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H Yukiue,
H Sasaki,
Y Kobayashi, Y Nakashima,
S Moriyama,
M Yano,
M Kaji,
M Kiriyama,
I Fukai,
Y Yamakawa,
Y Fujii
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ABSTRACT: Matrix metalloproteinases (MMPs) are proteolytic enzymes which degrade extracellular matrix and basement membrane. There is much evidence that their increased expression is correlated with tumor aggressiveness in various carcinomas. Tissue inhibitor of metalloproteinases (TIMPs) are the specific inhibitors of MMPs. MMPs and TIMPs are considered to play an important role in carcinoma invasion and metastasis. We hypothesized that MMPs and TIMPs also play an important role in thymoma.
This study included 34 thymoma cases. The mRNA levels of MMP-1, -7, and -9, TIMP-1 and -2, and GAPDH were quantified by real-time polymerase chain reaction using LightCycler. We also performed immunohistochemistry for TIMP-1.
The TIMP-1/GAPDH mRNA expression level was significantly higher in invasive (stage II-IV) thymomas (means +/- SE, 81.4 +/- 28.1) than in noninvasive (stage I) thymomas (30.9 +/- 8.3, P = 0.026). The MMP-1/GAPDH mRNA expression level was also higher in invasive thymomas (19.7 +/- 7.5) than in non invasive thymomas (2.26 +/- 1.72, P = 0.020). Immunopositivity of TIMP-1 was localized in stromal cells adjacent to the advancing margin of the tumor.
These findings suggest that TIMPs and MMPs play an important role in the invasion of thymoma.
Journal of Surgical Research 03/2003; 109(2):86-91. · 2.25 Impact Factor
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Y Nakashima,
M Yano,
Y Kobayashi,
S Moriyama,
H Sasaki,
T Toyama,
H Yamashita,
I Fukai,
H Iwase,
Y Yamakawa,
Y Fujii
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ABSTRACT: Tumors require ongoing angiogenesis to support their growth. Inhibition of angiogenesis by production of antiangiogenic factors should be a viable approach for cancer gene therapy. In this study, we investigated whether intravenous administration of endostatin gene complexed with a cationic vector (GL67/DOPE or PEI22K) could inhibit the development of lung tumors in mice injected i.v. with NFSa Y83 fibrosarcoma cells (5 x 10(5)) which frequently form lung metastasis. mRNA and protein of the transfected gene were produced in the lung and other organs of the transfected mice as assessed by immunohistochemistry, Western blotting and reverse transcription-polymerase chain reaction. Single intravenous injection of the endostatin gene (60 microg) complexed with either GL67/DOPE or PEI22K on day 3 or day 7 after fibrosarcoma cell inoculation significantly inhibited tumor formation in the lung as evidenced by the reduced number of lung tumors and lung weight, and prolonged survival of the endostatin gene-transfected mice compared with control mice. These findings suggested that the endostatin gene therapy, using cationic vector-mediated intravenous gene transfer, might be a feasible strategy for organ-targeted prevention and regulation of possible disseminated cancers.
Gene Therapy 02/2003; 10(2):123-30. · 3.71 Impact Factor
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ABSTRACT: The MTA1 gene is a recently identified metastasis-associated gene which has been implicated in the signal transduction or regulation of gene expression. We examined the mRNA expression levels of the MTA1, the human homologue of the rat mta1 gene in thymoma. Expression of MTA1 mRNA was evaluated by reverse transcription polymerase chain reaction (RT-PCR) in 30 thymoma samples using LightCycler. The data was analyzed in reference to clinicopathological data. There was no relationship between MTA1 gene expression and age and gender. MTA1/GAPDH mRNA level in stage IV thymoma (6.431+/-3.404) was significantly higher than the level in stage I thymoma (2.592+/-1.902, P=0.0081). There was a tendency towards higher MTA1/GAPDH mRNA level in stage IV thymoma when compared to stage II thymoma (3.746+/-3.292, P=0.072). Thus our results show that the expression of the MTA1 gene is closely related to invasiveness in thymoma. The gene MTA1 could potentially provide information on the mechanism of tumor invasion and metastasis.
