Synthetic emmprin peptides with chitobiose substitution stimulate MMP-2 production by fibroblasts.

BACKGROUND: Emmprin, a glycoprotein containing two Ig domains, is enriched on tumor cell surfaces and stimulates matrix metalloproteinase (MMP) production by adjacent stromal cells. Its first Ig domain (ECI) contains the biologically active site. The dependence of emmprin activity on N-glycosylation is controversial. We investigated whether synthetic ECI with the shortest sugar is functionally active. METHODS: The whole ECI peptides carrying sugar chains, a chitobiose unit or N-linked core pentasaccharide, were synthesized by the thioester method and added to fibroblasts to examine whether they stimulate MMP-2 production. RESULTS: ECI carrying a chitobiose unit, ECI-(GlcNAc) 2, but not ECI without a chitobiose unit or the chitobiose unit alone, dose-dependently stimulated MMP-2 production by fibroblasts. ECI with longer chitobiose units, ECI-[(Man)3(GlcNAc)2], also stimulated MMP-2 production, but the extent of its stimulation was lower than that of ECI-(GlcNAc)2. CONCLUSIONS: Our results indicate that ECI can mimic emmprin activity when substituted with chitobiose, the disaccharide with which N-glycosylation starts.

[Simultaneous resection of lung and liver metastases due to uterine leiomyosarcoma; report of a case].

We describe a case of simultaneous resection of lung and liver metastases from uterine leiomyosarcoma, with reference to previous reports. A 51-year-old female was admitted for treatment of nodules shadow in the right lung and in the left lateral side of the liver discovered by computed tomography (CT). She had been treated for uterine leiomyosarcoma 19 months earlier. Segmentectomy of the right S6 of the lung and left lateral segmentectomy of the liver were performed. The tumors pathologically diagnosed as metastases from uterine leiomyosarcoma. After 29 months, a metastasis to the left lung was detected and thoracoscopic resection was performed. The patient died due to multiple metastases from uterine leiomyosarcoma after 36 months.

Effectiveness of near-infrared spectroscopy during surgical repair of tracheo-innominate artery fistula.

Monitoring regional cerebral oxygen saturation (rSO(2)) by use of near-infrared spectroscopy (NIRS) is a useful method for detecting cerebral ischemia. Tracheo-innominate artery fistula is a rare but life-threatening complication of tracheostomy. The surgical procedures for management of tracheo-innominate artery fistula include direct or patch closure of the fistula, ligation or division of the innominate artery, and anatomical or extra-anatomical reconstruction of the flow of the innominate artery. Division of the innominate artery is the best method to prevent postoperative recurrence of bleeding and infection. However, cutting off the innominate artery flow may cause brain ischemia. We present the case of a patient with tracheo-innominate artery fistula successfully treated by dividing the innominate artery while the rSO(2) was monitored. In this case report, we have shown that NIRS is a useful method for deciding the surgical maneuver for tracheo-innominate artery fistula.

[Autopsy case of rapidly progressive pulmonary spindle cell carcinoma with multiple metastases to the brain and pancreas].

A 53-year-old man was admitted to our hospital because of an abnormal lung shadow on his chest X-ray film. His symptoms were cough and shortness of breath. Chest X-ray and computed tomography showed a large mass lesion in the right lower lobe of the lung. We diagnosed primary non-small cell lung cancer; cT3N1M1 stage IV. Systemic chemotherapy using carboplatin and paclitaxcel was performed. However, the treatment had no effect and he died two months after admission. An autopsy showed pulmonary spindle cell carcinoma, with multiple metastases to the brain, pancreas, etc. Pulmonary spindle cell carcinoma had been recognized as a variant of the squamous cell carcinoma for years, however, in the recent WHO and Japanese classification of lung tumors, it was redefined as an independent histological type. It is a rare form of lung cancer, representing 0.2 to 0.3% of all primary pulmonary malignancies and seems to have poor prognosis. We need to pay more attention to this type of lung cancer.

Small cluster invasion: a possible link between micropapillary pattern and lymph node metastasis in pT1 lung adenocarcinomas.

