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Hitoshi Nagatsuka

Publications and source records attributed to Hitoshi Nagatsuka.

At least 19 recordsLinked to original sources
PubMed2025

Cancer-associated fibroblast-derived SOD3 enhances lymphangiogenesis to drive metastasis in lung adenocarcinoma.

Despite advancements in diagnostic and therapeutic strategies, lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality due to its aggressive metastatic potential. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme that regulates oxidative stress and is regarded as a tumor suppressor. However, studies have demonstrated that SOD3 can either promote or inhibit cell proliferation and survival in various cancers, and its molecular mechanisms within the tumor microenvironment are poorly understood. In this study, we report a breakthrough in uncovering the role of SOD3 derived from cancer-associated fibroblasts (CAFs) in LUAD. Using LUAD xenograft models co-implanted with SOD3-overexpressing CAFs (CAFSOD3), we observe an aggressive tumor phenotype characterized by increased lymphangiogenesis and lymphatic vessel invasion (LVI) of the tumor. Additionally, LUAD patients with elevated SOD3 levels exhibit a higher incidence of LVI and metastasis. Notably, RNA sequencing of CAFSOD3 reveals that SOD3-mediated VEGF-dependent tumor progression and lymphangiogenesis are up-regulated. Furthermore, single-cell transcriptomic analysis of LUAD clinical samples confirms a strong correlation between SOD3 expression in fibroblasts and characteristics of tumor exacerbation, such as lymphangiogenesis and metastasis. These findings underscore new insights into the role of CAF-derived SOD3 in LUAD progression and highlight its potential as a biomarker and therapeutic target.

Lymphangiogenesis↗
PubMed2006

An immunohistochemical evaluation of BMP-2, -4, osteopontin, osteocalcin and PCNA between ossifying fibromas of the jaws and peripheral cemento-ossifying fibromas on the gingiva.

The present study examined histological difference between ossifying fibromas (OF, n=5) and peripheral cemento-ossifying fibromas (PCOF, n=7). Bone morphogenetic proteins (BMP)-2 and -4, osteopontin (OPN), osteocalcin (OCN) and proliferating cell nuclear antigen (PCNA) were used for the immunohistochemical examinations. Oxytalan fibers present at the periodontal tissue were stained to determine the tumor cell origin. Many OFs showed high immunohistochemical reactions for BMP-2, -4 and OPN compared to those of PCOFs. PCNA index (IP) of OFs was significantly higher than that of PCOFs. All the PCOFs showed a high expression of oxytalan fibers. Only two OFs exhibited a small number of oxytalan fibers. These results suggest that PCOF has only little ability to form hard tissue and seems to be a reactive lesion. The expression of oxytalan fibers reveals that OF does not only originate from periodontal tissue.

Adolescent↗
PubMed2006

Differential expression of basement membrane collagen-IV alpha1 to alpha6 chains during oral carcinogenesis.

This study aimed to resolve if basement membrane (BM) collagen alpha chains undergo remodeling during oral carcinogenesis. Using immunohistochemistry and transmission electron microscopy, we found that BMs in oral epithelial dysplasias (OED: mild, n=10; moderate, n=10; severe, n=10) and carcinoma in situ (CIS) (n=10) differed from normal mucosa (n=6) and oral epithelial hyperplasia (n=5) in showing: (1) excessive lamina densa-like material ultrastructurally, and (2) stronger immunoexpression for alpha5(IV) than for alpha1(IV), alpha2(IV), and alpha6(IV) chains-findings that implicate these molecules' role as an adhesive template for the attachment and persistence of basal dysplastic cells. Incipient loss of BM integrity in CIS, where alpha5(IV)/alpha6(IV) chains were more frequently absent than alpha1(IV)/alpha2(IV) chains, suggests that alpha(IV) network disruption is crucial for progression of dysplastic cells into the extracellular compartment, marking transition into the invasive phase. In carcinomatous BM, the disappearance of alpha(IV) chains was more severe in poorly differentiated oral squamous cell carcinoma (OSCC) (n=10) than in well-differentiated OSCC (n=10). In all samples examined, alpha3(IV) and alpha4(IV) chains were absent. These findings taken together suggest that BM collagen-IV alpha chains undergo remodeling where selective increase and loss of these molecules are probably early and late events, respectively, during progression of oral dysplasia to cancer.

Basement Membrane↗
PubMed2006

Fine deletion mapping of chromosome 2q21-37 shows three preferentially deleted regions in oral cancer.

