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Biomedical subjects

Hitoshi Kawamata

Publications and source records attributed to Hitoshi Kawamata.

At least 19 recordsLinked to original sources
PubMed2006

Differentiation-inducing therapy for solid tumors.

Treating malignant tumor through the induction of cell differentiation has been an attractive concept, but clinical development of differentiation-inducing agents to treat malignant tumor, especially for solid tumors has been limited to date. Nerve growth factor, all trans retinoic acid, dimethyl sulfoxide, active form vitamin D(3), peroxisome proliferator-activated receptorgamma, 12-0-tetradecanoylphorbol 13-acetate, hexamethylene-bis-acetamide, transforming growth factor-beta, butyric acid, cAMP, and vesnarinone are known to have a differentiation-inducing capability on solid tumors in vitro and/or in vivo. Moreover some of the differentiation-inducing agents have been used for treating patients with solid tumor, but the therapeutic effect of the differentiation-inducing agents on solid tumor is not strong when compared with that of conventional chemotherapeutic agents. However, because most of the differentiation-inducing agents can potentiate the effect of conventional chemotherapy or radiation therapy, combination of differentiation-inducing therapy with conventional chemotherapy or radiation therapy might be used as a second- or third-line therapy in patients with advanced cancer. Furthermore, analysis of the molecular mechanisms of the tumor differentiation therapy might provide selective and targeted molecules for novel cancer therapy.

Animals↗
PubMed2005

Tumor cell dissociation score highly correlates with lymph node metastasis in superficial esophageal carcinoma.

BACKGROUND: It is still not clear which parameters are important for predicting the metastatic potential of superficial esophageal squamous cell carcinoma (SESCC). The purpose of the present paper was thus to investigate tumor cell dissociation (TCD) in SESCC as a predictive factor of lymph node metastasis. METHODS: Thirty-three SESCC were classified into four groups based on the depth of tumor invasion. Carcinomas not invading as far as the muscularis mucosa were classified as group A; carcinomas invading to the muscularis mucosa or less than one-third of the upper submucosa were classified as group B; those invading to the middle layer of the submucosa were classified as group C; and those invading one-third of the lower submucosa were classified as group D. The TCD score was calculated by dividing the length of the TCD region by the maximal longitudinal length of the area of invasion into or beyond the lamina propria, and multiplying by 100. E-cadherin expression of the carcinomas was investigated in the TCD area and the successive area of mucosal invasive carcinoma (SAM). RESULTS: The incidence of lymph node metastasis was 0% in group A, 10% in group B, 36.4% in group C and 57.1% in group D. The mean TCD scores (+/-SEM) of SESCC with lymph node metastasis were higher than that without (85.3 +/- 5.7, 16.3 +/- 3.9, respectively; P < 0.001). In group C, the TCD score of cases with lymph node metastases was higher than in those without lymph node metastasis (P < 0.001). E-cadherin expression was significantly reduced in the area of TCD compared with the SAM located over the TCD area (P < 0.001). CONCLUSIONS: The TCD score is an important predictive marker for lymph node metastasis in SESCC. Clinical evaluation of TCD scores in endoscopic mucosal resection (EMR) specimens would enable accurate prediction of lymph node metastasis and extend the indication of EMR treatment for SESCC.

Aged↗
PubMed2005

Analysis of K-ras mutations and expression of cyclooxygenase-2 and gastrin protein in laterally spreading tumors.

BACKGROUND AND AIM: Recent advances in colonoscopic techniques have led to the increased detection of, and interest in, superficial type colorectal tumors, and a new category, the 'laterally spreading tumor (LST)', has been proposed. However, the characteristics of the genetic alterations in these LSTs have not yet been fully determined. We therefore classified LSTs as LST-granular (LST-G) or LST-non-granular (LST-NG), according to their macroscopic appearance, and examined the genetic alterations in these two tumor groups compared with those in protruded type tumors. METHODS: We obtained a total of 62 colorectal tumors, including 26 protruded type, 17 LST-G and 19 LST-NG, from specimens resected surgically or endoscopically. We examined K-ras codon 12 mutations by using the polymerase chain reaction-restriction fragment length polymorphism method and by fluorescence direct sequencing. We also performed immunohistochemistry to analyze cyclooxygenase (COX)-2 and gastrin abnormalities. RESULTS: The incidence of K-ras mutation was 50.0% in protruded type tumors, 76.5% in LST-G, and 26.3% in LST-NG. The frequencies of COX-2 overexpression were 73.1, 88.2, and 31.6%, respectively, and those of gastrin overexpression were 61.5, 82.4, and 26.3%, respectively. Therefore, LST-G is similar to protruded type tumors in that the incidence of K-ras mutation and the frequencies of COX-2 and gastrin overexpression are high. LST-NG differs from both of these tumor types in that the values of these three indicators are all low. CONCLUSIONS: These results show that LST-G and LST-NG have different genetic alterations.

