A subcloned human esophageal squamous cell carcinoma cell line with low thrombomodulin expression showed increased invasiveness compared with a high thrombomodulin-expressing clone – thrombomodulin as a possible candidate for an adhesion molecule of squamous cell carcinoma

Matsushita, Yosuke; Yoshiie, Kiyotaka; Imamura, Yoshiro; Ogawa, Hiroki; Imamura, Hiroshi; Takao, S.; Yonezawa, Suguru; Aikou, Takashi; Maruyama, Ikuro; Satô, Eiichi

doi:10.1016/s0304-3835(98)00038-x

Cited by 27 publications

(19 citation statements)

References 23 publications

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“…Additionally, all of the metastatic lesions shown in some cases of thrombomodulinpositive esophageal cancer (i.e., pathologically diagnosed as squamous cell carcinomas) were observed as thrombomodulinnegative or less thrombomodulin-expressed lesions than the primary lesions (26). As with squamous cell carcinomas, the study using a melanoma line also showed a less invasive and proliferative characteristics of high-thrombomodulin expressors (23,24). These evidences also support our conclusions that thrombomodulin-positive islet cell tumors are likely to be clinically benign tumors in character and hypothesis concerning the diagnostic value of thrombomodulin expression in islet cell tumors as a clinical predictor of disease prognosis.…”

Section: Discussionsupporting

confidence: 86%

The Antimetastatic Role of Thrombomodulin Expression in Islet Cell-Derived Tumors and Its Diagnostic Value

Iino¹,

Abeyama²,

Kikuchi³

et al. 2004

Clinical Cancer Research

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Islet cell tumors, endocrine neoplasm arising from pancreatic islets of Langerhans, are histologically difficult to diagnose as benign or malignant. Molecular markers are associated with the clinical characteristics that most of insulinoma are usually benign tumors, whereas other islet cell tumors are malignant but have not been identified. In this context, we newly found that an endothelial anticoagulant thrombomodulin was expressed in the normal islet ␤ cells and insulinoma, but not of other islet components or noninsulinoma islet cell tumors. Clinically, all of the subjects (n ‫؍‬ 15) of the insulinoma group showed no metastasis together with thrombomodulin expression in the lesions, whereas the other islet cell tumor groups showed a high incidence of metastasis (82%) and a low expression rate of thrombomodulin (6%). To examine the functional role of thrombomodulin, especially regarding the clinical characteristics of islet cell tumors, we tested the effect of exogenous thrombomodulin overexpression on cell adhesiveness and proliferation using MIN6 insulinoma cell line. In cell-based experiments, thrombomodulin overexpression reduced cell proliferation and enhanced Ca 2؉ -independent cell aggregation, possibly through direct interaction with neural cell adhesion molecule. Taken together, these results are suggesting that thrombomodulin may act as antimetastatic molecule of insulinomas. In addition, thrombomodulin is a clinically useful molecular marker not only for identifying ␤-cell-origin islet cell tumors (i.e., insulinomas) but also for predicting disease prognosis of islet cell tumors.

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Section: Discussionsupporting

confidence: 86%

The Antimetastatic Role of Thrombomodulin Expression in Islet Cell-Derived Tumors and Its Diagnostic Value

Iino¹,

Abeyama²,

Kikuchi³

et al. 2004

Clinical Cancer Research

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“…The domain organization of rat AA4 is very similar to TM, and we have recently found that both genes are clustered on chromosome 20 (20p11 locus) in human. 5 Although TM is recognized as a major natural anticoagulant expressed on endothelial cells, this lectin-like molecule has also been involved in cell differentiation, cell proliferation, and cellcell adhesion (42)(43)(44). It is possible that part or all of these properties actually involve the CTLD of TM, and the structure/ function relationship of this protein should be revisited in the near future.…”

Section: Figmentioning

confidence: 99%

Molecular and Cellular Properties of the Rat AA4 Antigen, a C-type Lectin-like Receptor with Structural Homology to Thrombomodulin