We analysed the loss of heterozygosity (LOH) of long arm of chromosome 2 by using 16 polymorphic microsatellite markers in 39 matched oral normal and cancer tissues, and defined the deletional mapping of the region with putative tumor suppressor genes. LOH was detected at least one location in 33 of 39 (85%) tumor tissues. Frequent deletions were detected at the locations of microsatellite markers, D2S2304 (35%), D2S111 (40%), D2S155 (35%), D2S1327 (29%), D2S164 (29%), D2S125 (68%) and D2S140 (32%). Three preferentially deleted regions at 2q21-24, 2q33-35 and 2q37.3 were observed. Several candidate tumor suppressor genes in these regions such as LRP1B, CASP8, CASP10, BARD1, ILKAP, PPP1R7, and ING5, are located. Further molecular analysis of each gene should be performed to clarify their roles in oral carcinogenesis.

Carcinoma, Squamous Cell↗
PubMed2006

The close relationship between heparanase and cyclooxygenase-2 expressions in signet-ring cell carcinoma of the stomach.

Signet-ring cell carcinoma (SRC) of the stomach exhibits diffuse growth and invasion without forming ducts. Destruction of the surrounding basal membrane and angiogenesis appear to be required for SRC to exhibit marked invasion and growth. We recently reported that heparanase (HPA) and cyclooxygenase-2 (COX-2) were strongly correlated with microvessel density, and that COX-2 expression is up-regulated by HPA in esophageal cancer. In this study, we examined the relationship between HPA expression and that of COX-2 in SRC of the stomach. We examined HPA and COX-2 expression in 3 cell lines derived from SRC of the stomach and in 50 SRC lesions of stomach by immunohistochemistry (IHC), in situ hybridization, and reverse transcriptase-polymerase chain reaction (RT-PCR). We also examined the relationships among HPA expression, COX-2 expression, and the clinicopathologic features of SRC, mean age, sex, invasion depth, regional lymph node metastasis, lymphatic invasion, and venous blood vessel invasion. Of the 3 cell lines, 2 exhibited both HPA and COX-2 mRNA expression on RT-PCR. Of the 3 cell lines, 1 exhibited only HPA mRNA expression on RT-PCR. Heparanase expression was confirmed in 23 (46%) of 50 tumor samples by IHC. COX-2 expression was confirmed in 25 (50%) of the 50 tumor samples by IHC. In situ hybridization revealed messenger RNA expression in the same area as in that revealed by IHC. A close correlation was noted between HPA and COX-2 expressions (P < .0001). The present study thus elucidated the biologic features of SRC of the stomach related to growth and angiogenesis.

Adult↗
PubMed2006

Epigenetic alterations of BRG1 leads to cancer development through its nuclear-cytoplasmic shuttling abnormalities.

SWI/SNF is a multiprotein chromatin remodeling complex important for gene regulation. BRG1 and its close relative BRM, have ATPase activity necessary for transcriptional regulation by conformational change of nucleosomes. Due to this role on gene expression, several members of SWI/SNF complex including BRG1 and BRM function as a tumor suppressor or negative regulator of cellular proliferation. On the other hand, the shuttling of proteins between nucleus and cytoplasm is strongly involved in the regulation of cell cycle and proliferation. Many of tumor suppressor gene (TSG)s including p53, BRCA1, ING1 play some of their functions through nucleocytoplasmic shuttling. Abnormalities related with this process abrogate the subcellular localization of the TSGs and lead to cancer development. We recently demonstrated BRG1 as a TSG in oral cancer. Our analysis also revealed an interesting finding that one of the splicing forms of BRG1 is selectively lost in cancer tissue as compared to normal counterparts. Our further analysis revealed a putative nuclear retention signal domain for this splicing form. In this article, we speculate the possible mechanism for the inactivation of BRG1 gene in oral cancer through an abnormality in its subcellular localization.

Active Transport, Cell Nucleus↗
PubMed2006

MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma.

