High‐mobility group box‐1 contributes tumor angiogenesis under interleukin‐8 mediation during gastric cancer progression

Many soluble factors are involved in tumor angiogenesis. Thus, it is valuable to identify novel soluble factors for effective control of tumor angiogenesis in gastric cancer ( GC ). We investigated the role of extracellular high‐mobility group box‐1 ( HMGB 1) and its associated soluble factors in the tumor angiogenesis of GC . Clinically, we measured serum levels of HMGB 1 and GC ‐associated cytokines/chemokines using GC serum samples ( n = 120), and calculated microvessel density ( MVD ) by CD 34 immunostaining using human GC tissues ( n = 27). Then we analyzed the correlation of serum HMGB 1 levels with MVD or that with cytokine/chemokine levels by linear regression. As in vitro angiogenesis assay for HMGB 1, HUVEC migration and capillary tube formation assay were carried out using different histological types of human GC cells (N87 and KATOIII ). CD 34‐positive microvessels were detected from early GC , but MVD increased according to GC stages, and were closely correlated with serum HMGB 1 levels ( R = 0.608, P = 0.01). The HUVEC s cultured in conditioned media derived from rh HMGB 1‐treated or HMGB 1‐ TF GC cells showed remarkably enhanced migration and tube formation activities. These effects were abrogated by anti‐ HMGB 1 antibody or HMGB 1 si RNA in both N87 and KATOIII cells (all P < 0.05). Among tested cytokines/chemokines, interleukin‐8 ( IL ‐8) was the most remarkable cytokine correlated with serum HMGB 1 ( P < 0.001), and enhanced HUVEC migration and tube formation activities by rh HMGB 1 or HMGB 1‐ TF were significantly reversed by IL ‐8 inhibition. These results indicate overexpressed HMGB 1 contributes to tumor angiogenesis through IL ‐8 mediation, and combined targeting of HMGB 1 and IL ‐8 can control tumor angiogenesis in GC .