Search

Colorectal cancer (CRC) is the third most common cancer worldwide, and its incidence is increasing. Inflammation associates with the pathogenesis of cancer by several mechanisms. Toll-like receptors (TLRs) mediate and regulate the inflammatory response and their role in cancer progression has been established in many cancers. This study aimed to clarify the roles of TLR2 and TLR4 and their significance in the development, progression, and prognosis of CRC in relation to inflammation in a series of 149 CRC patients operated in Oulu University Hospital (2006–2010). We characterized the tissue expression in CRC tumors and serum levels of TLR2 and TLR4, and the associations of expression patterns with tumor features and the prognosis of cancer. We found downregulation of TLR4 and upregulation of TLR2 in CRC, and low expression of TLR4 in the invasive front of the tumor predicted poor prognosis and metastatic disease. Serum TLR2 levels were inversely associated with systemic inflammation in patients with CRC, and our findings suggested that serum TLR2 levels might depend more on normal colorectal mucosa contributions than on tumor tissue. Also, the mean serum TLR4 levels were lower in patients than in controls. We also found that tumor necrosis in CRC associated with low TLR4 expression in carcinoma epithelium, and low TLR4 expression associated with systemic inflammation. Tumoral TLR2 expression did not correlate with necrosis from systemic inflammation, but low expression of TLR2 in normal mucosa was linked to indicators of systemic inflammation, supporting the concept that the normal colon mucosa may contribute to the regulation of systemic inflammation. In conclusion, TLR2 and TLR4 showed divergent roles in CRC. TLR2 was upregulated and TLR4 downregulated in CRC. Downregulation of TLR4 was related to tumoral necrosis and adverse prognosis. High normal mucosa TLR2 expression associated with high serum TLR2 concentration and signs of lower systemic inflammatio, Tiivistelmä Paksu- ja peräsuolisyöpä on maailmanlaajuisesti kolmanneksi yleisin syöpä ja sen ilmaantuvuus on kasvussa. Tulehdus vaikuttaa syövän syntyyn ja kehitykseen useilla mekanismeilla. Kohonnut elimistön tulehdusvaste liittyy huonoon ennusteeseen, mutta paikallinen tulehdus kasvaimen leviämisvyöhykkeessä on yhdistetty parempaan selviytymiseen. Tollin kaltaiset reseptorit (TLR) välittävät ja säätelevät tulehdusvastetta, ja niiden merkitys syövän etenemisessä on osoitettu monessa syövässä. Tämän tutkimuksen tarkoitus oli selvittää TLR2:n ja TLR4:n rooleja ja merkitystä tulehduksen kannalta paksu- ja peräsuolisyövän kehittymisessä, etenemisessä ja ennusteessa 149:n Oulun yliopistollisessa sairaalassa vuosina 2006–2010 leikatun potilaan aineistossa. Määritimme TLR2:n ja TLR4:n ilmentymistasot syöpäkasvaimissa ja niiden seerumitasot sekä näiden yhteyksiä kasvaimen ominaisuuksiin ja syövän ennusteeseen. TLR4:n ilmentyminen oli vähentynyt ja TLR2:n lisääntynyt kasvaimissa, ja matala TLR4:n ilmentyminen kasvaimen leviämisvyöhykkeessä liittyi huonompaan ennusteeseen ja etäpesäkkeiseen tautiin. TLR2:n seerumitasot korreloivat käänteisesti elimistön tulehdusvasteeseen syöpäpotilailla, ja löydöksemme viittaa siihen, että TLR2:n seerumipitoisuuteen myötävaikuttaa enemmän normaalin paksusuolen limakalvo kuin kasvainkudos. TLR4:n seerumitasot olivat matalammat potilailla verrattuna verrokkeihin. Myös kasvaimen kuolio liittyi matalaan TLR4:n ilmentymiseen kasvaimessa, mikä puolestaan oli yhteydessä elimistön tulehdukseen. Kasvaimen TLR2 ilmentyminen ei liittynyt kasvaimen kuolioon tai tulehdukseen, mutta matala TLR2:n ilmentyminen normaalilla limakalvolla liittyi elimistön tulehdusta kuvaaviin muuttujiin, mikä tukee ajatusta normaalin limakalvon vaikutuksesta elimistön tulehduksen säätelyssä. Yhteenvetona voidaan todeta, että TLR2:n ja TLR4:n roolit paksu- ja peräsuolisyövässä ovat erilaiset: TLR2:n ilmentyminen lisääntyy ja TLR4:n vähenee. TLR4:n ilmentymisen väheneminen lii

Toll‐like receptors (TLRs) are involved in colorectal cancer (CRC) pathogenesis. However, the significance of serum TLR concentrations in CRC is unknown. We analyzed serum TLR2 and TLR4 concentrations with ELISA in preoperative samples from 118 patients with CRC and 88 matched controls. We also assessed tissue TLR expression with immunohistochemistry and by detecting serum determinants of systemic inflammation. Most participants (>70%) had undetectable serum TLR2. The mean serum TLR4 levels were lower in patients than in controls (1.1 vs 1.8 ng/mL; p = 0.015). Undetectable TLR4 was more common in stage I (39%) than in stages II–IV (11%, p < 0.001). TLR2 or TLR4 expression in tumor cells did not correlate with serum levels, but abundant TLR2 expression in normal colon epithelium was associated with detectable serum TLR2 (p = 0.034). Undetectable serum TLR2 was linked to high modified Glasgow prognostic scores (p = 0.010), high CRP levels (p = 0.013), blood vessel invasion (p = 0.013), and tended to be associated with worse 5‐year survival (p = 0.052). In conclusion, serum TLR2 levels were inversely associated with systemic inflammation in patients with CRC. Moreover, serum TLR2 levels might depend more on normal colorectal mucosa contributions than on tumor tissue contributions. Further studies are required to assess the prognostic value of serum TLR2.

Aim: To characterize the expression of toll-like receptors (TLR) 2 and 4 in colorectal cancer (CRC) and in normal colorectal mucosa. Methods: We 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. Results: Normal 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. Conclusion: Tumour 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.