The Clinical Significance of Tenascin-C Splice Variant Expression in Chondrosarcoma

Abstract

Objectives: Tenascin-C (TNC) is an oligomeric glycoprotein of the extracellular matrix that is prominently expressed in malignant tumors. The purpose of this study was: (1) to determine the in vitro TNC splicing pattern in cultured human chondrocytes and chondrosarcoma cells, (2) to determine the in vivo TNC splicing pattern in clinical chondrosarcoma specimens, and (3) to perform survival analysis based on the TNC splicing pattern of the tumor specimens. Methods: Human articular chondrocytes and chondrosarcoma cells (cell line JJ012) were grown in a three-dimensional alginate bead system and harvested at two time points. Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) was used to determine the in vitro TNC splicing pattern for the two cell types. Clinical chondrosarcoma specimens were obtained intra-operatively and underwent RT-PCR to determine the in vivo TNC splicing pattern. Specific immunohistochemical staining for the large TNC splice variant was performed on the clinical specimens. Survival analysis was used to determine the association between the specific TNC splicing pattern and survival. Results: The in vitro mRNA expression pattern of TNC in normal human articular chondrocytes was characterized by a high ratio of the small to the large splice variant (TNC_small:TNC_large), whereas the in vitro mRNA expression pattern for cultured chondrosarcoma cells was characterized by a low TNC_small:TNC_large ratio. Clinical chondrosarcoma specimens with a lower TNC_small:TNC_large ratio showed a trend towards decreased survival. The TNC splicing pattern of these specimens was verified through specific immunohistochemical staining for the large TNC isoform. Conclusions: The specific TNC splicing pattern may have clinical significance in chondrosarcoma. TNC expression may therefore play a future role in objecitve tumor grading and novel therapeutic approaches to this malignancy.

Tenascin-C, over expressed in lung cancer down regulates effector functions of tumor infiltrating lymphocytes

“…els of the increased expression of the large isoform of TN-C did not correlate with the stage of the lung cancer. It is significant to note that analysis in chondrosarcoma by semi-quantitative RT-PCR showed that a decreased amount of small isoform relative to the amount of large isoform had a trend towards decreased survival [12].…”

“…In general, TN-C expression is suppressed in the adult stages and an increased expression is observed during wound healing [7]. TN-C is over-expressed in the stroma of variety of solid tumors including gliomas [8,9], melanomas [10], breast [11], and chondrosarcoma [12]. In breast tumors, increased expression of TN-C has been correlated with poor prognosis, local and distant recurrence and thought to predict the invasiveness [11].…”

A Peptide Derived from Tenascin-C Induces β1 Integrin Activation through Syndecan-4

“…Siri et al (41) have shown that large variants of TN-C are much more susceptible to MMP-2, and that MMP-2 completely digests a single FN-III repeat inside the splicing area. It should be noted that TN-C, especially its variants containing the alternative splicing domains, is highly expressed in developing tissues and in pathological tissues (20,42,43,44), where exposure of the matricryptic sites and release of matricryptins occurs frequently. Moreover, expression of syndecan-4 is also up-regulated under similar pathophysiological situations (45).…”

Role of tenascins in the ECM of gliomas

“…[51][52][53] The alternative splicing of the FNIII domains leads to various isoforms which influence different cell types in varying manners, depending on the individual set up of FNIII domains. 54,55 Whereas in the adult the smallest isoform with only one alternatively spliced FNIII domain is found in static tissues (e.g., cartilage), 56 the embryonic development 57,58,59,60 as well as pathological situations like inflammation, regeneration or tumorigenesis 61,62,42,63,60 is marked by the dominant expression of large isoforms.…”