Lung adenocarcinomas with micropapillary pattern (MPP) are associated with frequent nodal metastasis. However, little is known about the mechanisms that underlie MPP-associated nodal metastasis. In this study, we investigated how small micropapillary clusters of carcinoma cells present in tumoral alveolar spaces lead to increased lymph node metastasis. We analyzed 146 cases of pT1 lung adenocarcinomas with reference to the presence of MPP, small cluster invasion (SCI), and lymphatic involvement. SCI was defined as markedly resolved acinar-papillary tumor structures with single or small clusters of carcinoma cells invading stroma within fibrotic foci. The MPP-positive group (88/146 cases) was associated with significantly more frequent nodal metastasis and significantly worse survival. Moreover, SCI was significantly more frequent in the MPP-positive group (71/88 cases) than MPP-negative group (10/58 cases) and was significantly associated with lymphatic involvement (p < 0.0001) and nodal metastasis (p = 0.0073). The SCI-positive group showed significantly worse survival (5-year survival, 70%) than the SCI-negative group (91%, p = 0.0017). Carcinoma cells undergoing SCI demonstrated the same characteristic MUC-1 expression on the outer surface of cell clusters as those undergoing MPP. Thus, SCI could link MPP to nodal metastasis; carcinoma cells with MPP tend to undergo SCI in scars and invade lymphatics in pT1 lung adenocarcinomas.

Association between the expression of chemokine receptors CCR7 and CXCR3, and lymph node metastatic potential in lung adenocarcinoma.

Chemokines and their receptors are essential for leukocyte trafficking, and are also involved in cancer metastasis to specific organs. Although the migration of tumor cells into the lymph nodes is an important aspect of cancer, the processes involved are poorly understood. Chemokine receptors CCR7 and CXCR3 have been shown to play an important role in tumor cell migration and lymph node metastasis. Therefore, the assessment of chemokine receptor expression on lung adenocarcinomas may improve the prediction of the spread of this carcinoma to the lymph nodes. In this study, we examined the expression and function of these two chemokine receptors (CCR7 and CXCR3) in lung adenocarcinoma. By using flow cytometry, they were detected in all of the lung adenocarcinoma cell lines examined. In the chemotaxis assays, A549 cells exhibited CCL21-induced migration, which was significantly suppressed by neutralizing anti-CCR7 antibody. The CXCL10-induced migration of A549 cells was also significantly suppressed by neutralizing anti-CXCR3 antibody. In clinical lung adenocarcinoma samples, we found the expression of CCR7 and CXCR3 in 65 and 90% cases, respectively, most of which had lymph node metastasis. Importantly, the expression of CCR7 was significantly associated with lymph node metastasis, although the expression of CXCR3 was not. These results suggest that the activation of CCR7 and CXCR3 with their ligands preferentially stimulates lung adenocarcinoma metastasis to the draining lymph nodes.

Correlation between lymph node metastasis and the expression of VEGF-C, VEGF-D and VEGFR-3 in T1 lung adenocarcinoma.

Vascular endothelial growth factor (VEGF)-C and VEGF-D influence lymphangiogenesis through the activation of the vascular endothelial growth factor receptor (VEGFR)-3. They have been implicated in lymphatic tumor spread, which is an important prognostic factor in patients with non-small cell lung carcinoma (NSCLC). Whether or not the expression of VEGF-C, -D, and VEGFR-3 correlates with clinicopathological factors in patients with T1 lung adenocarcinoma was analysed. The tumor specimens were homogenized to determine the protein expression of VEGF-C, -D, and VEGFR-3 by enzyme-linked immunosorbent assay (ELISA). RNA fractions extracted from the tumor tissues were subjected to real-time reverse transcription-polymerase chain reaction (RT-PCR) to assess the mRNA levels of VEGF-C, -D, and VEGFR-3. The expression of VEGF-D protein and mRNA levels in patients without lymph node metastasis were significantly higher than those with metastasis (p=0.013, p=0.0494, respectively). However, the protein and mRNA levels of VEGF-C and VEGFR-3 were not significantly different in patients with or without metastasis. The 5-year survival rates of the patients with high VEGF-D levels were significantly higher than those of patients with low levels (p =0.0221). No significant difference in the survival rates was observed for VEGF-C and VEGFR-3. VEGF-D may be downregulated in NSCLC tissues in comparison to adjacent normal tissue, resulting in lymph node metastasis and poor prognosis.

Micropapillary pattern and grade of stromal invasion in pT1 adenocarcinoma of the lung: usefulness as prognostic factors.