Dean¹,

McGreal²,

Akatsu³

et al. 2000

Journal of Biological Chemistry

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The murine fetal stem cell marker AA4 has recently been cloned and is known to be the homolog of the human phagocytic C1q receptor involved in host defense. We herein report the molecular cloning and the cellular expression pattern of the rat AA4 antigen. Modular architecture analysis indicated that the rat AA4 is a member of C-type lectin-like family and, interestingly, displays similar domain composition and organization to thrombomodulin. Northern blot and reverse transcriptase-polymerase chain reaction analyses indicated that rat AA4 was encoded by a single transcript of 7 kilobases expressed constitutively in all tissues. In situ hybridization showed that AA4 was expressed predominantly by pneumocytes and vascular endothelial cells. Using an affinity purified polyclonal antibody raised against a rat AA4-Fc fusion protein, AA4 was identified as a glycosylated protein of 100 kDa expressed by endothelial cells > platelets > NK cells and monocytes (ED1؉ cells). The staining was associated to the cell surface and intracytoplasmic vesicles. Conversely, erythrocytes, T and B lymphocytes, neutrophils, and macrophages (ED2؉ cells) were consistently negative for AA4. As expected, the macrophage cell line NR8383 expressed weak levels of AA4. Taken together, our results support the idea that AA4/C1qRp is involved in some cell-cell interactions.

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“…In tumours, therefore, decreased TM may induce loss of differentiation and enhance metastatic behaviour. In vitro work has demonstrated that TM reduces tumour cell proliferation and invasion (Matsushita et al, 1998;Zhang et al, 1998;Hosaka et al, 2000;Huang et al, 2003) and TM expressing cells produce smaller tumours in vivo (Zhang et al, 1998;Huang et al, 2003). There are, therefore, many possible mechanisms by which increased TM expression could decrease the likelihood of metastasis.…”

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confidence: 99%

Thrombomodulin expression in colorectal carcinoma is protective and correlates with survival

et al. 2006

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Thrombomodulin (TM) is an endothelial receptor that exhibits anticoagulant, antifibrinolytic and anti-inflammatory activity by inhibiting thrombin and cellular adhesion. In this study, the expression and significance of TM was examined in primary colorectal cancer and its prognostic implications explored. TM immunostaining was performed on formalin-fixed, paraffin-embedded tissue sections, from primary lesions of 200 patients with colorectal carcinoma. Institutional Ethical approval was granted and clinical data retrieved from patients' records. All normal colonic tissue expressed TM on endothelial cells. TM tumour cell expression was demonstrated in 53 (26.5%) cases and 147 (73.5%) showed no neoplastic cell staining. On univariate and multivariate analysis TM expression on tumour cells correlated significantly with tumour stage, differentiation, Jass score and 5 year survival. TM expression decreases as overall stage and tumour size increase (P ¼ 0.03). In all, 91% TM positive tumours were well differentiated and 85% of TM negative tumours were poorly differentiated (Po0.01). Five year survival rates of patients with positive and negative TM expression were 71 and 41%, respectively. Survival rate was poorer in those patients who were TM negative compared with those who were positive (Po0.01). A total of 101 (50.5%) of the cases were node negative. In this group, 5 year survival rates of patients with positive and negative TM expression were 87.5 and 37.8%, respectively, demonstrating a poorer survival rate for those who are node negative and TM negative at the time of surgery (Po0.001). This study demonstrates that loss of TM is a key indicator in tumour biology and prognosis.

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A subcloned human esophageal squamous cell carcinoma cell line with low thrombomodulin expression showed increased invasiveness compared with a high thrombomodulin-expressing clone – thrombomodulin as a possible candidate for an adhesion molecule of squamous cell carcinoma

Cited by 27 publications

References 23 publications

The Antimetastatic Role of Thrombomodulin Expression in Islet Cell-Derived Tumors and Its Diagnostic Value

The Antimetastatic Role of Thrombomodulin Expression in Islet Cell-Derived Tumors and Its Diagnostic Value

Molecular and Cellular Properties of the Rat AA4 Antigen, a C-type Lectin-like Receptor with Structural Homology to Thrombomodulin

Thrombomodulin expression in colorectal carcinoma is protective and correlates with survival

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