PURPOSE: Mucoepidermoid carcinoma is the most common primary malignancy of the salivary gland. Mucoepidermoid carcinoma translocated gene 1-mastermind-like gene family (MECT1-MAML2) gene fusion was identified from a recurring t(11;19)(q21;p13) translocation, which is often the sole cytogenetic alteration in this disease. This fusion transcript has been frequently detected in mucoepidermoid carcinoma and shown to be involved in the transformation of epithelial cells. However, its clinicopathologic significance remains unclear. EXPERIMENTAL DESIGN: Seventy-one cases of mucoepidermoid carcinoma and 51 cases of nonmucoepidermoid carcinoma salivary gland tumors (including 26 Warthin tumor cases) were retrospectively analyzed. RNA was extracted from archival materials: histologic paraffin specimens in all cases and cytologic specimens in 10 mucoepidermoid carcinoma cases. The MECT1-MAML2 fusion transcript was detected by a reverse transcription-PCR assay, which can be applied to both histologic and cytologic specimens. The presence of the fusion transcript was correlated with relevant clinicopathologic and survival data of the mucoepidermoid carcinoma patients. RESULTS: The MECT1-MAML2 fusion transcript was detected in 27 of the 71 (38%) mucoepidermoid carcinoma cases but not in any case of nonmucoepidermoid carcinoma tumors. The reverse transcription-PCR results showed no difference between histologic and cytologic specimens. Detection of the MECT1-MAML2 fusion transcript was associated with a less advanced clinical stage and a low-grade tumor histology. The presence of the transcript was associated with longer disease-free and overall survivals on univariate analysis and emerged as an independent prognostic factor for longer overall survival on multivariate analysis. CONCLUSIONS: The MECT1-MAML2 fusion transcript may be specific to mucoepidermoid carcinoma and associated with a distinct mucoepidermoid carcinoma subset that exhibits favorable clinicopathologic features and an indolent clinical course.

Adolescent↗
PubMed2006

Efficacy of atelocollagen honeycomb scaffold in bone formation using KUSA/A1 cells.

To induce new bone formation, mesenchymal stem cells were seeded onto atelocollagen honeycomb scaffold. We evaluated the efficacy of this scaffold combined with KUSA/A1 cells in vivo. KUSA/A1 cells alone and with atelocollagen were implanted in the subcutaneous pockets of 4-week-old male SCID mice. The transplants were subjected to radiographical, histological, and immunohistochemical examinations after 2 and 4 weeks of implantation. Radiographically, both KUSA/A1 cells alone and KUSA/A1-atelocollagen showed some radiopaque areas formation but the latter disclosed a larger amount. Histologically, KUSA/A1 cells alone showed few small islands of new bone formation surrounded by a thin layer of cellular proliferation. On the other hand, KUSA/A1-atelocollagen revealed abundant new bone formation as well as cellular proliferation. We also determined the immunolocalization of type I collagen, CD34, osteocalcin, osteopontin, and PCNA in this newly formed bone. Our results indicated that collagen scaffold plays an important role allowing vessel formation and cell anchorage, especially through the proliferation and differentiation process in a confined space. This study supports tissue engineering as an alternative for treating different target diseases, such as trauma or congenital defects, and enhances existing therapeutic applications.

Animals↗
PubMed2006

Immobilized rhBMP-2/succinylated type I atelocollagen gene expression of intracellular signaling molecules on ST2 cells.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) chemically-bonded to succinylated type I atelocollagen, a biomaterial carrier with a porous structure, was reported to augment cellular activity of ST2 cells. The Smad protein family has been suggested to play an important role in the intracellular signaling pathway of BMP by its binding to receptors on target cells. However, there has been no study analyzing the downstream genes of the rhBMP-2 induced intracellular signal transduction pathway. The purpose of this study was to examine the effect of immobilized rhBMP-2 on gene expression of intracellular signaling molecules on ST2 cells. Our study showed two expression patterns of downstream genes of rhBMP-2 intracellular signal transduction pathway. In the first pattern, BMPR-IA, Smad 1, and Smad 5 genes showed high basic expression before the addition of rhBMP, and the high level of gene expression continued for long period and decreased in the late stage when rhBMP-2 was immobilized. In the second pattern, Smad 6, Smad 7, and Smad 8 genes showed low basic expression before the addition of rhBMP-2 and a continuous increase from the beginning was followed by a decrease in the late stage when rhBMP-2 was immobilized. Our results also showed that intracellular signaling continued for prolonged period when rhBMP-2 was immobilized to succinylated type I atelocollagen. This study indicated that immobilizing rhBMP-2 is an efficient method to increase bone induction.

Animals↗
PubMed2006

Comparison of ready-made and self-setting alginate membranes used as a barrier membrane for guided bone regeneration.

In order to understand the requirements of guided bone regeneration (GBR) involving alginate base self-setting barrier membranes, GBR was performed in the case of bicortical bone defects formed at the tibiae of experimental animals employing self-setting and ready-made alginate membranes. Connective tissue ingress into the bone defects at the skin side of the tibia was observed when GBR was generated utilizing ready-made alginate membrane. In contrast, bone defects were reconstructed with bone tissue when GBR was generated with self-setting alginate membrane formed from aqueous 3% sodium alginate and 3% CaCl(2) solutions. The unreacted aqueous sodium alginate solution inherent to self-setting alginate membrane did not inhibit bone tissue regeneration. Rather, callus bone was formed using sodium alginate as the nucleus. However, when GBR was effected with self-setting alginate membrane formed from aqueous 10% CaCl(2) solution, membrane was too thick and thus regeneration of bone tissue in the bone cavity was prevented. Therefore, we concluded that self-setting alginate membrane is very useful as a barrier membrane for GBR upon appropriate adjustment of conditions with respect to preparation of alginate membrane.

