Expression of tenascin‐C in various human brain tumors and its relevance for survival in patients with astrocytoma

Abstract

BACKGROUNDTenascin‐C (TN‐C), a large extracellular matrix (ECM) glycoprotein with a molecular weight of 180–250 kilodaltons, is present in several normal adult tissues. TN‐C is up‐regulated during embryogenesis, in wound healing, and in tumor tissues. Glioblastoma multiforme (GBM) is the most frequent and malignant astrocytic tumor comprised of poorly differentiated, neoplastic astrocytes. Recently, TN‐C‐based radioimmunotherapy was administered to patients with GBM.METHODSIn the current study, the authors used immunohistochemistry to conduct a systematic investigation of TN‐C distribution patterns in normal human brain tissue and in a large variety of brain tumors (n = 485 tumors). Immunoreactivity for TN‐C was assessed with regard to its localization within tumor cells, blood vessels, and ECM using three different monoclonal antibodies (clones BC2, BC4, and TN2).RESULTSIn control human brains, a significant difference was noted in the expression of TN‐C when comparing gray with white matter using either Western blot analysis or immunohistochemistry. TN‐C was found in the white matter of the frontal, temporal, parietal, and occipital lobes and in the hippocampus, where the immunoreaction was especially strong in the hippocampal formation. In 181 astrocytomas of different grades (World Health Organization [WHO] Grade 2–4), TN‐C immunopositivity was seen to varying degrees in the cellular and stromal components of the tumor and in tumor‐associated vessels. Glioblastomas (n = 113 tumors) showed strong immunopositivity in the vessels and moderate immunopositivity of the ECM. A statistically significant reduction of TN‐C immunopositivity in tumor‐associated vessels or ECM was observed in anaplastic astrocytomas (WHO Grade 3) compared with GBM (WHO Grade 4). A Kaplan–Meier analysis showed that patients who had GBM lesions that lacked TN‐C immunopositivity in the ECM had a significantly longer survival (median, 28 months; standard error, 7.8 months) (n = 12 patients) compared with patients who had GBM lesions with TN‐C immunopositivity (median, 12 months; standard error, 1.6 months) (n = 87 patients). In meningiomas (n = 24 tumors), the neoplastic cells, the ECM of the tumor, and the vessels were TN‐C negative. In schwannomas (n = 31 tumors), the tumor cells were TN‐C negative; whereas, in > 50% of tumors, the vessels and the ECM of regressively altered tumor areas were positive. In metastatic carcinomas (n = 53 tumors), the tumor cells were negative; seldom were vessels stained positive for TN‐C. Focal areas of the ECM, often accompanied with fibrotic changes, were immunopositive for TN‐C.CONCLUSIONSThe most constant TN‐C immunopositivity was noted in the ECM of the fibrotic stroma in highly malignant brain tumors and along the tumor border, especially in high‐grade astrocytomas. The current results suggest that TN‐C expression may be correlated with the grade of malignancy in astrocytic tumors and that the presence or absence of TN‐C expression in the stroma of astrocytic tumors may play a not yet clearly understood role in shortening or prolonging, respectively, the survival of patients. Cancer 2003. © 2003 American Cancer Society.

Tenascin-C Stimulates Glioma Cell Invasion through Matrix Metalloproteinase-12

“…The identification of tenascin-C as a facilitatory factor for glioma invasiveness in a three-dimensional matrix is relevant because it is increased in brain tumors where its expression increases with tumor grade (15,16,18,20,38). In vitro studies have found that tenascin-C increases the migration of glioma cells in monolayer or spheroid cultures (39)(40)(41).…”

“…In malignant gliomas, many ECM components are overexpressed both in the tumor stroma and at the advancing edge of the tumor within brain parenchyma. These ECM molecules include vitronectin, collagen I, collagen IV, osteopontin, tenascin-C, secreted protein acidic and rich in cysteine, and brain enriched hyaluronan binding (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Glioma invasion is thought to occur along ECM protein-containing structures, such as along tracts of myelinated fibers (22)(23)(24).…”

Apoptotic Death of Hematopoietic Tumor Cells through Potentiated and Sustained Adhesion to Fibronectin via VLA-4

“…TN-C is characterized by its regulated expression and by its cell adhesion modulatory function (14,15). Constitutive expression of TN-C has been observed in lymphoid tissues, such as adult bone marrow and lymph nodes (16,17), whereas it is transiently expressed in pathological states, including inflammation and tumorigenesis (18,19). Therefore, lymphoid tissues of patients with hematopoietic malignancy have highly increased expression of TN-C. TN-C acts as both an adhesive and an antiadhesive substrate, depending on the cellular context (20).…”

Elevated Expression of Nuclear Protein Kinase CK2α as a Poor Prognosis Indicator in Lymph Node Cancerous Metastases of Human Thyroid Cancers

“…TNC is early described as a stormal marker associated with malignant behavior of breast cancer (Mackie et al, 1987). In addition, TNC is highly expressed in brain tumor (Leins et al, 2003), head and neck cancers (Lyons et al, 2007;Atula et al, 2003). In the above described tumors, the high expression TNC is associated with invasion and worse prognosis.…”