Mikihiko Kogo

Investigation of CXCR4 in squamous cell carcinoma of the tongue

Cancer metastasis is not a random process and different cancer types have favorite metastatic sites. Recent studies on metastasis have focused on chemoattraction, particularly on the role of chemokines. Therefore, in this study we investigated whether CXCR4 (receptor for stromal cell-derived factor-1) is expressed in squamous cell carcinoma of the tongue. For this purpose, immunohistochemical staining was performed on 26 sections obtained from 23 patients (15 patients having tongue tumor without lymph node metastasis and eight patients having lymph node metastasis). All tumor cells expressed CXCR4, whereas normal mucosa of the tongue had no or faint expression CXCR4. Metastatic tumor cells in lymph nodes had stronger expression than primary tongue tumor cells. Our data raises the possibility that CXCR4 could be involved in lymph node metastasis of oral squamous cell carcinoma.

Tumor Thickness and Paralingual Distance of Coronal MR Imaging Predicts Cervical Node Metastases in Oral Tongue Carcinoma

BACKGROUND AND PURPOSE: The presence of cervical lymph node metastases is an important prognostic factor for oral tongue cancer. The accurate preoperative assessment is essential for treatment. Several studies have suggested that histologic tumor thickness is related to the metastases. The aim of this study was to determine whether MR images of oral tongue tumor have the potential to predict cervical lymph node metastases. MATERIALS AND METHODS: A total of 43 patients with squamous cell carcinoma of the oral tongue were investigated. Tumor thickness, sublingual distance between tumor and sublingual space, and paralingual distance between tumor and paralingual space, as determined from coronal MR imaging, were preoperatively estimated. Logistic regression analysis was used to identify independent predictors of lymph node metastases. RESULTS: Univariate logistic regression analysis showed that T classification, N classification, and 3 measured MR imaging distances (millimeters) were significantly associated with lymph node metastases. Multivariate logistic regression analysis showed that tumor thickness (odds ratio, 1.34; 95% confidence interval [CI], 1.11–1.63; P < .005) and paralingual distance (odds ratio, 0.53; 95% CI, 0.35–0.82; P < .005) were significant predictors for lymph node metastases. The probability of metastases was estimated with these models. The preoperative decision (20% probability) as to whether to perform neck dissection could be based on tumor thickness of >9.7 mm and paralingual distance of <5.2 mm. CONCLUSION: MR images provide satisfactory accuracy for the preoperative estimation of the tumor thickness and the paralingual distance, which are valuable for predicting cervical lymph node metastases.

IL-12 plays a pivotal role in LFA-1-mediated T cell adhesiveness by up-regulation of CCR5 expression

The chemokine receptor CCR5 has been implicated in the recruitment of T cells to inflammatory sites. However, the regulation of CCR5 induction on T cells and its contribution to T cell adhesiveness are poorly understood. Using a Th1 clone, 2D6, that can be maintained with interleukin (IL)‐12 or IL‐2 alone (designated 2D6IL‐12 or 2D6IL‐2, respectively), we investigated how CCR5 is induced on T cells and whether CCR5 is responsible for up‐regulating the function of adhesion molecules. 2D6IL‐12 grew, forming cell aggregates, in culture containing IL‐12. This was due to lymphocyte function‐associated antigen (LFA)‐1–intercellular adhesion molecule (ICAM)‐1 interaction, because 2D6IL‐12 expressed both LFA‐1 and ICAM‐1 and cell aggregation was inhibited by anti‐ICAM‐1 monoclonal antibody. Despite comparable levels of LFA‐1 and ICAM‐1 expression, 2D6IL‐2 cells did not aggregate in culture with IL‐2. It is important that there was a critical difference in CCR5 expression between 2D6IL‐12 and 2D6IL‐2; the former expressed high levels of CCR5, and the latter expressed only marginal levels. Both types of cells expressed detectable albeit low levels of RANTES (regulated on activation, normal T expressed and secreted) mRNA. Unlike IL‐12 or IL‐2, IL‐18 induced high levels of RANTES mRNA expression without modulating CCR5 expression. Therefore, combined stimulation with IL‐12 and IL‐18 strikingly up‐regulated 2D6 cell aggregation. Notably, LFA‐1‐mediated aggregation of 2D6IL‐12 cells was suppressed by anti‐CCR5 antibody. These results indicate that IL‐12 plays a critical role in CCR5 expression on Th1 cells and consequently contributes to CCR5‐mediated activation of LFA‐1 molecules.