Alginates↗
PubMed2006

Expression of Notch1 and Hes5 in the developing olfactory epithelium.

CONCLUSION: Notch signaling pathway may play an important role in the development of the olfactory epithelium (OE). Objectives. To elucidate whether the Notch signaling pathway mediates the developmental processes in the developing OE. MATERIALS AND METHODS: The expression of Notch1 and Hes5 in the developing OE of mice with ages ranging from embryonic day (E) 11 to postnatal day (PN) 14 was examined. RESULTS: As detected by in situ hybridization, Notch1 was expressed in scattered cells located in the basal portion of the embryonic OE and later in the cell layer adjacent to the basal lamina from E11 to PN14. Hes5 was expressed in scattered cells located in the basal portion of the embryonic OE from E11. However, at the late embryonic stage, the number of Hes5-positive cells decreased and after birth distinct Hes5-positive cells were not observed in the OE.

Animals↗
PubMed2006

Microcystic adnexal carcinoma with mandibular bone marrow involvement: a case report with immunohistochemistry.

Microcystic adnexal carcinoma is a rare, locally aggressive cutaneous neoplasm with a high probability of persistence locally but a low probability of metastasis. We report a case of a 69-year-old female patient with an indurated plaque at the mental region. Histologically, the tumor cells invaded the subcutaneous tissue and mandibular bone. The tumor consisted mainly of squamous and basaloid epithelial nests and cords embedded in a desmoplastic stroma. A few keratin-filled microcysts and ductal structures were also observed. Perineural encroachment was also noted but there was no mitosis, cytologic features of malignancy, or metastasis. The epithelial nests were positive to various cytokeratins except for CK20 and the lumina of the ductal structures were positive to carcinoembryonic antigen. Our results indicate that microcystic adnexal carcinoma consists of tumor cells capable of both follicular and eccrine differentiation. It is locally aggressive, extends far beyond its clinical presentation and may involve the bone. It may persist and remain asymptomatic for so many years without metastasis. A lifetime postsurgery monitoring is mandatory to ensure early and proper management.

Aged↗
PubMed2006

COX-2 induction by heparanase in the progression of breast cancer.

Breast cancer confined within the lactiferous duct or lobule, without invading the stroma, is called ductal carcinoma in situ (DCIS), whereas breast cancer that has invaded the stroma through the basal membrane is called invasive cancer. Heparanase, an endo-beta-D-glucuronidase that specifically degrades heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM), plays an important role when breast cancer cells breach the basal membrane. Recently, we have reported that heparanase is involved in angiogenesis through direct induction of cyclo-oxygenase-2 (COX-2). COX-2 induces vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and is thus involved in neovascularization. The present study was undertaken to analyze surgically resected breast cancer specimens for heparanase and COX-2 expression, using specimens from 59 patients with invasive cancer and 85 patients with DCIS (including 41 cases of DCIS adjacent to invasive cancer). This study yielded the following results: a) the distribution of heparanase within tumor tissue was identical to that of COX-2; b) heparanase expression was more frequent in invasive cancer than in non-invasive cancer; c) a close positive correlation was noted between heparanase and COX-2 expression (this correlation was particularly strong in cases of invasive cancer); and d) COX-2 expression was always seen in cases positive for heparanase expression. Our results indicate that heparanase expression increases during the progression of breast cancer into invasive cancer, and that this change is accompanied by increased COX-2 expression. They also suggest that heparanase may play a novel role for COX-2 mediated tumor angiogenesis in breast-cancer progression.

Adult↗
PubMed2005

Immunolocalization and distribution patterns of type IV collagen alpha chains in oral mucosal melanoma.

