BACKGROUND & AIMS: Toll-like receptor (TLR)-dependent signaling was proposed as immunotherapeutic targets against invading pathogens and tumorigenesis. Here, we investigated whether TLR5-dependent signaling modulates colonic tumor development in mouse xenograft model of human colon cancer. METHODS: The expression of myeloid differentiation factor 88 (MyD88) or TLR5 was stably knocked down in human colon cancer cells (DLD-1). Nude mice were subcutaneously implanted with MyD88-knocked down (KD), TLR5-KD, or control cells (n = 16) to examine the pathophysiology of tumor xenografts. Protein microarray assessed the differential expression of cytokines in these tumors. Leukocyte infiltration and tumor angiogenesis were assessed by immunohistochemistry with antibodies against neutrophil (Gr-1, 7/4) or macrophage-specific antigens (CD68, F4-80) and the vascular endothelial cell marker CD31, respectively. Tumor xenografts from DLD-1 cells were treated with flagellin (5.0 microg/kg, 1 injection/every 2 days for 3 weeks), and tumor regression and histopathology were examined. RESULTS: Lack of MyD88 or TLR5 expression dramatically enhanced tumor growth and inhibited tumor necrosis in mouse xenografts of human colon cancer. In contrast, TLR5 activation by peritumoral flagellin treatment substantially increased tumor necrosis, leading to significant tumor regression. Tumors from MyD88-KD or TLR5-KD cells revealed the reduced production of neutrophil attracting chemokines (epithelial cell-derived neutrophil-activating peptide-78, macrophage-inflammatory protein alpha, and interleukin-8). Consequently, neutrophil infiltration was dramatically diminished in MyD88- or TLR5-KD xenografts, whereas tumor-associated macrophage infiltration or angiogenesis was not changed. CONCLUSIONS: TLR5 engagement by flagellin mediates innate immunity and elicits potent antitumor activity, indicating that TLR5-dependent signaling could be a potential immunotherapeutic target to modulate colonic tumors.
BACKGROUND & AIMS: Toll-like receptor (TLR)-dependent signaling was proposed as immunotherapeutic targets against invading pathogens and tumorigenesis. Here, we investigated whether TLR5-dependent signaling modulates colonic tumor development in mouse xenograft model of humancolon cancer. METHODS: The expression of myeloid differentiation factor 88 (MyD88) or TLR5 was stably knocked down in humancolon cancer cells (DLD-1). Nude mice were subcutaneously implanted with MyD88-knocked down (KD), TLR5-KD, or control cells (n = 16) to examine the pathophysiology of tumor xenografts. Protein microarray assessed the differential expression of cytokines in these tumors. Leukocyte infiltration and tumor angiogenesis were assessed by immunohistochemistry with antibodies against neutrophil (Gr-1, 7/4) or macrophage-specific antigens (CD68, F4-80) and the vascular endothelial cell marker CD31, respectively. Tumor xenografts from DLD-1 cells were treated with flagellin (5.0 microg/kg, 1 injection/every 2 days for 3 weeks), and tumor regression and histopathology were examined. RESULTS: Lack of MyD88 or TLR5 expression dramatically enhanced tumor growth and inhibited tumor necrosis in mouse xenografts of humancolon cancer. In contrast, TLR5 activation by peritumoral flagellin treatment substantially increased tumor necrosis, leading to significant tumor regression. Tumors from MyD88-KD or TLR5-KD cells revealed the reduced production of neutrophil attracting chemokines (epithelial cell-derived neutrophil-activating peptide-78, macrophage-inflammatory protein alpha, and interleukin-8). Consequently, neutrophil infiltration was dramatically diminished in MyD88- or TLR5-KD xenografts, whereas tumor-associated macrophage infiltration or angiogenesis was not changed. CONCLUSIONS:TLR5 engagement by flagellin mediates innate immunity and elicits potent antitumor activity, indicating that TLR5-dependent signaling could be a potential immunotherapeutic target to modulate colonic tumors.
Authors: Sang Hoon Rhee; Bryan W Jones; Vladimir Toshchakov; Stefanie N Vogel; Matthew J Fenton Journal: J Biol Chem Date: 2003-04-09 Impact factor: 5.157
Authors: T Yamada; A S Takaoka; Y Naishiro; R Hayashi; K Maruyama; C Maesawa; A Ochiai; S Hirohashi Journal: Cancer Res Date: 2000-09-01 Impact factor: 12.701
Authors: Lyudmila G Burdelya; Anatoli S Gleiberman; Ilia Toshkov; Semra Aygun-Sunar; Meghana Bapardekar; Patricia Manderscheid-Kern; David Bellnier; Vadim I Krivokrysenko; Elena Feinstein; Andrei V Gudkov Journal: Int J Radiat Oncol Biol Phys Date: 2011-10-14 Impact factor: 7.038
Authors: Elise L Ma; Yoon Jeong Choi; Jinyoung Choi; Charalabos Pothoulakis; Sang Hoon Rhee; Eunok Im Journal: Int J Cancer Date: 2010-08-15 Impact factor: 7.396