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Metastasis-associated protein MTA1 and histone deacetylase form a protein complex with histone deacetylase activity that plays an important role in histone deacetylation, alteration of chromatin structure and transcriptional control. The precise role of the MTA1 protein in the malignant progression of human cancers remains unknown, however, especially its overexpression and relationship with histone acetylation/ deacetylation in experimental and clinical tumors. The expression levels of MTA1 protein and the acetylation levels of histone H4 were examined in 70 cases of surgically resected esophageal squamous cell carcinomas, using immunohistochemistry. The intensities of immunostaining of MTA1 protein and acetylated histone H4 in carcinoma tissues (Ca) were compared to normal epithelium (N) contained in the same section. Thirty of 70 cases (42.9%) displayed overexpression of MTA1 protein (N < Ca). Cancers overexpressing MTA1 protein invaded deeper into the esophageal wall (p < 0.005) and showed significantly higher degrees of lymph node metastasis (p < 0.01), higher pathological stage, more lymphatic involvement and poorer prognosis (p < 0.05) than the remaining cases. The acetylation levels of histone H4 inversely correlated to the depth of cancer invasion and pathological stage (p < 0.05), and the patients with higher level of histone H4 acetylation had a better prognosis (p < 0.05). Furthermore, immunostaining patterns of MTA1 and acetylated histone H4 were inversely correlated (p < 0.001), demonstrating the relationship of deacetylation of histone H4 in MTA1-overexpressing carcinomas. In conclusion, the data suggest that the overexpression of MTA1 protein and acetylation level of histone H4 protein, both of which are closely related, might be useful predictors of malignant potential of esophageal squamous cell carcinomas. Thus, strategies involving inhibition of MTA1 function as well as inhibition of histone deacetylation could be novel approaches for the treatment of esophageal squamous cell carcinomas. © 2004 Wiley-Liss, Inc. Key words: esophageal squamous cell carcinoma; metastasis-associated protein MTA1; histone deacetylation; cancer progression; prognosisModifications of chromatin structure by acetylation/deacetylation of the histone proteins play a central role in the regulation of transcription. 1,2 The levels of acetylation/deacetylation of histone proteins are determined by 2 opposing enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs), especially HDAC1 and HDAC2. 2 These alterations of chromatin structure by HATs and HDACs have been implicated in the process of carcinogenesis. 3,4 For example, the retinoblastoma protein pRB has been shown to have the ability to associate with HDAC1 and recruit the pRB complex to the E2F-regulated promoters of genes such as cell-cycle regulatory genes, resulting in inhibition of E2-regulated gene expression. Thus, the pRB/HDAC1 complex is likely to be a key element in the control of cell proliferation and differentiation. 4 -6 HDAC inhibito...

Abstract. Disseminated carcinimatosis of the bone marrow is accompanied by solid tumors, and gastric cancer accounts for the majority. The prognosis of this condition is poor, however, the pathogenesis for wide-spread bone lesions has yet to be elucidated. In 9 patients with gastric cancer demonstrating disseminated carcinomatosis of the bone marrow, the characteristic clinicopathological features were examined. Immunohistochemistry for receptor activator of NF-κB ligand (RANKL) and parathyroid hormone-related protein was also performed on gastric cancer tissue and bone marrow specimens to identify the factors responsible for the occurrence of bone lesions in patients presenting with this condition. The characteristic features of disseminated carcinomatosis of the bone marrow due to gastric cancer include a yonger patient age, an elevation of serum alkaline phosphatase and/or lactate dehydrogenase levels, wide-spread bone metastases with osteolytic bone destruction, a low incidence of hypercalcemia and a histological gastric cancer type of either signet ring cell carcinoma or poorly diffentiated adenocarcinoma. The expression of RANKL, which is one of the master regulators of osteoclastic bone resorption in bone metastasis, was also found in gastric cancer cells obtained from such patients. The RANKL expressed in gastric cancer may therefore play a critical role in the promotion of osteoclast formation, which has been suggested to be involved in the pathogenesis of bone lesions.

