Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1

Abstract

The endothelium plays a pivotal role in the progression of solid tumors and is considered a highly relevant target for therapy. However, it emerges that current clinical angiogenesis inhibitors that act through inhibition of tumor-derived growth factors are prone to inducing drug resistance. Therefore, markers of tumor endothelial cells (ECs) themselves provide attractive novel therapeutic targets. In a screen for markers of tumor angiogenesis, we recently identified high-mobility group box 1 (HMGB1), known to act as proinflammatory cytokine and chromatin-binding molecule. Here we report on the role of HMGB1 in angiogenesis by showing that its overexpression is associated with an increased angiogenic potential of ECs. HMGB1 stimulates the expression of players in vascular endothelial growth factor and platelet-derived growth factor signaling, both in vitro and in vivo. Importantly, we show that HMGB1 triggers and helps to sustain this proangiogenic gene expression program in ECs, additionally characterized by increased activity of matrix metalloproteinases, integrins and nuclear factor-κB. Moreover, we found that HMGB1 is involved in several autocrine and/or paracrine feedback mechanisms resulting in positive enforcement of HMGB1 expression, and that of its receptors, RAGE (receptor for advanced glycation end products) and Toll-like receptor 4 (TLR4). Interference in HMGB1 expression and/or function using knockdown approaches and antibody-mediated targeting to break this vicious circle resulted in inhibited migration and sprouting of ECs. Using different in vivo models, therapeutic efficacy of HMGB1 targeting was confirmed. First, we demonstrated induction of HMGB1 expression in the chicken embryo chorioallantoic membrane (CAM) neovasculature following both photodynamic therapy and tumor challenge. We subsequently showed that anti-HMGB1 antibodies inhibited vessel density in both models, accompanied by a reduced vascular expression of angiogenic growth factor receptors. Collectively, these data identify HMGB1 as an important modulator of tumor angiogenesis and suggest the feasibility of targeting HMGB1 for multi-level cancer treatment.

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction

“…With regards to angiogenesis, HMGB1 promotes tissue angiogenesis by increasing the production of proangiogenic cytokines including VEGF, TNF-α, and IL-8 from endothelial cells and macrophages. 34,35) DPP4, a type of peptidase and one of the therapeutic targets for DM, reportedly degrades and inactivates not only incretin hormones but also other substances, including SDF-1, BNP, and substance P. 19) Because HMGB1 has a component of partial DPP4 cleavage sites, 20) it can also be degraded and inactivated by DPP4 in vivo. Straino, et al reported that HMGB1 levels of mice skin tissue were decreased in the diabetic state, and HMGB1 application to skin wounds promoted the tissue angiogenesis and wound healing.…”

Extracellular HMGB1 promotes differentiation of nurse-like cells in chronic lymphocytic leukemia

“…[10][11][12][13][14] HMGB1 regulates transcription factors but also behaves as a proinflammatory cytokine mediating inflammation. 13,[15][16][17][18] Nonprotein DAMPs, including DNA, RNA, and ATP, are also released by damaged or dying cells. 6,7,19 DAMPs are associated with acute inflammatory responses, chronic inflammation, and wound healing, but are also important components of the disordered tumor microenvironment.…”

Human Mesenchymal Stem Cells Migrate toward Colon Cancer Partially Regulated by HMGB1

“…HMGB1 was reported to have a potential role in the regulation of cancer autophagy and apoptosis as response to the administration of anti-cancer agent [42] as well as to regulate migration and sprouting of endothelial cells as angiogenesis in tumor progression [35]. Moreover, the blockade of its receptor resulted in suppression of tumor growth and metastasis [66].…”

“…Previous studies suggested that HMGB1 is one of the key modulators of tumor development and its receptor, the receptor for advanced glycation end products (RAGE) [55] or Toll Like Receptor4 (TLR4) [35], is expressed on variety of cancer cells [66][67][68][69] including colon cancer [69]. HMGB1 was reported to have a potential role in the regulation of cancer autophagy and apoptosis as response to the administration of anti-cancer agent [42] as well as to regulate migration and sprouting of endothelial cells as angiogenesis in tumor progression [35].…”

“…HMGB1 is involved in several autocrine and/or paracrine feedback mechanisms resulting in positive enforcement of its expression, and that of its receptor, TLR4, has been reported to express on MSCs [34]. Since HMGB1 stimulates the expression of molecules correlated to vascular endothelial growth factor and platelet-derived growth factor signaling by inducing their secretion from tumor cells, HMGB1 has been identified as an important modulator of tumor angiogenesis [35].…”