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Biomedical subjects

Tomoki Sumida

Publications and source records attributed to Tomoki Sumida.

9 recordsLinked to original sources
PubMed2004

Reduction of human metastatic breast cancer cell aggressiveness on introduction of either form a or B of the progesterone receptor and then treatment with progestins.

The sex steroid hormone progesterone (Pg) is critically involved in the development of the mammary gland, and it also is thought to play a role in breast cancer progression. However, the effect of Pg on malignant phenotypes is not fully understood in breast cancer. We previously reported that in Pg receptor (PR)-positive T47D breast cancer cells, Pg was able to counterbalance the stimulatory effect of estrogen or serum on proliferation and on expression level of Id-1, which generally stimulates cell proliferation and inhibits differentiation. Conversely, metastatic MDA-MB231 breast cancer cells lack PR and express high levels of Id-1 constitutively, and Pg showed no effect on Id expression, proliferation, and invasion in these cells. However, after introducing PR (either PR-A or PR-B) into MDA-MB231 cells, Pg inhibited the expression of Id-1 mRNA drastically. PR-transfected MDA-MB231 cells exhibited less proliferative activity after Pg treatment than parental or control MDA-MB231 cells, an effect which correlated well with reduction of Id-1 mRNA. This inhibitory effect on proliferation was accompanied by p21 up-regulation and c-myc down-regulation. Moreover, Pg-treated PR transfectants showed significant morphologic change, appearing more flattened and spread out than control ethanol-treated cells. Boyden chamber invasion assay revealed that PR-transfected MDA-MB231 cells also lost most of their invasive properties after Pg treatment. Zymographic analysis revealed that Pg drastically inhibited matrix metalloproteinase-9 (MMP-9) activity in cells transfected with either PR-A or PR-B. To determine whether Id-1 could act as a key mediator of the effects of Pg, we prepared cells transfected with Id-1 and PR. The morphologic change and p21 up-regulation still were observed after Pg treatment. However, c-myc down-regulation was not observed; the proliferative and invasive activities were mostly recovered; and MMP-9 down-regulation could not be detected anymore. From these observations, we conclude that either form of the PR is sufficient to reduce the malignant phenotypes on treatment with Pg and that Id-1 plays an important role as a mediator of the effects of Pg on breast cancer cell proliferation and invasion.

Breast Neoplasms↗
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↗
PubMed2003

Role of Id-2 in the maintenance of a differentiated and noninvasive phenotype in breast cancer cells.

Id proteins are inhibitors of basic helix-loop-helix transcription factors and generally stimulate cell proliferation and inhibit differentiation. We have shown that ectopic expression of Id-1 in murine mammary epithelial cells resulted in loss of differentiation and gain of invasive and proliferative abilities. Moreover, Id-1 was highly expressed in aggressive breast cancer cells in culture and in biopsies from infiltrating carcinomas. In contrast to Id-1, we found that, in vitro and in vivo, Id-2 mRNA and protein were up-regulated as mammary epithelial cells lost proliferative capacity and initiated differentiation. We further determined that this up-regulation of Id-2 was a necessary step toward a fully differentiated phenotype in breast cells. Here we show that one of the components of the extracellular matrix network, laminin, is responsible for the increase in Id-2 expression during differentiation. We also show that Id-2 expression is inversely correlated with the rate of proliferation in murine mammary epithelial cells and that Id-2 is expressed at a higher level in differentiated human breast cancer cells in comparison with very aggressive and metastatic cells. When reintroduced in aggressive breast cancer cells, Id-2 is able to reduce their proliferative and invasive phenotypes and decrease their level of matrix metalloproteinase 9 secretion as well as increase syndecan-1 expression. Moreover, little Id-2 protein expression is detectable in human biopsies from aggressive and invasive carcinomas in comparison with in situ carcinomas. In conclusion, Id-2 expression not only follows a pattern opposite to that of Id-1 during mammary gland development and breast cancer progression but also appears to act as an important protein for the maintenance of a differentiated and noninvasive phenotype in normal and transformed breast cells.

Animals↗
PubMed2003

Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis.

Mammary epithelial cells constitutively expressing Id-1 protein are unable to differentiate, acquire the ability to proliferate, and invade the extracellular matrix. In addition, Id-1 is aberrantly over-expressed in aggressive and metastatic breast cancer cells, as well as in human breast tumor biopsies from infiltrating carcinomas, suggesting Id-1 might be an important regulator of breast cancer progression. We show that human metastatic breast cancer cells become significantly less invasive in vitro and less metastatic in vivo when Id-1 is down-regulated by stable transduction with antisense Id-1. Expression of the matrix metalloproteinase MT1-MMP is decreased in proportion to the decrease in Id-1 protein levels, representing a potential mechanism for the reduction of invasiveness. Further, to more accurately recapitulate the biology of and potential therapeutic approaches to tumor metastasis, we targeted Id-1 expression systemically in tumor-bearing mice by using a nonviral approach. We demonstrate significant reduction of both Id-1 and MT1-MMP expressions as well as the metastatic spread of 4T1 breast cancer cells in syngeneic BALB/c mice. In conclusion, our studies have identified Id-1 as a critical regulator of breast cancer progression and suggest the feasibility of developing novel therapeutic approaches to target Id-1 expression to reduce breast cancer metastasis in humans.

