Thyroid transcription factor-1 (TTF-1) is considered as a reliable marker for differential diagnosis in distinguishing primary adenocarcinomas of the lung from extrathoracic origins. We previously reported the first case of lung metastasis of colorectal origin, with nuclear expression of TTF-1. As most previous studies were performed on series of extrathoracic primary tumors, we raised the question of a possible role of lung microenviroment in TTF-1 expression. We investigated the rate of TTF-1 expression in lung metastases of extrathoracic adenocarcinomas and compared results of immunohistochemistry performed with different primary antibodies. Two different clones of antibodies (8G7G1/1 from Dako, SPT24 from Novocastra) raised against TTF-1 were used on 56 lung-metastatic malignant tumors, 41 from colorectal origin. A series of primary colorectal (90 cases) and primary pulmonary adenocarcinomas (86 cases) were also investigated. Four of 41 (10%) lung metastases of colorectal adenocarcinomas displayed a nuclear staining for TTF-1 with SPT24 clone. Three of the four positive cases displayed similar nuclear staining in primary and/or other extrathoracic metastatic sites as well as four of 90 (5%) primary colorectal adenocarcinomas, ruling out the role of lung microenvironment. None of them was positive with 8G7G1/1 clone. Sensitivity between two sets of antibodies was compared in 86 primary pulmonary adenocarcinomas. Nuclear staining was detected in 72 cases (84%) with Novocastra's antibody and 56 cases (65%) with Dako's. Significant discordance was observed (Po 0.01). These results suggest that the diagnostic virtue of TTF-1 detection depends on the used antibody's clone. The SPT24 clone seems to have a stronger affinity for TTF-1 protein but may lead to a few positive colorectal adenocarcinomas. Keywords: TTF-1; lung; carcinoma; metastasis; colorectal Thyroid transcription factor-1 (TTF-1) is a tissuespecific transcription factor expressed in the epithelial cells of thyroid and lung (type II pneumocytes and Clara cells). Carcinomas arising from lung and thyroid also show frequent TTF-1 expression. 1,2 As the lung is one of the most common sites of metastasis, TTF-1 is considered as a reliable marker to distinguish between primary lung carcinoma and lung metastasis, especially when dealing with an adenocarcinoma or a large-cell carcinoma. [3][4][5][6] It is also considered as a reliable marker in the differential diagnosis between pleural localization of lung origin carcinoma and malignant mesothelioma. 7 Two main commercial available clones of monoclonal antibodies have been raised against TTF-1 for immunohistochemical use, 8G7G1/1 and SPT24, their diagnostic value in determining the lung or thyroid origin of adenocarcinoma has not yet been compared. Most of the studies show the high specificity of TTF-1 detection and have been published used the 8G7G1/1 clone. We previously reported one case of lung metastasis of colorectal origin, which showed a focal nuclear staining with the anti-TTF-1 antibody (clone SPT24)...

Tumor necrosis factor receptor (TNFR) associated factor 4 (TRAF4) was initially identified as a gene amplified and overexpressed in breast carcinomas. Our aim was to evaluate whether TRAF4 protein overexpression exists in other cancer types. Immunohistochemistry analysis of tumor samples from 623 patients with 20 different tumor types showed that TRAF4 was overexpressed in 268 tumors (43%), including 82 of 137 lung adenocarcinomas (60%). Interestingly, 32 primary tumors and their matching metastases exhibited mostly similar TRAF4 expression pattern. TRAF4 protein overexpression was limited to cancer cells and the subcellular localization was consistently cytoplasmic in a large majority of cases. To investigate changes in TRAF4 gene copy number, 125 cases from six different types of carcinomas were also analysed by fluorescence in situ hybridization. Out of the 28 cases (22%) showing an increased TRAF4 gene copy number, 23 (82%) were overexpressing the protein. Thus, TRAF4 gene amplification is one of the mechanisms responsible for TRAF4 protein overexpression in human cancers. Considering that TRAF4 is located at 17q11.2 in a region of amplification devoid of known oncogenes and is commonly overexpressed in cancer, our data support an oncogenic role for TRAF4. Oncogene Keywords: TRAF4; chromosome 17q11; ERBB2; amplification; lung TRAF proteins belong to a family of cytoplasmic adaptors involved in the signalling cascade activated by receptors of the TNFR and interleukin-1/Toll-like receptor (IL-1R/TLR) families (Chung et al., 2002). Six TRAF proteins that share common structural features, including a carboxy-terminal TRAF domain, are encoded by the mammalian genome. Their main functions are exerted in the immune system where they regulate intracellular signalling pathways leading to the activation of a common set of transcription factors including NF-kB and AP-1 (Aggarwal, 2003).Unlike other members of the TRAF family, the biological function of TRAF4 remains elusive. Several reports suggested that TRAF4 could be recruited to different TNFR and TLR signalling pathways (Krajewska et al., 1998;Ye et al., 1999;Esparza and Arch, 2004;Takeshita et al., 2005), and in mitogen-activated protein kinase (MAPK) pathways (Xu et al., 2002;Abell and Johnson, 2005;Li et al., 2005) but in vivo evidence of such a role is still missing. Mice deficient for TRAF4 exhibit clear ontogenic defects affecting neural tube closure, tracheal formation and skeletal patterning, phenotypes that might be linked to abnormal cell migration (Regnier et al., 2002).TRAF4 was the first member of the TRAF protein family found upregulated in human carcinomas. Indeed, the TRAF4 cDNA was initially isolated from metastatic breast cancer Tomasetto et al., 1995), where the TRAF4 gene was amplified, leading to overexpression of the gene product (Bieche et al., 1996). Detailed analysis of the amplification pattern of five genes located on the long arm of the chromosome 17, including the ERBB2 oncogene (Slamon et al., 1989), revealed the existence of at least...

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