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

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. Cancer, 6, 2006
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