Divergent expression of bacterial wall sensing Toll-like receptors 2 and 4 in colorectal cancer

Abstract

AIMTo characterize the expression of toll-like receptors (TLR) 2 and 4 in colorectal cancer (CRC) and in normal colorectal mucosa.METHODSWe analysed tissue samples from a prospective series of 118 unselected surgically treated patients with CRC. Sections from formalin fixed, paraffin embedded specimens were analysed for TLR2 and TLR4 expression by immunohistochemistry. Two independent assessors evaluated separately expression at the normal mucosa, at the invasive front and the bulk of the carcinoma, and in the lymph node metastases when present. Expression levels in different locations were compared and their associations with clinicopathological features including TNM-stage and the grade of the tumour and 5-year follow-up observations were analysed.RESULTSNormal colorectal epithelium showed a gradient of expression of both TLR2 and TLR4 with low levels in the crypt bases and high levels in the surface. In CRC, expression of both TLRs was present in all cases and in the major proportion of tumour cells. Compared to normal epithelium, TLR4 expression was significantly weaker but TLR2 expression stronger in carcinoma cells. Weak TLR4 expression in the invasive front was associated with distant metastases and worse cancer-specific survival at 5 years. In tumours of the proximal colon the cancer-specific survival at 5 years was 36.9% better with strong TLR4 expression as compared with those with weak expression (P = 0.044). In contrast, TLR2 expression levels were not associated with prognosis. Tumour cells in the lymph node metastases showed higher TLR4 expression and lower TLR2 expression than cells in primary tumours.CONCLUSIONTumour cells in CRC show downregulation of TLR4 and upregulation of TLR2. Low expression of TLR4 in the invasive front predicts poor prognosis and metastatic disease.

Serum TLR2 and TLR4 levels in colorectal cancer and their association with systemic inflammatory markers, tumor characteristics, and disease outcome

“…As described in a previous study, in carcinoma cells, TLR2 expression was increased and TLR4 expression was reduced compared to levels in normal colorectal epithelium . In the present study, we found that serum levels of TLR2 and TLR4 were not correlated with the levels of TLR2 and TLR4 expression in carcinomas or their nodal metastases (based on staining intensity, histoscores, and tumor mass‐weighted histoscores; data not shown).…”

“…In contrast, there could be important physiological differences between TLR2 and TLR4. In normal mucosa, TLR2 staining was weaker than TLR4 staining, as shown in our previous study . This difference in physiological tissue expression levels of these receptors, taken together with the correlation between serum TLR2 levels and normal colorectal mucosa TLR2 expression, suggested a potential mechanistic link that might explain why serum TLR2 concentrations were undetectable or low more often than serum TLR4 concentrations.…”

“…We collected data prospectively from 149 patients newly diagnosed with CRC who underwent surgery in Oulu University Hospital between April 2006 and January 2010. Prior to entering the study, all patients provided signed informed consent to participate . Control serum samples were collected from age‐ and sex‐matched healthy individuals who had voluntarily donated blood (Finnish Red Cross, Oulu, Finland; n = 36, age < 65 years) and from patients who underwent cataract surgery (Oulu University Hospital; n = 52, age ≥ 65 years).…”

“…Immunohistochemistry of TLR2 and TLR4 was conducted and analyzed as previously described . We analyzed cancer specimens with tissue microarrays, and we analyzed whole sections of normal mucosa and lymph node metastasis samples mounted on slides . Two independent researchers (KP and SAV) analyzed TLR2 and TLR4 expression in a blinded manner.…”

“…In a previous study, we characterized TLR2 and TLR4 tissue expression in CRC and found downregulation of TLR4 and upregulation of TLR2 in tumor tissues compared to normal mucosa. In addition, low TLR4 expression at the invasive front in the proximal colon was associated with a poor prognosis and the presence of distant metastases .…”