Colorectal Neoplasms↗
PubMed2005

Histopathological study of small (<2 cm) gastric carcinoma with signet-ring cell component: significance of the admixed glandular components.

Admixture of signet-ring cell carcinoma component (SIG) and glandular component (GC) is sometimes found in a gastric cancer. The aim of this study was to elucidate the biological behavior of the gastric cancer containing either SIG only (SIG-type tumor) or SIG admixed with GC (SIG-GC-type tumor). Forty-three cases of SIG-type tumor and 26 cases of SIG-GC-type tumor, less than 2 cm in largest diameter, were examined. Twenty-six cases (60%) of SIGs were less than 10 mm in size, whereas only 3 cases (12%) of SIG-GCs were less than 10 mm in size (p<0.0001). Submucosal invasion by cancer cells was found in 12 cases of SIG-GCs but was not found in any of the SIGs. Those SIG-GCs showed gastric phenotype. It is important to note SIG-GC-type tumor for histopathological diagnosis.

Adenocarcinoma↗
PubMed2005

PTEN and p53 abnormalities are indicative and predictive factors for endometrial carcinoma.

PTEN (phosphatase and tensin homologue deleted on chromosome 10) and p53 alterations were expected to be diversely involved in endometrial carcinogenesis. Patients (n=92) with endometrial carcinoma (EC) were analyzed, and PTEN and p53 were immunostained in the tissue sections. Tumor histology, grade of differentiation, presence of endometrial hyperplasia, staining status of PTEN and p53 and clinical information were examined. There were 37 cases (40%) negative for PTEN staining, which suggests lost or reduced PTEN function. Loss of PTEN staining was significantly related to the advanced staging in the grade 1 (G1) and grade 2 (G2) endometrioid adenocarcinoma group (p=0.026). Also, 18 cases (20%) showed positive staining for p53. p53 staining was largely found in grade 3 (G3) endometrioid adenocarcinoma and other phenotypes of EC. In the G1 and G2 group, all 29 cases with reduced PTEN staining showed p53-negative staining (p=0.025). In the G3 and others group, 6 of 8 cases with reduced PTEN staining showed p53-positive staining. p53-positive staining was associated with a high probability of tumor recurrence in the G1 and G2 group (p=0.0234). In contrast, in the G3 and others group, p53-positive cases had a low probability of tumor recurrence (p=0.0473). Both PTEN and p53 staining may be good indicators of clinical stage and probability of tumor recurrence in EC. Reciprocal abnormality of p53 or PTEN occurred at an early phase of carcinogenesis, however simultaneous abnormality of p53 and PTEN often occurred at the a late phase of carcinogenesis. Thus, immunohistochemistry for PTEN and p53 in biopsy specimens of EC can provide supportive information for determining a treatment plan.

Adult↗
PubMed2004

Correlations between lymph node metastasis and depth of submucosal invasion in submucosal invasive colorectal carcinoma: a Japanese collaborative study.

BACKGROUND: Depth of submucosal invasion (SM depth) in submucosal invasive colorectal carcinoma (SICC) is considered an important predictive factor for lymph node metastasis. However, no nationwide reports have clarified the relationship between SM depth and rate of lymph node metastasis. Our aim was to investigate the correlations between lymph node metastasis and SM depth in SICC. METHODS: SM depth was measured for 865 SICCs that were surgically resected at six institutions throughout Japan. For pedunculated SICC, the level 2 line according to Haggitt's classification was used as baseline and the SM depth was measured from this baseline to the deepest portion in the submucosa. When the deepest portion of invasion was limited to above the baseline, the case was defined as a head invasion. For nonpedunculated SICC, when the muscularis mucosae could be identified, the muscularis mucosae was used as baseline and the vertical distance from this line to the deepest portion of invasion represented SM depth. When the muscularis mucosae could not be identified due to carcinomatous invasion, the superficial aspect of the SICC was used as baseline, and the vertical distance from this line to the deepest portion was determined. RESULTS: For pedunculated SICC, rate of lymph node metastasis was 0% in head invasion cases and stalk invasion cases with SM depth <3000 micro m if lymphatic invasion was negative. For nonpedunculated SICC, rate of lymph node metastasis was also 0% if SM depth was <1000 micro m. CONCLUSIONS: These results clarified rates of lymph node metastasis in SICC according to SM depth, and may contribute to defining therapeutic strategies for SICC.

