Abstract
Colorectal cancer (CRC) was the first solid tumor to be successfully targeted with anti‐angiogenic therapy in the clinic. Tumor angiogenesis is critical for cancer progression in that it permits expansion of the tumor mass and fosters malignant dissemination. Angiogenesis is a multistep process involving endothelial cells as well as numerous stromal components within the tumor microenvironment that also represent potential therapeutic targets. Inflammation dependent‐angiogenesis is increasingly recognised as a central force in tumor growth and progression, while use of anti‐inflammatory drugs has been found to reduce incidence of CRC carcinoma potentially through repression of tumor angiogenesis. We investigated the link between inflammatory angiogenesis and colorectal cancer in archival tissues across a range of pathologies that represent diverse steps in the progression of CRC: 16 cases of ulcerative colitis (URC), 16 adenocarcinomas developed from pre‐existing tubular or tubulo‐villous adenomas, 33 tubular or tubulo‐villous adenomas with low grade dysplasia, and 33 infiltrating adenocarcinomas. Immunohistochemical analysis was performed with antibodies targeting markers of endothelial cells (CD31), macrophages (CD‐68), neutrophils (CD15), growth factors (HGF), cytokines (IL‐6) and up‐stream receptors (TLR4). Epithelial, interstitial and endothelial/vascular compartments were chosen for analysis. Staining for (HGF) showed a rapid drop from healthy to pathological conditions, but did not show changes in staining intensity with the different stages of CRC progression. In contrast, the markers for vascularization (CD31) inflammatory cells (CD68, CD15) and inflammation (IL‐6 and TLR4) increased in staining intensity as a function of tumor progression as determined by histopathology. IL‐6 and TLR4 staining appear to correlate with event‐free survival. These data suggest that inflammation increases along with tumor progression, and staining for CD68, CD15, IL‐6, and CD31 appear to act as early tumor markers that increase with tumor progression, from precursor entities to invasive CRC. Increased TLR‐4 and IL‐6 was also found in tumor tissues derived from animals lacking Tir‐8, an interleukin‐1/Toll‐like receptor family member highly expressed in the intestinal mucosa, in the azoxymethane and dextran sulfate sodium salt (DSS) model of CRC, confirming that these markers of inflammatory events are associated with colorectal tumor progression.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A33.
