Background: Cancer-Associated Fibroblasts (CAFs) are stromal activated fibroblasts known to promote tumor growth, angiogenesis and invasion in certain carcinomas.Microvascular proliferation (MVP) is a hallmark of angiogenesis in aggressive cancers.We examined the presence of MVP in relation to clinical risk factors, and quantified CAF infiltration, across the spectrum of human neuroblastoma (NB) tumors, and in xenografts before and after enrichment for Schwann cells or anti-angiogenic treatment.Methods: Human NB tumors were classified into six diagnostic categories according to the WHO and International Neuroblastoma Pathologic Classification criteria for Schwannian stroma (SS)-poor,-rich or-dominant tumors.NB (SMS-KCNR) cells were inoculated either inside or outside the sciatic nerve of nude mice to generate xenografts with infiltrating Schwann cells.Valproic acid was used as antiangiogenic agent.MVP was assessed on H&E stain.CAFs were characterized by positive immunostaining for alpha-Smooth Muscle Actin (alpha-SMA) and were distinguished from pericytes by staining negatively for high-MW Caldesmon.CAF infiltration was assessed by percent alpha-SMA positive areas either by semiquantitative microscopy or by automated cellular image analysis (ACIS Ⅱ).Associations between MVP, survival, risk groups, tumor stage,histology and CAFs were assessed by Kaplan-Meier curves, regression analysis, Chi-square and Students t-tests.Results: We demonstrated significant associations between MVP and SS-poor histology, decreased survival and high risk cases.The level of CAFs was strongly associated with SS-poor histology and with MVP.Anti-angiogenic treatment abrogated MVP.In xenografts with infiltrating Schwann cells, the number of CAF/mm2 was ~7-fold less than in the controls.Conclusion: Our results suggest that CAFs play a role in promoting angiogenesis and aggressive behavior of Neuroblastoma tumors, and that Schwannian stroma may inhibit CAF infiltration or activation.This may guide development of anti-stromal therapeutics, and may impact risk group classification and patient stratification for future clinical trials in Neuroblastoma.