Adult↗
PubMed2004

Clear cell adenocarcinoma of the tongue.

A firm, ulcerated tumor formed on the left side of the tongue of an elderly woman. Histopathological analysis showed that this unusual neoplasm was composed of monomorphic polygonal cells that exhibited a clear cytoplasm containing large amounts of periodic acid Schiff (PAS)-positive, diastase-digestive material. Most of the tumor cells stained immunohistochemically for Cytokeratin, high-molecular, CAM5.2, and epithelial membrane antigen (EMA), but were negative for alpha-smooth muscle actin, vimentin, glial fibrillary acid protein (GFAP), and S-100 protein. These findings supported a diagnosis of clear cell adenocarcinoma. Although patients with this type of tumor generally have a favorable prognosis, the tumor in our patient was fast-growing and contained a large number of Ki-67 positive cells, which are known to be highly proliferative. Thus, this case highlights the fact that even clear cell adenocarcinomas that are usually slow-growing should be investigated by conventional morphological techniques and their proliferative activity quantified in order to select the most appropriate treatment strategy.

Adenocarcinoma, Clear Cell↗
PubMed2004

Phenotypic switch from paracrine to autocrine role of hepatocyte growth factor in an androgen-independent human prostatic carcinoma cell line, CWR22R.

Support mechanisms involved in growth of androgen-independent prostate cancer are primarily unknown. Hepatocyte growth factor (HGF)/Met has been suggested to be one of them based primarily on immunohistochemical studies. We conducted a series of experiments to assess the role of the HGF/Met system in an androgen-dependent human prostate carcinoma, CWR22 and its androgen-independent derivative, CWR22R. We found that action of HGF changed from paracrine to autocrine in progression to androgen-independent state. CWR22 tumors did not express HGF but expressed Met, whereas prostate stromal cells expressed HGF at a high level. Growth of CWR22 was stimulated either by addition of HGF to the culture or by the presence of prostate stromal cells. On the other hand, CWR22R cells expressed both HGF and Met. Knockdown of Met expression by RNA interference method suppressed the growth of CWR22R cells. Our data suggest that HGF is intimately involved in growth of human prostate cancer and that progression from the androgen-dependent to the androgen-independent state is associated with an adaptive switch in support mechanism from paracrine to autocrine. Our data offer one mechanism to account for androgen-independent human cancer growth.

Androgens↗
PubMed2004

Troglitazone inhibits the progression of chronic pancreatitis and the profibrogenic activity of pancreatic stellate cells via a PPARgamma-independent mechanism.

We have previously reported that troglitazone inhibits proinflammatory cytokine production in chronic pancreatitis. In the present study, we show that troglitazone prevents the progression of chronic pancreatitis by inhibiting the proliferation of pancreatic stellate cells (PSCs) via a PPARgamma-independent mechanism. WBN/Kob rats with spontaneous chronic pancreatitis were fed troglitazone-containing rat chow for 3 or 6 months. Pancreatic fibrosis and expression of alpha-SMA were markedly attenuated by troglitazone. Rat PSCs expressed a higher level of PPARgamma1 mRNA than of PPARgamma2 mRNA. PSCs were transiently cotransfected with a dominant negative mutant PPARgamma1 and a PPAR-driven reporter gene. Troglitazone increased reporter activity and the mutant receptor abrogated wild-type receptor activity in a dose-dependent manner. Troglitazone inhibited cell proliferation by blocking cell-cycle progression beyond the G1 phase. These effects were observed in mutant receptor-transfected cells as well as cells transfected with the control vector. The effect of troglitazone on alpha1(I) procollagen mRNA and MCP-1 mRNA was unaffected by inhibition of endogenous PPARgamma1 receptor activity. These results suggest that troglitazone may serve as novel therapeutic agent for the treatment of chronic pancreatitis. The antifibrotic effect of troglitazone appears to be mediated, in part, via a PPARgamma-independent mechanism.