Recently, the stromal invasion grading system was proposed for small adenocarcinomas of < or =2.0 cm. The system is based on the presence or absence of a fibrotic focus, and the extent of invasion into the fibrotic focus. Although stromal invasion grading system closely correlated with the prognosis, stromal invasion grade 3, representing stromal invasion into the center of a fibrotic focus, was the largest group of tumors and showed variable prognosis. In this study, we investigated whether stromal invasion grading system could be applied to and validated in pT1 adenocarcinomas as the TNM classification is the most universally used system. Furthermore, we investigated whether stromal invasion grade 3 cases could be subclassified according to the presence and absence of micropapillary pattern. The study included 120 cases of pT1 lung adenocarcinomas, of which 81 (68%) cases were stromal invasion grade 3. Micropapillary pattern was positive in 80% of grade 3 cases. For stromal invasion grade 3 cases, the 5-year survival rate of patients with micropapillary pattern-positive carcinomas was 63%, which was significantly worse than 94% of those with micropapillary pattern-negative carcinomas (P=0.0196). The latter was very close to that for patients with stromal invasion grade 0-2 (95%). Moreover, small cluster invasion was observed at sites of stromal invasion significantly more often in micropapillary pattern-positive cases than negative cases. Thus, the stromal invasion grading system is reproducible and correlates with prognosis even in pT1 lung adenocarcinomas. Moreover, among patients with stromal invasion grade 3 carcinomas, favorable prognosis is noted in micropapillary pattern-negative cases. The micropapillary pattern subclassification provides an advantage to the stromal invasion grading system and reconfirms the importance of micropapillary pattern as a prognostic marker. Our study is the first to point to the possible association of micropapillary pattern-positive carcinomas and small cluster invasion.

A case of mixed connective tissue disease complicated with thymic carcinoma and Hashimoto's thyroiditis.

We report the case of a 63-year-old woman who suffered from mixed connective tissue disease (MCTD) complicated with thymic carcinoma and Hashimoto's thyroiditis. Although many systemic syndromes associated with thymoma and thymic carcinoma, i.e., myasthenia gravis, pure red cell aplasia, hypogammaglobulinemia, and Hashimoto's thyroiditis, are known, this is the first report of MCTD complicated with thymic carcinoma. It was suggested that MCTD may be a paraneoplastic syndrome associated with thymic carcinoma.

Emmprin in epithelioid sarcoma: expression in tumor cell membrane and stimulation of MMP-2 production in tumor-associated fibroblasts.

Emmprin is a transmembrane glycoprotein on tumor cells that stimulates peritumoral fibroblasts to produce matrix metalloproteinases (MMPs). Emmprin and the induced MMPs play a crucial role in tumor progression, invasion and metastasis of human carcinomas (epithelial malignancies). However, only a few reports have addressed its role in soft tissue sarcomas. This study investigated the expression and role of emmprin in epithelioid sarcoma (ES). Immunoblot studies of 2 ES cell lines showed that they express emmprin, and co-culture of these ES cells with dermal fibroblasts resulted in upregulation of gelatinase A (MMP-2) in fibroblasts, as shown by zymography, immunoblotting and enzyme immunoassay. This stimulation was inhibited by an activity-blocking peptide against emmprin and by antiemmprin antibody. In addition, in vivo, immunohistochemical analysis of 5 ES patient cases demonstrated diffuse emmprin expression in ES cells and MMP-2 expression in both ES cells and peritumoral fibroblasts. The histopathological findings that peritumoral fibroblasts that were not in direct contact with emmprin-expressing ES cells exhibit upregulated MMP-2 prompted us to look for a soluble form of emmprin. Soluble full-length emmprin released from ES cells was detected in conditioned medium and shown to stimulate MMP-2 production by fibroblasts. In conclusion, emmprin is expressed in ES in both membrane and soluble forms and stimulates MMP-2 production via interactions with fibroblasts, which could play a role in ES cell stromal invasion and vascular involvement.

Overexpression and diffuse expression pattern of IQGAP1 at invasion fronts are independent prognostic parameters in ovarian carcinomas.

IQGAP1 is a multifunctional protein involved in actin cytoskeleton assembly and E-cadherin-mediated cell adhesion. To determine the role of IQGAP1 in ovarian tumors, we evaluated IQGAP1 expression by immunohistochemistry in 17 adenomas, 30 borderline tumors and 80 adenocarcinomas and its relation with patient survival. IQGAP1 was overexpressed in adenocarcinomas compared with adenomas and borderline tumors. Enhanced immunostaining in invasive tumor fronts was categorized as focal or diffuse. The diffuse expression pattern correlated with high histological grade and clinicopathological stages. IQGAP1 overexpression and diffuse invasion pattern were significantly associated with poor prognosis by multivariate analysis. Our findings suggest the involvement of IQGAP1 in the progression and spread of ovarian adenocarcinomas. Overexpression and diffuse expression pattern of IQGAP1 are potentially useful independent molecular predictors of highly aggressive ovarian carcinomas.

Synchronous multicentric thymona: report of a case.

We report a case of multiple thymoma with different histological subtypes, not associated with myasthenia gravis. We describe the histological findings, especially the results of immunohistochemical staining, which support the possibility of multicentric thymoma. The validity of extended thymectomy is also discussed.