Toll-like receptor (TLR) 7 and TLR8 expression on CD133+ cells in colorectal cancer points to a specific role for inflammation-induced TLRs in tumourigenesis and tumour progression.
Toll-like receptor (TLR) stimulation results in activation of NF-κB, a key modulator in driving inflammation to cancer and mitogen-activated protein kinases that have been shown to recruit mitotic and cyclooxygenase-2 (COX-2) induced pathways in carcinogenesis. Here we asked whether different TLR, COX-2 and stem cell marker expression profiles in colorectal cancer (CRC) provide further evidence for this hypothesis from a clinical perspective. We analysed gene and protein expression of TLR7-TLR10, COX-2 and CD133 as a marker for colon-initiating cells in CRC patients (n=65). Gene analysis demonstrated significantly upregulated TLR7-TLR10 and COX-2 expression in CRC tumour tissues. Analysis of isolated tumour cells from primary tumours showed co-expression of TLR7 and TLR8 with CD133 and gave evidence for a subpopulation of colon cancer-initiating cells. In multivariate analyses TLR8 expression was found to be an independent prognostic factor. Persistent TLR-specific activation of NF-κB in CRC and particularly in tumour-initiating cells may thus sustain further tumour growth and progression through perpetuated signalling known from inflammatory and tissue repair mechanisms with consecutive self-renewal in pluripotent tumour cells. Activation through self-ligands or viral RNA fragments may putatively maintain this inflammatory process, suggesting a key role in cancer progression.
Grimm
Martin
M
Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany.
Kim
Mia
M
Rosenwald
Andreas
A
Heemann
Uwe
U
Germer
Christoph-Thomas
CT
Waaga-Gasser
Ana Maria
AM
Gasser
Martin
M
D000071916:AC133 Antigen; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000378:metabolism; D011379:Prognosis; D051201:Toll-Like Receptor 10 / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D051201:Toll-Like Receptor 10; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051546:Cyclooxygenase 2