We examined the role of the hepatocyte growth factor (HGF)/c-met system on invasion and metastasis of oral squamous cell carcinoma (SCC) cells. In monolayer culture, exogenous HGF marginally affected the growth of oral SCC cells (BHY, HN, IH) and human gingival epithelial cells (GE). In type I collagen matrix, however, HGF significantly enhanced the invasive growth of the cancer cells (p < 0.05). We detected the expression of c-met (HGF receptor) mRNA in all of the cancer cells, but not in human gingival fibroblasts (GF). Oral SCC cells did not secret HGF protein into the medium, but GF secreted a large amount of HGF protein (15 ng/ml). Furthermore, HGF markedly enhanced the migration of cancer cells in a Transwell invasion chamber. Then, we examined the serum levels of HGF in oral SCC patients, or HGF concentrations in oral cancer tissues. Serum levels of HGF in the patients were significantly higher than those in healthy volunteers (p < 0.05). After initial treatment, all of the tumor-free survivors showed a marked decline in the serum HGF levels. Furthermore, HGF concentrations in metastatic cancer tissues were significantly higher than those of nonmetastatic cancer tissues and normal gingiva (p < 0.01). These results suggest that HGF plays an important role in invasion and metastasis of oral SCC cells as a paracrine factor, and an elevated HGF level in the cancer tissue can be a predictive marker for metastasis formation in patients with oral SCC. © 2001 Wiley-Liss, Inc. Key words: oral SCC; HGF; c-met; metastasisOral SCCs are characterized by a high degree of local invasion and a high rate of metastases to cervical lymph nodes, but a low rate of metastases to distant organs. Moreover, oral SCC frequently show local recurrence after initial treatment, probably due to micro-invasion or micro-metastasis of the tumor cells at the primary site. We recently reported that oral SCC cells produced a large amount of matrix-degrading enzymes and that the net activity of MMP2 (active-MMP2/TIMP2) produced by cancer cells contributes to lymph-node metastasis in a nude-mouse orthotopic inoculation model. 1 We also noted that cancer cells in the peripheral blood of patients with oral SCC were frequently detected by RT-PCR for cytokeratin 20 mRNA, and that there was no clear relationship between the hematogenous cancer cells and the metastasis. 2 Furthermore, by microdissection zymography, we demonstrated that active MMP2 in cancer cell nests could be a predictive marker for metastasis formation in patients with oral SCC. 3 The precise molecular mechanisms of invasion and metastasis of oral cancer, however, especially the interaction between cancer cells and host cells, are still unknown.
Summary We undertook the present study to clarify the molecular mechanism of the effect of a new anti-cancer drug, vesnarinone, on a human salivary gland cancer cell line, TYS. We isolated TSC-22 cDNA as a vesnarinone-inducible gene from a cDNA library constructed from vesnarinone-treated TYS cells. TSC-22 was originally reported as a transforming growth factor (TGF)-,-inducible gene. The expression of TSC-22 was up-regulated within a few hours after treatment with vesnarinone and was continued for 3 days. The level of TSC-22 mRNA in TYS cells was continuously increased until the cells reached confluency. Furthermore, the induction of TSC-22 by vesnarinone was inhibited by treatment with cycloheximide. When we treated the cells with an antisense oligonucleotide against TSC-22 mRNA under quiescent conditions, the antisense oligonucleotide stimulated the growth of TYS cells; however, under growing conditions the antisense oligonucleotide did not affect cell growth. Furthermore, the antisense oligonucleotide suppressed the antiproliferative effect of vesnarinone. These results suggest that TSC-22 may be a negative growth regulator and may play an important role in the antiproliferative effect of vesnarinone.
sophageal squamous cell carcinoma (SCC) is one of the most aggressive cancers. Esophageal SCC is relatively common in countries in Eastern Asia, such as China and Japan, and is characterized by poor prognosis and rapid clinical progression, with a high frequency of lymph node metastasis and recurrence. The 5-year survival rate of patients with esophageal SCC showing submucosal invasion is low (40-75%) 1-5) compared with that for patients with colon cancer (over 80%). 4,5) In addition, lymph node metastasis is commonly found in esophageal SCC, even when the tumor invades only the submucosa. Lymph node metastasis is the main cause of the poor prognosis for the patients with esophageal SCC.Consequently, the identification of the genes associated with metastasis of esophageal SCC is very important. Microarray analysis has been used to investigate the gene expression profiles of esophageal SCC tissues and esophageal cancer cell lines with various characteristics.6-10) When clinical materials are used for microarray analysis, it might be necessary to look at the overall expression profiles of genes (if possible) by clustering analysis in the different pathological stages, such as dysplasia, carcinoma in situ, and invasive cancer with or without metastasis. However, to isolate gene(s) related to metastasis, it would be convenient to use cell lines with different metastatic potentials derived from the same parental cells, and a reliable model system is therefore required for examining the metastatic potential of cancer cells.In our previous experiments, we established in vitro and in vivo model systems for studying invasion and metastasis of esophageal SCC cells. 11,12) We first clarified in detail the molecular and genetic characteristics of a human non-metastasizing esophageal SCC cell line, T.Tn, 12) and then developed an orthotopic inoculation model for esophageal cancer cells in nude mice.11) In the present study, we isolated a metastasizing subclone from the parental non-metastasizing T.Tn cell line by in vitro selection and by the use of a nude mouse orthotopic inoculation model. Then, we compared the expression profiles of 9206 genes in the parental T.Tn cells and the metastasizing subclone by cDNA microarray analysis, and identified several genes differentially expressed in the metastasizing subclone. Materials and MethodsCell line. A human esophageal SCC cell line, T.Tn 13) was obtained from JCRB (Japanese Collection of Research Bioresources, Osaka). T.Tn cells were grown in 1:1 mixture of Dulbecco's modified Eagle's medium (Nissui, Tokyo) and F-12 (Life Technologies, Inc., Gaithersburg, MD) supplemented with 10% fetal calf serum (FCS; Sigma, St. Louis, MO), 100 µg/ml streptomycin, 100 units/ml penicillin (Life Technologies, Inc.), and 0.25 µg/ml amphotericin B (Life Technologies, Inc.) in a humidified atmosphere of 95% air and 5% CO 2 at 37°C. HT1080 cells are derived from a human fibrosarcoma cell line known to secrete a large amount of several matrix-degrading enzymes (purchased from Dai-Nippon Seiyaku, Osa...
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