Animals↗
PubMed2003

Helix-loop-helix proteins in mammary gland development and breast cancer.

The basic helix-loop-helix (bHLH) family of transcription factors functions in the coordinated regulation of gene expression, cell lineage commitment, and cell differentiation in most mammalian tissues. Helix-loop-helix Id (Inhibitor of DNA binding) proteins are distinct from bHLH transcription factors in that they lack the basic domain necessary for DNA binding. Id proteins thus function as dominant negative regulators of bHLH transcription factors. The inhibition of bHLH factor activity by forced constitutive expression of Id proteins is closely associated with the inhibition of differentiation in a number of different cell types, including mammary epithelial cells. Moreover, recent literature suggests important roles of HLH proteins in many normal and transformed tissues, including mammary gland. Therefore, future directions for prognosis or therapeutic treatments of breast cancer may be able to exploit bHLH and Id genes as useful molecular targets. The purpose of this review is to summarize the evidence implicating HLH proteins in the regulation of normal and transformed mammary epithelial cell phenotypes.

Animals↗
PubMed2003

Enhancement of radiosensitivity in head and neck cancer cells by ZD1839 ('IRESSA'), a selective epidermal growth factor receptor tyrosine kinase inhibitor.

Overexpression of epidermal growth factor receptor (EGFR) is frequently observed in many solid tumor types, including head and neck squamous cell carcinomas (HNSCC). Recent laboratory experiments have demonstrated that high EGFR levels correlate with increased tumor resistance to radiation. This study investigated the relationship between EGFR expression levels and radiosensitivity in 5 HNSCC cell lines (HSC2, HSC3, HSC4, SCC25, and Ca9-22) and whether treatment with ZD1839 ('Iressa'), a selective EGFR-tyrosine kinase inhibitor (TKI), would improve tumor cell response to radiotherapy. ZD1839 suppressed the growth of HNSCC cell lines in a dose- and time-dependent manner. Radiosensitivity of these HNSCC cell lines, assessed by a clonogenic survival assay, differed greatly and the expression of EGFR varied. EGFR expression levels (EGFR numbers/cell) correlated with increased tumor resistance to radiation (f[x]= 4.54 X, R2 = 0.715; f[x]: EGFR numbers/cell, X: radiosensitivity; D10). Following exposure of the HNSCC cells to 1.0 microM ZD1839 and radiation (0-10 Gy), greater than additive growth inhibitory effects were observed. These results suggest that ZD1839 could enhance tumor radiosensitivity and inhibit tumor growth after radiation, indicating that this combination could have clinical potential in the treatment of patients with head and neck cancer.

Antineoplastic Agents↗
PubMed2003

Detection of circulating cancer cells in human oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) cells can invade adjacent tissues and the vascular system at an early stage of tumor progression. In the present study, we have attempted to detect circulating cancer cells. We used human OSCC cells expressing green fluorescent protein (GFP) in an orthotopic nude mouse model and were able to detect GFP-expressing cells using a fluorescence activated cell sorter and fluorescence microscopy. We also detected the expression of GFP, squamous cell carcinoma antigen (SCCA), or epidermal growth factor receptor (EGFR) mRNA in the blood of tumor-bearing mice by conventional reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time quantitative RT-PCR (TaqMan RT-PCR). TaqMan RT-PCR was the more sensitive method to detect the circulating cancer cells. Furthermore, we examined the expression of SCCA and EGFR mRNA in the peripheral blood of patients with OSCC by conventional RT-PCR and TaqMan RT-PCR. We detected SCCA and EGFR mRNA in few cases by conventional RT-PCR, whereas TaqMan RT-PCR showed their expression in about 50% of cases. However, there was no correlation between detection of circulating viable cancer cells and metastasis to lymph nodes and distant organs. These results suggest that TaqMan RT-PCR is a very useful method and both SCCA and EGFR mRNA may be available as a marker for detection of circulating cancer cells.

Animals↗
PubMedDate not supplied

Surface osteosarcoma: 2 case reports.

Surface osteosarcoma of the jaw bone is extremely rare, and it differs from the central type in its clinicopathologic features. This type of osteosarcoma generally shows low-grade malignancy, grows slowly, metastasizes less often, and the prognosis is better than that of the central type. We report 2 cases of surface osteosarcoma of the jaw bone, and discuss some clinical important issues.

Adolescent↗