Insulin‐like growth factor‐1 receptor and phosphorylated AKT‐serine 473 expression in 132 resected thymomas and thymic carcinomas

Abstract

BACKGROUND: Thymic malignancies are rare tumors. The insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) system is involved in the development of the thymus. IGF-1R expression in thymic epithelial malignancies is unknown. METHODS:The authors investigated the expression of IGF-1R and phosphorylated AKT serine 473 (p-AKT) by using immunohistochemistry and examined the clinicopathologic correlations in a retrospective, single-institution surgical series of 132 patients with thymic epithelial malignancies. RESULTS: Earlier disease stage, less aggressive histologic types, and complete resection were significant positive prognostic factors for disease-related survival and progression-free survival, and being a woman was a better prognostic factor for disease-related survival. IGF-1R and p-AKT protein levels were expressed in 20% and 36% of thymic tumors, respectively. Both markers were expressed more commonly in recurrent disease than in primary tumors, in more aggressive subtypes, and in more advanced disease stages. There was a trend toward better survival and progression-free survival in patients who were negative for IGF-1R or p-AKT expression in the whole series. When only the 91 primary tumors, IGF1R expression was associated with worse progression-free survival (P < .001). CONCLUSIONS: The current retrospective analysis demonstrated that disease stage, tumor histology, sex, and resection type were major prognostic factors in the survival of patients with thymic malignancies. The expression levels of IGF-1R and p-AKT in thymic tumors suggested that IGF-1R is a potential target for treatment. Cancer 2010;116:4686-95. Published

Heat Shock Protein 90-Sheltered Overexpression of Insulin-Like Growth Factor 1 Receptor Contributes to Malignancy of Thymic Epithelial Tumors

“…Subsequent expression analyses in human thymic tumors moreover revealed that IGF-1R is overexpressed particularly in highly aggressive, advanced stage TEMs. Recently, TMA analyses in a large panel of TEMs (n ¼ 132) confirmed an overexpression of IGF-1R and found correlations with WHO classification, stage, and relapse (27). Interestingly, loss of heterozygosity in the 6q23.3-25.3 region, harboring among others IGF-2R, has been observed to be the most frequent chromosomal aberrations in TEMs (24).…”

“…Uncovering the effector mechanisms of IGF-1R-mediated signaling cascades that eventually contribute to apoptosis evasion in TEMs will very likely help in the identification of novel treatment strategies. Meanwhile, a phase 2 trial with an anti-IGF-1R antibody is currently being conducted in patients with TEMs (27).…”

NUT Rearrangement is Uncommon in Human Thymic Epithelial Tumors

“…The tissue microrarray used in this study containing 132 TET samples resected at the Istituto Clinico Humanitas (Rozzano, Milan, Italy), out of which 124 were evaluable in this study, has been previously described elsewhere 19 . Tumors were classified according to the 2004 WHO criteria and staged according to the revised Masaoka system 1 .…”

Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors

“…Xenograft tumor sections were incubated with anti-Ki67 (Abcam), anti-cleaved caspase-3 (Cell Signaling Technology), or anti-p27 (Abcam) primary antibody, followed by exposure to horseradish peroxidase labeled polymer and DAB chromogen (Dako). For detection of XPO1 expression in human TETs, tissue microarray sections (14) were stained with an anti-XPO1 antibody (SigmaAldrich), reviewed, and scored by a pathologist who was blinded to patient information and clinical outcomes. The percentage of positive cells was scored as 0 (0%), 1 (1-10%), 2 (11%-50%), 3 (51%-80%), or 4 (!…”