Cancer Letters 01/2002; 174(2):159-63. · 4.24 Impact Factor
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ABSTRACT: Matrix metalloproteinase-7 (MMP-7) is a member of the MMP family and has a wide variety of substrate spectra. Ets domain transcription factors are reported to play an important role in carcinoma invasion and metastasis. The regulatory role of Ets-1 has been shown in several MMPs. We have hypothesized that MMP-7 and Ets-1 mRNA levels could be predictors of the development and invasion of lung cancer.
The study included 73 lung cancer cases. The mRNA levels were quantified by real-time reverse transcription-polymerase chain reaction (RT-PCR) using a LightCycler.
No significant difference in MMP-7 and Ets-1 mRNA levels was found among gender, age, and pathological subtype. The MMP-7 mRNA levels were elevated in tumor tissues from stage II-IV lung cancer (1.629 +/- 2.267) compared to those from stage I lung cancer (0.762 +/- 1.463) (P = 0.0290). There was a tendency toward higher MMP-7 mRNA expression levels in tumors with lymph node metastasis (1.728 +/- 2.432) compared to those without lymph node metastasis (1.141 +/- 1.838) (P = 0.1076). Thus, MMP-7 mRNA levels may serve as a marker of higher stages in lung cancer. No significant difference in Ets-1 mRNA levels was found among clinical stages and T-status. The Ets-1 mRNA levels were elevated in tumors from N2 patients (7.512 +/- 13.306) compared to those from N0 patients (2.525 +/- 4.719) (P = 0.0209). Ets-1 mRNA levels showed a positive correlation with MMP-7 expression (P = 0.0042).
Using the LightCycler RT-PCR assay, the determination of MMP-7 and Ets-1 mRNA levels might provide a potential marker for advanced lung cancer. However, further studies and a longer follow-up are needed to confirm the impact of MMP-7 in the biological behavior of the tumor.
Journal of Surgical Research 01/2002; 101(2):242-7. · 2.25 Impact Factor
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ABSTRACT: There is an evidence to suggest that cdc25B phosphatase is an oncogenic. We hypothesized that cdc25B gene may be expressed in tumors of patients with non-small cell lung cancer (NSCLC) and affect their clinical outcome. Expression of cdc25B messenger RNA was evaluated by reverse transcription polymerase chain reaction in 55 non-small cell lung carcinomas and adjacent histological normal lung samples using LightCycler. The data was analyzed in reference to clinicopathological data and survival data. There was no difference of cdc25B expression level between the NSCLC tissue and normal lung tissue. There was no relationship between cdc25B gene expression and age, gender, N or T-status and clinical stage. However, the NSCLC patients with high cdc25B expression had significantly poor survival than the patients with low cdc25B expression (P=0.0173). Thus we suggest that cdc25B may predict poor survival.
Cancer Letters 12/2001; 173(2):187-92. · 4.24 Impact Factor
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ABSTRACT: Inhibition of programmed cell death (apoptosis) is associated with increased tumor aggressiveness. We hypothesized that a novel sensitive to apoptosis gene, SAG, may be expressed in tumors of patients with nonsmall cell lung cancer (NSCLC) and may affect their clinical outcome. Expression of SAG messenger RNA was evaluated by reverse transcription polymerase chain reaction in 80 nonsmall cell lung carcinomas and 65 adjacent histologic nonmalignant lung samples using a LightCycler. The data were analyzed in reference to clinicopathologic data and survival. The SAG/GAPDH mRNA level in 80 NSCLC was 2.337 +/- 1.972. Of 65 paired NSCLC and nonmalignant lung samples, SAG/GAPDH mRNA levels were 2.313 +/- 2.064 and 1.696 +/- 1.910, respectively. The SAG mRNA level was significantly higher in NSCLC compared with nonmalignant lung tissue (p = 0.0169). There was no relationship between SAG gene expression and age, gender, T- or N-status or clinical stages. The NSCLC patients with high SAG/GAPDH expression (>1.8) had significantly poorer survival than the patients with low SAG/GAPDH expression (<1.8, p = 0.0227). Thus we suggest that SAG gene expression in NSCLC may be a useful prognostic marker.
