Expression of CXCR-4 and IDO in human colorectal cancer: An immunohistochemical approach

Abstract

Abstract. C-X-C chemokine receptor type 4 (CXCR4), the receptor for the chemokine stromal cell-derived factor (SDF)-1 [also known as C-X-C motif chemokine 12 (CXCL12)], is involved in lymphocyte trafficking. Recent studies have demonstrated that, during pregnancy, a placental enzyme called indoleamine 2, 3-dioxygenase (IDO) exerts a key role in suppressing the maternal T-cell response against the fetus. In the present study, the significance of CXCR4 and IDO expression in human colorectal cancer (CRC) has been investigated by immunohistochemical assay, and their association with survival was analyzed. Tumor specimens (n=60) from patients with different American Joint Committee on Cancer (AJCC) stages of CRC (I or IV) were assessed. In the stage IV group, 23 of 30 cases (77%) stained positive for CXCR4, and 9 of 30 (30%) were positive for IDO. By contrast, in the stage I group, 7 of 30 cases (23%) stained positive for CXCR4, and 15 of 30 cases (50%) were positive for IDO. The 5-year survival rate of those with high CXCR4 expression in tumor specimens (n=30) was significantly worse compared with those with negative CXCR4 expression (16.3 vs. 60.7%, P=0.02). By contrast, the 5-year survival rate of those with high IDO expression in tumor specimens (n=24) was not significantly different compared with those with negative IDO expression (36.4 vs. 56.8%). In the stage I group, 4 patients in the high IDO expression group (n=15) had distant metastases (2 in the liver 1 in the brain, and 1 in the lung). Taken together, CXCR4 appears to be a novel predictive indicator of survival, and IDO expression in the early stage may be a predictor of distant metastasis.

IDO Expression in Cancer: Different Compartment, Different Functionality?

“…Furthermore, tumoral IDO expression has been proposed to stimulate the metastasic process. An association between strong IDO expression at the primary tumor and development of lymph node and/or metachronous metastases is described in various malignancies ( 36 – 42 ). Studies detecting IDO in the primary tumor and the corresponding lymph node and metastatic tissue reported a highly consistent expression pattern of IDO throughout the disease course ( 44 , 87 ).…”

Peritumoral endothelial indoleamine 2, 3-dioxygenase expression is an early independent marker of disease relapse in colorectal cancer and is influenced by DNA mismatch repair profile

“…A negative impact on survival was also observed with IDO expression in tumor draining lymph nodes (TDLNs) [ 12 ]. Moreover, strong IDO expression at the primary seemed to be associated with development of metachronous metastases [ 13 – 15 ]. Paradoxically, tumoral IDO expression was recently reported to be a positive prognostic marker on disease-free survival in microsatellite instable (MSI-H) CRCs [ 16 ].…”

Design, synthesis and bioevaluation of novel 6-substituted aminoindazole derivatives as anticancer agents

“…In summary, four series of 6-substituted aminoindazoles were designed based on an anticancer privileged structure, indazole, targeting to inhibit the IDO1 activity, and the designed compounds were synthesized through 3 steps. Of them, the acetyl, pyridinylmethyl, and uorobenzyl substituted compounds (22,(35)(36)(37) showed potential cytotoxicity towards colorectal cancer cells HCT116. A study on the IDO1 activity indicated that compound 36 had a moderate inhibition activity of IDO1 towards the HCT116 cell line.…”

“…In order to examine the effects on IDO1 expression, which can be well correlated to human colon cancer cell growth, 37,38 we selected the compounds with the most anti-proliferative potency against HCT116 for the analysis of the IDO1suppressive activity (Fig. 2).…”