Tenascin-C, over expressed in lung cancer down regulates effector functions of tumor infiltrating lymphocytes.
OBJECTIVE
Extracellular matrix (ECM) proteins play a significant role in the survival and metastasis of cancer cells. Tenascin-C (TN-C) is an extracellular matrix protein and its large isoform has been implicated in tumor progression. Goal of this study was to analyze the expression of the small and large isoforms of TN-C in non-small cell lung cancer (NSCLC) and determine its functional significance.


METHODS
TN-C expression was studied in tumor and non-tumor tissue of patients with NSCLC at the mRNA and protein level. Immunomodulatory properties of the large isoform of TN-C were analyzed by determining its effect on lymphocyte proliferation and cytokine secretion by tumor-infiltrating lymphocytes (TIL).


RESULTS
Quantitative real-time PCR analysis showed an eight-fold increase in the amount of large isoform in cancer cells compared to adjacent normal tissue. Expression at the protein level by Western blot analysis using a murine monoclonal anti-TN-C antibody detected increased expression of the large isoform in the tumor tissue that was correlated with the development of recurrent disease. A 18-fold increase in the expression of the large TN-C isoform was observed in patients with recurrent NSCLC compared to non-recurrent NSCLC. Large isoform of TN-C significantly inhibited anti-CD3 and mitogen-induced proliferation of human peripheral blood lymphocytes and interferon-gamma production by TIL isolated from the lung cancer specimens.


CONCLUSIONS
Increased expression of TN-C observed at the site of tumor in NSCLC correlates with recurrence. TN-C inhibits TIL proliferation and cytokine thereby may promote tumor immune evasion and recurrence.
Parekh
Kalpaj
K
Department of Surgery, Washington University School of Medicine, Box 8109-CSRB.3328, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Ramachandran
Sabarinathan
S
Cooper
Joel
J
Bigner
Darell
D
Patterson
Alexander
A
Mohanakumar
T
T
D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D009361:Neoplasm Invasiveness / Q000276:immunology; D009364:Neoplasm Recurrence, Local / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019063:Tenascin / Q000096:biosynthesis* / Q000494:pharmacology*; D015854:Up-Regulation
D016207:Cytokines; D019063:Tenascin