Myeloid-derived suppressor cells and plasmacytoid dendritic cells are associated with oncogenesis of oral squamous cell carcinoma.

Myeloid-derived suppressor cells (MDSCs) help establish the tumor microenvironment by suppressing T-cell response in tumor-bearing hosts. Plasmacytoid dendritic cells (pDCs) activate antigen-specific T cells, thereby, maximizing their antitumor effects. IDO1 is associated with both MDSCs and pDCs and plays a major role in the formation of the tumor-mediated immunosuppressive environment. We utilized immunohistochemistry to examine the involvement of IDO1 in oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs, precancerous lesions). We examined the expression of MDSC markers, CD11b and CD33, as well as pDC markers, CD303 and IDO1, in 60 OSCC and 45 precancerous lesion specimens and analyzed their association with clinicopathological parameters. Expression of these biomarkers identifying MDSCs and pDCs was high in precancerous lesions in patients with severe dysplasia and OSCC. While detecting pDCs, high CD303 and IDO1 expression levels were frequently observed in moderately or poorly differentiated OSCCs. CD11b, CD33, and CD303 levels were significantly correlated with the mode of invasion; CD33 was correlated with OSCC invasion depth while the other three markers tended to be highly expressed in superficial cancer cases showing microinvasion. Expression levels of all four biomarkers were significantly associated with the cancerization of OPMDs to OSCCs. We show, for the first time, that the infiltration of MDSCs and pDCs is significantly associated with progression of premalignant lesions to OSCC. This suggests that these cells may act as prognostic biomarkers for premalignant lesion progression and that immunotherapeutic approaches that control each of these immunosuppressive cells may protect against progression to malignancy.

Expression of Urokinase-type Plasminogen Activator (uPA), uPA Receptor, and Plasminogen Activator Inhibitor-1 in Oral Squamous Cell Carcinoma / Oral Science International

We investigated whether the expression levels of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) correlate with clinicopathological features of oral squamous cell carcinoma (SCC). We immunohistochemically examined the expression levels of uPA, uPAR, and PAI-1 in 160 biopsy specimens of oral SCC. Positive stainings for uPA, uPAR, and PAI-1 were observed mainly in SCC cells, and their intensity and number of positive cells were related to lymph node involvement (<i>p</i> < 0.001, <i>p</i> < 0.001, and <i>p</i> < 0.001, respectively). The expression levels of uPA and uPAR were also related to the pattern of invasion (<i>p</i> < 0.05 and <i>p</i> < 0.001, respectively), while both were associated with tumor size (<i>p</i> < 0.05). Moreover, a poor survival rate was related to the expression of uPAR (<i>p</i> < 0.01) and PAI-1 (<i>p</i> < 0.05). These findings suggest that the uPA system may regulate the invasion and metastasis of oral SCC cells.

An Adenoid Cystic Carcinoma Cell Line Possessing High Metastatic Activity has High NF-κB Activation in Response to TNF-α / Oral Science International

Adenoid cystic carcinoma (AdCC) is characterized by frequent recurrence and distant metastasis. Although lung metastasis in AdCC is very common, the mechanism by which this occurs is uncertain. When five AdCC cell lines (ACCS, ACCT, ACCH, Acc-3, and Acc-M) were screened for metastatic ability by injecting tumor cells into nude mice via the tail vein, lung metastases were found in mice injected with Acc-M (15/16 mice) but not in mice injected with any of the other four cell lines (0/10 mice with each line). To determine why Acc-M metastasizes to the lung but the others do not, we examined the biological characteristics of Acc-M and compared them with those of the other lines.Nuclear factor-κB (NF-κB) may play a key role in malignant tumor behaviors such as invasion and metastasis. Thus, we examined these cell lines for response to tumor necrosis factor (TNF-α), one of the typical stimulators of NF-κB. Although treatment with TNF-α stimulated matrix metalloprotease 9 (MMP-9) expression in all cell lines, the response to TNF-α varied between cell lines; the greatest stimulation was observed in Acc-M. Acc-M expressed higher levels of TNF receptors (both TNF-R1 and TNF-R2) than did the other AdCC lines. Judging from inhibitor-κBα degradation and nuclear translocation and DNA binding by NF-κB, the degree of activation of NF-κB in response to TNF-α in Acc-M cell lines was very high compared to the other lines. Moreover, the ability of Acc-M cells to adhere to endothelial cells, which was greater than that of the other cell lines, was further enhanced by pretreatment with TNF-α. Acc-M cells also expressed higher levels of sialyl Lewis^x than did the other AdCC cell lines. These findings suggest that lung metastasis is mediated by tumor-endothelial cell interaction, which is probably associated with the NF-κB activation pathway. Further experiments are required to identify the molecules that mediate both lung metastasis and NF-κB activation.