Tumor-Promoting Roles for CAFs. proliferation (MVP) is present in Schwannian 14 Neuroblastoma Poorly Differentiated 2 (14%) 8 (57%) 4 (29%) 2.41% ±1.64 Stroma (SS)-Poor but not in SS-Rich regions 23 Neuroblastoma Differentiating 6 (26%) 9 (39%) 8 (35%) 2.39% ±1.78 Histopathologic Evaluation of NB Tumors for MVP and CAFs May of human NB tumors, and is associated with 4 Ganglioneuroblastoma Nodular 0 (0%) 4 (100%) 0 (0%) 2.48% ±0.34 Help Refine Risk Group Classification and Guide Development poor prognosis (1). Vascularity was reduced of Novel Anti-Angiogenic and Anti-Stromal Treatment Strategies 7 Ganglioneuroblastoma Intermixed 5 (71%) 2 (29%) 0 (0%) 0.96% ±0.31 for Children with Aggressive Neuroblastoma. in NB xenografts Infiltrated by Schwann cells 7 Ganglioneuroma 7 (100%) 0 (0%) 0 (0%) 0.79% ±0.19 (2). Cancer Associated Fibroblasts (CAF) are αSMA+ve/ hCD–ve stromal cells that promote 46 14 Schwannian Stroma-POOR Schwannian Stroma-RICH 9 (20%) 12 (86%) 23 (50%) 2 (14%) 14 (30%) 0 (0%) 2.48% ±1.70 0.88% ±0.30 p˂0.001 References tumor angiogenesis and invasion (3). Here Fibrovascular 1. Peddinti, Zeine et al., Clin. Cancer Res., 13 (12), 2007 Stroma with MVP 37 WITH Microvascular Proliferation 6 (16%) 18 (49%) 13 (35%) 2.70% ±1.70 p˂0.001 we examine NB tumors for the relationship 2. Liu et al., Am. J. Pathol., 166 (3), 2005 in SS-Poor NB 22 NO Microvascular Proliferation 15 (68%) 7 (32%) 0 (0%) 1.13% ±0.60 between SS, MVP and CAFs. 3. Kalluri and Zeisberg, Nat. Rev. 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