Alternative splicing of fibronectin-like type III (FNIII) repeats of tenascin-C (Tn-C) generates a number of splice variants. The distribution of large variants, typical components of provisional extracellular matrices that are up-regulated during tumor stroma remodeling, was here studied by immunoblotting and immunohistochemistry using a monoclonal antibody against the FNIII B domain (named 4C8MS) in a series of human breast cancers. Large Tn-C variants were found at only low levels in normal breast tissues, but were highly expressed at invading sites of intraductal cancers and in the stroma of invasive ductal cancers, especially at invasion fronts. There was a positive correlation between the expression of large Tn-C variants and the cell proliferation rate determined by immunolabeling of the Ki-67 antigen. Of the Tn-C recombinant fragments (all FNIII repeats or mFNIII FL, the conserved FNIII domain only, the epidermal growth factor-like domain, and the fibrinogen-like domain) which were expressed by CHO-K1 cells transfected with mouse Tn-C cDNAs, only the mFNIII FL enhanced in vitro migration and mitotic activity of mammary cancer cells derived from a Tn-C-null mouse. Addition of 4C8MS blocked the function of mFNIII FL. These findings provide strong evidence that the FNIII alternatively spliced region has important roles in tumor progression of breast cancer. During tumor progression, the cancer stroma becomes remodeled by both tumor cells and stromal cells, and protein components of the extracellular matrix (ECM) are dynamically changed by degradation and neosynthesis. Cellular interaction with the ECM strongly influences the behavior of cancer and stromal cells, resulting in modulation of cell growth, migration, differentiation, and apoptosis. 1-3 Compositional change of the ECM in cancer stroma is thus a key determinant of tumor growth and cancer progression. A variety of ECM glycoproteins, such as tenascin-C (Tn-C) and fibronectin, are overexpressed in cancer stroma. In addition, splice variants of these proteins, which are generally absent in normal adult tissues, become predominant. 4 -11 It has been reported that overexpression of Tn-C in breast cancer is related to a poor prognosis, and local and distant recurrence, 12-14 this being attributable to the ability to promote cell migration and proliferation demonstrated in vitro. 15,16 Tn-C is a hexameric glycoprotein, each subunit consisting of a TA (Tn assembly) domain; 14 ϩ 1/2 epidermal growth factor (EGF)-like domains, a variable number of fibronectin type III (FN III) repeats, and a C-terminal fibrinogen-related domain (FBG). [17][18][19][20][21] The size of Tn-C monomers varies as a result of alternative splicing in the FN III repeats at the pre-mRNA level. There are eight conserved FN III repeats (designated as numbers 1-8) and, in the case of human Tn-C, up to nine alternatively spliced FN III repeats (designated as letters A-D) inserted between the conserved repeats 5 and 6. In adults, the smallest Tn-C variant in which the alternatively splic...

Epithelial cells play an important role in maintaining the airway barrier, which is impaired in inflammatory conditions. Recently, thrombin was reported to be increased in the airway of patients with asthma, and thrombin has been shown to increase the permeability of endothelial cell monolayers. Therefore, we suspected that thrombin affects airway permeability. Calu-3 cell monolayers were established on microporous membranes of tissue culture cell inserts. We examined the effects of topically applied thrombin or thrombin receptor-activating peptide (TRAP) on: (1) transepithelial permeability (luminal to serosal transfer) of radiolabeled mannitol and albumin, (2) changes in electrical resistance, and (3) actin fiber content as assessed by fluorescence microscopy. Compared with untreated control cultures, treatment of the monolayers for 24 h with thrombin or TRAP significantly decreased the electrical resistance and increased the permeability to mannitol and albumin. In addition, these treatments enhanced the appearance of actin stress fibers, and small gaps became visible at areas of cell-cell contact. Thrombin appears to increase epithelial permeability by receptor-mediated reorganization of the actin network in airway epithelial cells. This is likely to contribute to the impairment of the airway barrier function.

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We have already reported the suitability of the Odor Stick Identification Test for the Japanese (OSIT J) in patients suffering from an olfactory disturbance. In the present study, we studied whether the suitability of the OSIT J is affected by aging and we can use the OSIT J as an olfactory detection test. In 191 patients with olfactory disturbances, ranging in age from 12 to 85 years, aging never reduced statistically significant correlation coefficients between the odor identification rate on the OSIT J and the recognition threshold on the Japanese standardized olfactory test (T&T olfactometry) or the grade of their symptom scores. The OSIT J prepared a choice of "odorless" in the list for describing odors, so we considered that the patient could at least detect odors when they chose either of the correct answer, incorrect answer (s) or "detectable but not recognizable", regardless of their success in the odor identification. The odor detection rate on the OSIT J strongly correlated with the detection threshold on T&T olfactometry. The degree of separation between olfactory detection -( 167)23-and recognition rates on the OSIT J significantly correlated with that between olfactory detection and recognition thresholds on T&T olfactometry.In conclusion, the OSIT-J is applicable regardless of aging and has the capacity to point out separation between olfactory detection and recognition abilities.

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