International Journal of Cancer 12/2001; 95(6):375-7. · 5.44 Impact Factor
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ABSTRACT: In a tumor, increased deubiquitination of cyclins by a protein gene product gene, PGP9.5, could contribute to the uncontrolled growth of somatic cells that is a hallmark of cancer. We hypothesized that PGP9.5 may be expressed in tumors of patients with non-small cell lung cancer (NSCLC).
Expression of PGP9.5 messenger RNA was evaluated by reverse transcription polymerase chain reaction (RT-PCR) in 95 non-small cell lung carcinomas and adjacent histological normal lung samples. The data were analyzed with reference to clinicopathological factors.
PGP9.5 transcripts were detected in 18 (12.8%) of the tumor samples, although some of paired normal lung samples showed very weak expression. There was no relationship between PGP9.5 gene expression and age, gender, N-status or pathological subtype. PGP9.5 gene was preferentially expressed in T3/T4 NSCLC (12/41, 29.3%) compared with T1/T2 NSCLC (6/54, 11.1%) (p = 0.0482).
Although the PGP9.5 gene was not expressed in a majority of NSCLC tumors, we suggest that PGP9.5 may correlate with tumor invasion or progression of NSCLC.
Japanese Journal of Clinical Oncology 12/2001; 31(11):532-5. · 1.78 Impact Factor
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ABSTRACT: Inhibition of programmed cell death (apoptosis) is associated with increased tumor aggressiveness. We hypothesized that a novel apoptosis inhibitor gene, antiapoptosis clone 11 (AAC-11), may be expressed in tumors of patients with non-small cell lung cancer (NSCLC) and affect their clinical outcome. Expression of AAC-11 messenger RNA was evaluated by reverse transcription polymerase chain reaction (RT-PCR) in 94 non-small cell lung carcinomas and adjacent histologically normal lung samples. The data was analyzed in reference to clinicopathological and survival data. AAC-11 transcripts were detected in 12 (12.7%) of the tumor samples, although five of paired normal lung samples showed very weak expression. There was no relationship between AAC-11 gene expression and age, gender, N or T-status. AAC-11 was preferentially expressed in squamous cell carcinoma (26.9% of squamous cell carcinoma vs. 7% of adenocarcinoma). The NSCLC patients with AAC-11 expression had significantly poor survival than the patients without AAC-11 expression (P=0.0360). Although the AAC-11 gene was not expressed in a majority of NSCLC tumors, we suggest that AAC-11 may predict poor survival.
Lung Cancer 11/2001; 34(1):53-7. · 3.43 Impact Factor
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ABSTRACT: We used our palindromic polymerase chain reaction (PCR)-driven cDNA differential display technique to identify and isolate a gene, designated periostin, from cancer tissues and found it to be overexpressed in several human tumors. We attempted to determine the influence of periostin expression on clinical outcome in patients with non-small cell lung cancer (NSCLC) by reverse transcriptase (RT)-PCR analysis. Periostin gene was highly expressed at the tumor periphery of lung cancer tissue but not within the tumor by in situ RNA hybridization, suggesting that expression of periostin may be involved in the process of tumor invasion. Periostin transcripts were detected in 50 (49.0%) of the tumor samples, although some paired normal lung samples showed weak expression. There was no relationship between periostin gene expression and gender, N- or T-status. The NSCLC patients with periostin expression had significantly poorer survival than the patients without periostin expression (P = 0.0338).
Japanese journal of cancer research: Gann 09/2001; 92(8):869-73.
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ABSTRACT: In lung ischemia-reperfusion injury, neutrophil migration from the vasculature to the interstitial spaces plays a major role in tissue injury. Degradation of the basement membrane, which is composed of extracellular matrix (ECM) molecules, is necessary for neutrophil migration. Matrix metalloproteinases (MMPs) might play a role in ECM degradation in lung ischemia-reperfusion injury. We evaluated the changes in the activity of MMP-2 and MMP-9, and tissue inhibitor of metalloproteinase 1 (TIMP-1) gene expressions using rat lung transplantation models.