Induction chemotherapy is Associated with an increase in the incidence of locoregional recurrence in patients with carcinoma of the oral cavity

This study was conducted to determine long term survival rates and the pattern of failure in patients with carcinoma of the oral cavity treated with induction chemotherapy or preoperative radiotherapy followed by surgery.

Induction of Tumor Regression by Administration of B7-Ig Fusion Proteins: Mediation by Type 2 CD8+ T Cells and Dependence on IL-4 Production

CD28 signals contribute to either type 1 or type 2 T cell differentiation. Here, we show that administration of B7.2-Ig fusion proteins to tumor-bearing mice induces tumor regression by promoting the differentiation of antitumor type 2 CD8+ effector T cells along with IL-4 production. B7.2-Ig-mediated regression was not induced in IL-4−/− and STAT6−/− mice. However, it was elicited in IFN-γ−/− and STAT4−/− mice. By contrast, IL-12-induced tumor regression occurred in IL-4−/− and STAT6−/− mice, but not in IFN-γ−/− and STAT4−/− mice. Moreover, B7.2-Ig treatment was effective in a tumor model not responsive to IL-12. B7.2-Ig administration elicited elevated levels of IL-4 production. Tumor regression was predominantly mediated by CD8+ T cells, although the induction of these effector cells required CD4+ T cells. Tumor regression induced by CD8+ T cells alone was inhibited by neutralizing the IL-4 produced during B7.2-Ig treatment. Thus, these results indicate that stimulation in vivo of CD28 with B7.2-Ig in tumor-bearing mice results in enhanced induction of antitumor type 2 CD8+ T cells (Tc2) leading to Tc2-mediated tumor regression.

Induction of surface CCR4 and its functionality in mouse Th2 cells is regulated differently during Th2 development.

T helper cell type 1 (Th1) and Th2 cells express distinct sets of chemokine receptors. In contrast to Th1 chemokine receptors, it is largely unknown how Th2 chemokine receptors such as CC chemokine receptor 4 (CCR4) are induced during Th2 differentiation. Here, we investigated the induction of CCR4 surface expression and ligand responsiveness evaluated by functional assays such as chemokine binding and chemotaxis. This was done in comparison with those of a Th1 chemokine receptor, CXC chemokine receptor 3 (CXCR3). Resting T cells expressed neither CXCR3 nor CCR4. CXCR3 expression and ligand responsiveness were observed when resting T cells were stimulated with anti‐CD3 plus anti‐CD28 in the presence of [interleukin (IL)‐12+anti‐IL‐4] and then recultured without T cell receptor (TCR) stimulation. Unlike CXCR3, CCR4 was induced immediately after anti‐CD3/anti‐CD28 stimulation in the presence of (IL‐4+anti‐interferon‐γ+anti‐IL‐12). However, these CCR4‐positive cells failed to exhibit chemokine binding and chemotaxis. Although the levels of surface CCR4 expression were not increased after the subsequent reculture in the absence of TCR stimulation, CCR4 responsiveness was induced in this stage of Th2 cells. The induction of CCR4 expression and the acquisition of CCR4 responsiveness did not occur in IL‐4‐deficient (IL‐4–/–) and signal transducer and activator of transcription (STAT)6–/– T cells. CCR4 expression and functionality were regained in IL‐4–/– but not in STAT6–/– T cells by the addition of recombinant IL‐4. Although surface expression and functionality of CCR4 are induced depending on the IL‐4/STAT6 signaling pathway, the present results indicate that the functionality of CCR4 does not correlate with CCR4 expression but emerges at later stages of Th2 differentiation.