Actins↗
PubMed2004

Basic and clinical studies on quantitative analysis of lymph node micrometastasis in oral cancer.

Metastasis to cervical lymph nodes (LN) is significantly associated with the outcome of patients with oral cancer. To provide a useful method for the detection of micrometastases, we analyzed 115 LNs from 10 patients with oral cancer using real-time quantitative polymerase chain reaction (PCR) based on the expression of squamous cell carcinoma antigen (SCCA) and cytokeratin 13 (CK13). The sensitivity and quantification of this method were assessed by means of limited dilution of cultured oral cancer cells and a model of cervical LN-metastasis established by inoculating green fluorescent protein (GFP)-expressing cells into the tongue of nude mice. In both investigations, a few cancer cells were detected by real-time quantitative PCR, but not by conventional reverse transcription-PCR (RT-PCR). SCCA mRNA was detected at high levels in metastatic LNs. In contrast, 26 of the 30 control cervical LNs did not express the gene at all, and the rest showed fairly low levels. Of 108 histologically metastasis-negative LNs, 19 (17.6%) expressed SCCA mRNA levels higher than the cut-off value (1.0: mean expression of control LNs + 2SD). CK13 mRNA is not a suitable marker for the real-time PCR since it was detected frequently even in the control LNs. These findings suggest that genetic diagnosis by real-time quantitative PCR based on SCCA mRNA expression may be clinically useful for detecting occult tumor cells in cervical LNs.

Animals↗
PubMed2004

Inhibitory effects of etodolac, a selective COX-2 inhibitor, on the occurrence of tumors in colitis-induced tumorigenesis model in rats.

Ulcerative colitis (UC)-associated neoplasia is one of the complications seen in patients with long-standing UC. Based on many epidemiological studies, colitis is assumed to promote colon tumorigenesis. Tumorigenesis is known to be suppressed in rodents and humans by selective cyclooxygenase-2 inhibitors. However, whether these drugs would serve as protective agents against UC-associated neoplasia remains unclear. Therefore, using a colitis-induced tumorigenesis rat model, we investigated the effects of etodolac, a selective cyclooxygenase-2 inhibitor, on tumorigenesis. The following 4 groups were examined: group A, administered trinitrobenzene sulfonic acid and 1,2-dimethylhydrazine; group B, in addition to the treatment in group A, also received etodolac; group C, administered etodolac alone; and group D, did not receive any agent throughout the study and served as an untreated control. The rats were sacrificed 163 days after the start of experiment, and the number of aberrant crypt foci and tumors in the intestine were counted using a stereoscopic microscope following methylene blue staining. The mean number of aberrant crypt foci was 52.4 in group A, 18.9 in group B, 0 in group C and 0.5 in group D. A total of 9 tumors were observed in group A alone, with none in the remaining groups. The numbers of aberrant crypt foci and tumors in group B were significantly lower than in group A. Etodolac, a selective cyclooxygenase-2 inhibitor, suppresses the occurrence of aberrant crypt foci and tumors in colitis-induced tumorigenesis in rats.

Animals↗
PubMed2004

Dysfunction of p53 pathway in human colorectal cancer: analysis of p53 gene mutation and the expression of the p53-associated factors p14ARF, p33ING1, p21WAF1 and MDM2.

Mutations of p53 tumor suppressor gene increase with tumor progression in colorectal cancers. In this study, we examined the expressions of p33ING1, p14ARF, MDM2 and p21WAF1 mRNA in 25 advanced colorectal cancers by quantitative RT-PCR method, and compared the expression levels of p33ING1, p14ARF, p21WAF1 and MDM2 in relation to p53 status in the tumors. Fifteen of 25 colorectal cancers (60%) showed abnormal accumulation of p53 protein in the nucleus, and the remaining 10 colorectal cancers (40%) were negative for p53 immunostaining. We found a G --> T transition (nonsense mutation) at the first nucleotide of codon 298 (exon 8) in one p53-negative case, and a frame shift mutation on exon 7 in another p53-negative case. In remaining eight p53-negative cases, there was no mutation in the entire open reading frame of p53 cDNA. Interestingly, in eight cases with p53 wild-type gene, 6 cases (75%) showed a marked down-regulation of p14ARF mRNA, and three cases (37.5%) over-expressed MDM2 mRNA. Only one case with wild-type p53 gene showed normal level expression of p53 regulatory-factors (p33ING1, p14ARF, and MDM2). Thus, p53 tumor suppressor pathway was disrupted in 24 of 25 colorectal cancers (96%).