We divided animals into 4 groups. Groups I and II served as control groups with intact lungs (Group I) and 24-hour cold-preserved lungs (Group II). Groups III and IV received lung grafts after 24-hour cold preservation. The recipient animals were sacrificed 1 hour (Group III) or 24 hours (Group IV) after transplantation. We evaluated lung injury histologically. We assessed MMP activity using zymography. We assessed MMP-2, MMP-9, and TIMP-1 gene expression using biplex reverse transcriptase-polymerase chain reaction method.
In Groups III and IV, we noted severe ischemia-reperfusion injury. We noted no significant difference in enzyme activity and gene expression of MMP-2 between Groups I and IV. The MMP-9 activity and gene expression were low during ischemia and increased on reperfusion. TIMP-1 gene expression was low during ischemia and at the early phase of reperfusion, and showed a dramatic increase at the late phase of reperfusion.
Matrix metalloproteinase 9, but not MMP-2, may play an important role in ischemia-reperfusion injury. TIMP-1 increases at the late phase of reperfusion and may compensate for the activity of MMP-9.
The Journal of Heart and Lung Transplantation 07/2001; 20(6):679-86. · 4.33 Impact Factor
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ABSTRACT: Neovascularization, an essential event for the growth of solid tumors, is regulated by a number of angiogenic factors, among which vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are considered to exert potent angiogenic activity. In this study, we investigated whether serum VEGF and bFGF levels could be predictors of the development and extension of thymic epithelial neoplasms. The subjects of this study were 37 patients with thymoma, 6 with thymic carcinoma, and 23 healthy volunteers. Serum samples were collected before clinical treatment. Serum VEGF levels were significantly (P < 0.05) elevated in the patients with thymic carcinoma (1,080 +/- 1,185pg/ml) compared with those in the healthy volunteers (407 +/- 589 microg/ml). Serum bFGF levels were also significantly (P < 0.05) elevated in the patients with thymic carcinoma (2740 +/- 631 pg/ml) compared with those in the healthy volunteers (1728 +/- 1,192 pg/ml). However, the serum VEGF and bFGF levels did not significantly differ between the patients with thymoma and the healthy volunteers. Serum VEGF and bFGF levels did not significantly differ according to the stage and pathological subtype of thymoma. Moreover, there was no correlation between the serum levels of VEGF and those of bFGF. Thus, while serum VEGF and bFGF levels may serve as markers for thymic epithelial tumors, it is unlikely that circulating VEGF and bFGF could be used as markers for assessing the progression of thymoma tumors.
Surgery Today 02/2001; 31(11):1038-40. · 1.22 Impact Factor
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ABSTRACT: A new staging system for lung cancer was proposed by the Union Internationale Contre le Cancer in 1997, with Stages I and II subdivided and T3N0M0 assigned as stage IIB. We studied the usefulness of this new classification.
Subjects were 753 patients with non-small-cell lung cancer undergoing pulmonary resection and follow-up data were retrospectively reviewed.
A significant difference was seen between stage IA and IB survival--70.4% vs 52%. No significant difference was seen between survival for T3N0M0, T1N1M0 and T2N1M0--35.3%, 42.3%, and 43.8%--at 5 years. We found, however, that the prognosis for T3N2M0 tumors--6.5% 5-year survival--is too poor to be grouped with other N2 diseases having a better prognosis--23.9% 5-year survival. Significant differences were also seen in the survival of T3N0 or T3N1 patients by organ and diseases involving the rib, diaphragm, or mediastinum may be classified as T4.
The new staging system predicts patient outcome fairly well and the modification is well grounded. It appears, however, to be appropriate to subdivide T3 tumors by invaded organs and T3N2M0 disease may be better classified as stage IIIB. The classification of pulmonary metastasis appears to require further improvement.
The Japanese Journal of Thoracic and Cardiovascular Surgery 09/2000; 48(8):499-505.