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a presumed activator of MMP2, which is one of the major proteinases in tumor cell invasion. In this study, we determined the clinico-pathologic significance of MT1-MMP expression in 68 human gastric carcinomas. The tumor-normal ratio (T/N ratio) of MT1-MMP expression was determined by reverse transcription-polymerase chain reaction analysis. To visualize the localization of MT1-MMP, an immunohistochemical study was performed. In addition, a gelatin zymography was done to examine the activation ratio of MMP2, and a correlation between MT1-MMP expression and activation of MMP2 was studied. The expression of MT1-MMP mRNA was higher in tumor tissue than in corresponding normal tissue in most cases. The mean value of the T/N ratio was 4.8. Twenty cases with T/N H 4.8 showed significantly deeper invasion and higher frequency of lymph node metastasis than 48 cases with T/N F 4.8. MT1-MMP expression was an independent factor influencing both tumor invasion of the gastric wall and lymph node metastasis. Although MT1-MMP expression was not an independent prognostic factor, the patients with T/N H 4.8 showed a significantly worse prognosis than those with T/N Cancer cell metastasis to distant organs is the major cause of death in cancer patients. Metastasis is a multi-step process, and the initial step is considered to be the invasion of surrounding stromal tissue by cancer cells. Matrix metalloproteinases (MMPs), which contain a zinc atom in a highly conserved active site, are chiefly responsible for this step, and they are frequently overexpressed in a variety of tumors (Davies et al., 1993;Emmert-Buck et al., 1994;Mori et al., 1995a;Sato H. et al., 1992).Overexpression of MMPs in tumor tissues themselves does not mean actual function of the enzymes, since several of these are secreted as latent pro-enzymes that need modification or removal of the aminoterminal domain for the expression of activity (Cao et al., 1995;Emonard et al., 1992;Sato et al., 1994). Of 12 MMPs so far identified, MMP2 (gelatinase A) and MMP9 (gelatinase B) are believed to play a major role in tumor invasion by degradation of type IV collagen, which is the main component of the extracellular matrix (Cao et al., 1995;Emonard et al., 1992). MMP9 is activated by other proteases such as trypsin, stromelysin or collagenase. On the other hand, MMP2 has been shown to be activated by membrane-type 1 MMP (MT1-MMP), which possesses a functional transmembrane domain (Sato et al., 1994). To our knowledge, 4 MT-MMPs have been reported at present (Puente et al., 1996;Sato et al., 1994;Takino et al., 1995;Will and Hinzmann, 1995). These 4 enzymes have similar molecular structures, and 2 of these activate pro-MMP2. The first MT1-MMP discovered, which was described as MT1-MMP-1, is the focus of our study.Overexpression of MT1-MMP has been observed in cervical cancers and lung cancers as being associated with invasiveness of the cancer cells, probably via activation of MMP2 (Gilles et al., 1996;Tokuraku et al., 19...

Cancer stem-like cells (CSCs)/ cancer-initiating cells (CICs) are defined by their higher tumor-initiating ability, self-renewal capacity and differentiation capacity. CSCs/CICs are resistant to several therapies including chemotherapy and radiotherapy. CSCs/CICs thus are thought to be responsible for recurrence and distant metastasis, and elucidation of the molecular mechanisms of CSCs/CICs are essential to design CSC/CIC-targeting therapy. In this study, we analyzed the molecular aspects of gynecological CSCs/CICs. Gynecological CSCs/CICs were isolated as ALDH1high cell by Aldefluor assay. The gene expression profile of CSCs/CICs revealed that several genes related to stress responses are preferentially expressed in gynecological CSCs/CICs. Among the stress response genes, a small heat shock protein HSP27 has a role in the maintenance of gynecological CSCs/CICs. The upstream transcription factor of HSP27, heat shock factior-1 (HSF1) was activated by phosphorylation at serine 326 residue (pSer326) in CSCs/CICs, and phosphorylation at serine 326 residue is essential for induction of HSP27. Immunohistochemical staining using clinical ovarian cancer samples revealed that higher expressions of HSF1 pSer326 was related to poorer prognosis. These findings indicate that activation of HSF1 at Ser326 residue and transcription of HSP27 is related to the maintenance of gynecological CSCs/CICs.