Aged↗
PubMed2003

Possible role of stromal-cell-derived factor-1/CXCR4 signaling on lymph node metastasis of oral squamous cell carcinoma.

We examined the role of chemokine signaling on the lymph node metastasis of oral squamous cell carcinoma (SCC) using lymph node metastatic (HNt and B88) and nonmetastatic oral SCC cells. Of 13 kinds of chemokine receptors examined, only CXCR4 expression was up-regulated in HNt and B88 cells. CXCR4 ligand, stromal-cell-derived factor-1alpha (SDF-1alpha; CXCL12), induced characteristic calcium fluxes and chemotaxis only in CXCR4-expressing cells. CXCR4 expression in metastatic cancer tissue was significantly higher than that in nonmetastatic cancer tissue or normal gingiva. Although SDF-1alpha was undetectable in either oral SCC or normal epithelial cells, submandibular lymph nodes expressed the SDF-1alpha protein, mainly in the stromal cells, but occasionally in metastatic cancer cells. The conditioned medium from lymphatic stromal cells promoted the chemotaxis of B88 cells, which was blocked by the CXCR4 neutralization. SDF-1alpha rapidly activated extracellular signal-regulated kinase (ERK)1/2 and Akt/protein kinase B (PKB), and their synthetic inhibitors attenuated the chemotaxis by SDF-1alpha. SDF-1alpha also activated Src family kinases (SFKs), and its inhibitor PP1 diminished the SDF-1alpha-induced chemotaxis and activation of both ERK1/2 and Akt/PKB. These results indicate that SDF-1/CXCR4 signaling may be involved in the establishment of lymph node metastasis in oral SCC via activation of both ERK1/2 and Akt/PKB induced by SFKs.

Animals↗
PubMed2003

Posttranscriptional regulation of TSC-22 (TGF-beta-stimulated clone-22) gene by TGF-beta 1.

TSC-22 gene was composed of three exons and its length was approximately 5.5 kb including 2.9 kb promoter region. The transcription starting site was located at 7 and 29 bp downstream from TATA box. Promoter analysis revealed that 2146 bp of TSC-22 promoter was activated by several differentiation inducing drugs. Although originally TSC-22 was isolated as a TGF-beta-inducible gene, TSC-22 promoter was not activated by the enhanced TGF-beta signaling. We found 3 copies of the Shaw-Kamens sequence (AUUUA) in the human TSC-22 mRNA 3'-UTR and identified three proteins (40, 20, and 15 kDa) which bound to this. Only the 40 kDa protein-RNA complex was decreased by treatment with TGF-beta 1. Moreover, the TSC-22 mRNA 3'-UTR destabilized the heterologous luciferase mRNA, but the destabilization was recovered with TGF-beta 1. These observations suggest that up-regulation of TSC-22 mRNA by TGF-beta 1 is achieved by mRNA stabilization, but not by transcriptional activation.

3' Untranslated Regions↗
PubMed2003

Extranodal diffuse follicular center lymphoma mimicking mantle cell lymphoma of the intestine.

We report a case of diffuse follicular center lymphoma (FCL), which is a morphological variant of follicular lymphoma, resembling multiple lymphomatous polyposis (mantle cell lymphoma of the intestine). The patient was a 48-year-old Japanese man who was found, by colonoscopy, to have numerous small polypoid lesions along the entire large intestine. Abdominal computed tomography revealed hepatosplenomegaly and enlargement of multiple mesenteric lymph nodes. Histologically, the lesion was characterized by diffuse proliferation of small- to medium-sized lymphocytes with cleaved nuclei in the mucosa and submucosa. Immunohistochemical studies showed that the tumor cells were CD20+, CD10+, BCL-2+, CD5-, surface IgM-, and cyclin D1-. Moreover, a cytogenetic study showed a translocation at (14;18)(q32;q21). Finally, this case was diagnosed as diffuse FCL, although the tumor was mimicking mantle cell lymphoma.

Chromosomes, Human, Pair 14↗