The basement membrane (BM) is mainly composed of type IV collagen, which is composed of triple combinations of six distinct alpha (alpha) chains in a tissue-specific manner. The six collagen chain-specific antibodies (alpha1-alpha6) were used to examine the BMs of the oral epithelium (OE) and tumor clusters in oral mucosal melanoma (OMM). Eight OMM cases were examined. Results showed that the alpha1 and alpha2 chains were constantly detected at the BM of the normal OE as well as at the OE with atypical melanocytic proliferation and in invasive melanoma with nodular nests. The alpha1 and alpha2 chains were intermittently detected in in situ OMM, early invasive OMM and advanced invasive OMM with sheet-like nests. Gradual loss of alpha5 and alpha6 from the OE with atypical melanocyte through in situ OMM and early invasive OMM was observed. These findings suggest that changes in the immunolocalization and distribution patterns of type IV collagen alpha chains are associated with the progression of OMM. The distribution pattern of type IV collagen alpha chain varies depending on the architecture of the nest.

Basement Membrane↗
PubMed2005

Effects of immobilized recombinant human bone morphogenetic protein-2/succinylated type I atelocollagen on cellular activity of ST2 cells.

The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) to induce ectopic bone formation requires a carrier. Type I atelocollagen, a biomaterial with a porous structure, excellent operational features, and biocompatibility, is an effective carrier for rhBMP-2. However, the conventionally used lyophilized rhBMP-2/collagen mixture does not necessarily give adequate bone-induction effect. In the present study, we examined the effect of immobilizing rhBMP-2 to type I atelocollagen on the cellular activity of ST2 cells. The following results were obtained: (1) rhBMP-2 was effectively immobilized to succinylated type I atelocollagen, indicating the usefulness of succinylated type I atelocollagen in immobilization; (2) studies of alkaline phosphatase activity confirmed the effectiveness of rhBMP-2 immobilized on succinylated atelocollagen in augmenting cellular activity.

Alkaline Phosphatase↗
PubMed2005

Identification of a candidate tumor suppressor gene RHOBTB1 located at a novel allelic loss region 10q21 in head and neck cancer.

PURPOSE: Aims of the study are to narrow-down the hotspot region on 10q21 defined by previous genome-wide loss of heterozygosity (LOH) analysis in head and neck squamous cell carcinomas (HNSCC) and to define candidate tumor suppressor genes (TSG) concerned with 10q21. MATERIALS AND METHODS: LOH analysis was carried out with ten polymorphic microsatellite markers. Expression analysis was performed by semi-quantitative RT-PCR, and mutation analysis by PCR and direct sequencing. RESULTS: LOH analysis on 10q21 in 52 HNSCC indicated distinctive and frequent allelic loss at D10S589 (42%). Among flanking genes, we found the RHOBTB1 gene as a candidate TSG, since an intragenic marker demonstrated the highest LOH (44%). Expression analysis revealed down-regulation of RHOBTB1 mRNA in 37% of tumors. Interestingly, all the five tumors that showed decreased expression of RHOBTB1 were accompanied with LOH, supporting the haploinsufficiency and class 2 TSG characteristics of RHOBTB1. No pathogenic mutation of RHOBTB1 was found. Furthermore, another gene within the region, EGR2, was also taken under scope. LOH frequencies around the EGR2 gene were relatively low (23 and 33%). Albeit semi-quantitative expression analysis of EGR2 demonstrated downregulation in 45% of tumor samples, no relation was found between the expression levels and LOH status. CONCLUSION: Frequent allelic loss and decreased expression of RHOBTB1 suggested that this gene has a role in tumorigenesis of a subset of HNSCC.

Base Sequence↗
PubMed2005

Frequent deletion and down-regulation of ING4, a candidate tumor suppressor gene at 12p13, in head and neck squamous cell carcinomas.

We previously showed two members of the ING family, ING1 and ING3 as a tumor suppressor gene in head and neck cancer. Progress in human genome sequencing provided additional information of the new members of the ING family genes. ING4 is localized to chromosome 12p13.31 region and harbors the PHD domain highly homologous among ING family proteins. We analyzed loss of heterozygosity at 12p12-13 region in 50 head and neck squamous cell carcinomas by using six highly polymorphic microsatellite markers and found allelic loss in 66% (33/50) of the informative cases. To clarify the role of ING4 in head and neck carcinogenesis, we first checked mutation status in tumor samples. As mutation of the ING4 gene was not found in head and neck cancers, we examined the mRNA expression level. Quantitative real-time RT-PCR analysis demonstrated decreased expression of ING4 mRNA in 76% of primary tumors as compared with that of matched normal samples. Since p53 dependent pathways of other ING family members have been shown, we examined p53 mutation status and compared with ING4 mRNA expression in tumor samples. However, no such direct relationship has been detected. In conclusion, frequent deletion and decreased mRNA expression of ING4 suggested it as a class two tumor suppressor gene and may play an important role in head and neck cancer.

Carcinoma, Squamous Cell↗