Different Susceptibility of Small and Large Human Tenascin-C Isoforms to Degradation by Matrix Metalloproteinases

Siri, Annalisa; Knäuper, Vera; Veirana, Natalia; Caocci, F.; Murphy, Gillian; Zardi, Luciano

doi:10.1074/jbc.270.15.8650

Cited by 151 publications

(127 citation statements)

References 38 publications

Supporting

Mentioning

121

Contrasting

Order By: Relevance

“…In addition, we established a significantly shorter survival time for patients showing the diffuse tenascin staining pattern than for patients showing the subglandular tenascin staining pattern. A possible explanation for this difference in prognosis between the two staining patterns could be that subglandular tenascin may fulfil a protective function in preventing tumour invasion and/or metastases, as suggested previously (Sakakura and Kusakabe, 1994;Siri et al, 1995).…”

Section: Discussionmentioning

confidence: 65%

Stromal tenascin distribution as a prognostic marker in colorectal cancer

Kressner

Lindmark²,

Tomasini-Johansson³

et al. 1997

Br J Cancer

View full text Add to dashboard Cite

Summary A total of 169 colorectal adenocarcinomas, obtained from patients with a median follow-up of 6.5 years, were studied with immunohistochemical staining on cryosections using a monoclonal anti-tenascin antibody to evaluate the possible association between the staining patterns and tumour stage, tumour differentiation and survival. We found two different staining patterns in the tumour stroma -a diffuse stromal fibrillar staining in 92 out of 169 (54%) tumours and a subglandular staining in the remaining 77 tumours. When the entire group of patients (P < 0.01) and the group of potentially cured patients (P < 0.03) were analysed univariately, it was found that diffuse stromal fibrillar staining was associated with a shorter survival time than subglandular staining. In a multivariate analysis, the Dukes' stage and age were independent prognostic factors, whereas the tenascin expression did not retain a clear independent relationship to survival (P = 0.06).Hence, it appears that the tumour expression of tenascin may be a potential prognostic marker in colorectal cancer, in so far as a diffuse stromal fibrillar staining pattern seems to indicate an increased risk of poor outcome. However, after adjustment for age and Dukes' stage, the additional prognostic value of tenascin remains to be established in further analyses.Keywords: tenascin; colorectal cancer; tumour stage; tumour differentiation; survival; immunohistochemistry Tenascin is a large hexameric extracellular matrix protein that is present during embryonic development but essentially absent in normal adult tissues (Schenk and Chiquet-Ehrismann, 1994) and is expressed only at low levels or in a very restricted distribution. Several tenascin isoforms have been described . Tenascin has been suggested to be of importance in the normal healing process and in tumours, in which its role is presumed to be connected with cell adhesion and detachment, cell growth, cell migration and angiogenesis (Mackie et al, 1988;Ekblom and Aufterheide, 1989;Erickson and Bourdon, 1989; ChiquetEhrismann, 1993;Hahn et al, 1995; Joshi et al, 1995). It has been proposed that, although tenascin has no cell adhesion activity, it does affect the cell shape and, thus, may inhibit cell attachment to other extracellular proteins, including fibronectin (Mackie, 1994). It is also thought that tenascin plays a role in coordinating the provisional extracellular matrix surrounding the cancer tissue (Sakakura and Kusakabe, 1994).Several reports have shown an up-regulation of tenascin in various tumour stroma, such as breast (Moch et al, 1993;Shoji et al, 1993;Yoshida et al, 1995), lung (Natali and Zardi, 1989), prostatic (Ibrahim et al, 1993) and gastric carcinomas (Ikeda et al, 1995;Ilunga and Iriyama, 1995). Studies of this putative marker of the tumour matrix are also of considerable interest in colorectal cancer (Sugawara et al, 1991;Riedel et al, 1992;Sakai et al, 1993;Hauptmann et al, 1995;Riedel et al, 1995) because of the potential involvement of tenascin (or tenascin-like proteins) i...

show abstract

Section: Discussionmentioning

confidence: 65%

Stromal tenascin distribution as a prognostic marker in colorectal cancer

Kressner

Lindmark²,

Tomasini-Johansson³

et al. 1997

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…This indicates that the amount of degraded fragments of TN-C may be related to the degree of dynamic remodelling of cancer tissues. According to Siri et al (1995), the large isoform is degraded by MMPs-2 and -3, with cleavage occurring inside the alternatively spliced region. Thus, it is extremely important to identify what proteolytic enzymes are active in lung cancers and how they influence the clinicopathological behaviour.…”

Section: Discussionmentioning

confidence: 99%

Expression and degeneration of tenascin-C in human lung cancers

Kusagawa

Onoda²,

Namikawa³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

Summary Tenascin-C is an extracellular matrix glycoprotein produced in response to epithelial-mesenchymal interactions during organogenesis and tissue remodelling. It has therefore been proposed as a stromal marker for epithelial malignancy. To test this hypothesis, 30 human lung cancers, presenting a variety of clinicopathological features, and six specimens of normal tissue were examined by Western and Northern blotting of tenascin-C protein and mRNA. The results obtained were: (1) elevated tenascin-C expression was detected in all 30 cases by Western blotting, with mRNA increase in 22 of them; (2) mRNA for a large isoform of tenascin-C, including an alternatively spliced sequence, was expressed in lung cancer tissues but not in normal lungs; and (3) metastasis to lymph nodes was frequently found in cases whose tenascin-C was degraded into small fragments. These results suggest that tenascin-C degradation can be used as a marker for metastatic potential of a tumour.

show abstract

“…Large Tn-C variants may be preferentially expressed at the border, and the weaker staining in the central areas possibly illustrates their degradation, since they are known to be more susceptible to matrix metalloproteinase than the small variant. 48 Furthermore, while strong staining of basement membrane zones of the ducts containing intraductal cancer was observed with 4F10TT, the staining of 4C8MS was absent. The smallest variant (with complete omission of the alternatively spliced region) binds to fibronectin with higher affinity than the large variants and is incorporated into the matrix.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Large Tenascin-C Splice Variants in Breast Cancer Progression

Tsunoda

Inada

Kalembeyi

et al. 2003

The American Journal of Pathology

105

View full text Add to dashboard Cite

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...

show abstract

Different Susceptibility of Small and Large Human Tenascin-C Isoforms to Degradation by Matrix Metalloproteinases

Cited by 151 publications

References 38 publications

Stromal tenascin distribution as a prognostic marker in colorectal cancer

Stromal tenascin distribution as a prognostic marker in colorectal cancer

Expression and degeneration of tenascin-C in human lung cancers

Involvement of Large Tenascin-C Splice Variants in Breast Cancer Progression

Contact Info

Product

Resources

About