Tumor Inflammatory Angiogenesis and Its Chemoprevention

Abstract

The importance of angiogenesis for the growth of tumors is widely recognized. Drugs that successfully target the endothelium, such as antivascular endothelial growth factor antibodies, are beginning to have an effect on the life expectancy of cancer patients. However, the endothelial cell is not the only possible target for antiangiogenic therapy or prevention of vascularization (angioprevention). It is evident from the literature that native immune cells recruited into tumors in turn stimulate the endothelium and are responsible for an indirect pathway of tumor vascularization. Inflammation-dependent angiogenesis seems to be a central force in tumor growth and expansion, a concept supported by the observation that the use of ''classic'' anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs, leads to angiogenesis inhibition. The mechanisms of inflammatory angiogenesis provide new approaches to target, cure, or even better, prevent tumor angiogenesis by treatment with synthetic or natural agents with anti-inflammatory properties. We propose chemoprevention of inflammatory angiogenesis as a way of checking the cancer before it progresses. (Cancer Res 2005; 65(23): 10637-41)

Thyroid cancer metabolism: A review

“…Collectively, these components make up the TME, which serves as a conduit for the cytokine signaling needed to meet the cancer cells' high metabolic requirements. Various signaling pathways, such as NF-kb, HIF-1α, and VEGF continue to be explored as therapeutic targets in the TME [30][31][32]. In HNSCC, for instance, tumorigenesis has been shown to be driven by signaling pathways such as EGFR, p53, p16, IGFR, cyclin D1, HPV-E6-E7, PI3K-AKT-mTOR, NFkB and HIF-1α [33].…”

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…In vivo studies, which show that neutralization of CXCR2 in various models of lung tumorigenesis leads to inhibition of tumor progression and angiogenesis, highlight the importance of the TME in this process [90,93,94]. Also, stimulation with CXCL5 and CXCL8 induces release of VEGF into the TME by neutrophils [84]. Recent studies have shown that CXCL8, a transcriptional target of Ras signaling, along with CXCR2, is upregulated in cancers harboring oncogenic KRas mutations, further supporting the role of proangiogenic signaling at all stages of tumorigenesis [94].…”

“…Angiogenesis facilitates growth and metastasis by supplying nutrients to the tumor through a vascular system that is typically incompletely constructed [13]. The recruitment of endothelial cells and other blood vessel components is promoted by a number of cytokines and secreted signals present in the TME, including the prototypical proangiogenic mediator VEGF [84]. While tumor cells may secrete VEGF minimally, it is secreted at high levels by activated CAFs and the inflammatory cells they recruit [13].…”

“…Other cells present in the inflammatory TME are capable of promoting angiogenesis as well. Inflammatory leukocytes release endothelial cell stimulating molecules, including VEGF, HGF and IL-8 [84]. Eosinophils are recruited to the TME by cytokines secreted by the tumor cells.…”

“…Because they express Flt-1 and Tie-2, the receptors for VEGF and angiopoietins respectively, they are also recruited by the pro-angiogenic stimuli secreted by tumor cells. Recruited eosinophils release VEGF stored in their granules and, under stimulation, produce additional VEGF [84].…”