Gene Summary

Gene:NKX2-1; NK2 homeobox 1
Aliases: BCH, BHC, NK-2, TEBP, TTF1, NKX2A, NMTC1, T/EBP, TITF1, TTF-1, NKX2.1
Summary:This gene encodes a protein initially identified as a thyroid-specific transcription factor. The encoded protein binds to the thyroglobulin promoter and regulates the expression of thyroid-specific genes but has also been shown to regulate the expression of genes involved in morphogenesis. Mutations and deletions in this gene are associated with benign hereditary chorea, choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress, and may be associated with thyroid cancer. Multiple transcript variants encoding different isoforms have been found for this gene. This gene shares the symbol/alias 'TTF1' with another gene, transcription termination factor 1, which plays a role in ribosomal gene transcription. [provided by RefSeq, Feb 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:homeobox protein Nkx-2.1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NKX2-1 (cancer-related)

Huang TS, Lee JJ, Li YS, Cheng SP
Ethacridine Induces Apoptosis and Differentiation in Thyroid Cancer Cells
Anticancer Res. 2019; 39(8):4095-4100 [PubMed] Related Publications
BACKGROUND/AIM: Ethacridine is used as a topical antiseptic as well as for second-trimester abortion. Recent studies showed that ethacridine is an inhibitor of poly(ADP-ribose) glycohydrolase (PARG) and an activator of the transcriptional coactivator with PDZ-binding motif (TAZ). This study examined the effects of ethacridine on thyroid cancer cells.
MATERIALS AND METHODS: Thyroid cancer cell lines (FTC133 and SW1736) and thyroid follicular epithelial cells (Nthy-ori 3-1) were treated with ethacridine. Viability, clonogenicity, cell-cycle distribution, and apoptosis were evaluated. The expression of thyroid differentiation markers (TTF-1, PAX8, and NIS) was determined by real-time PCR.
RESULTS: Ethacridine suppressed cell growth and clonogenic ability of thyroid cancer cells in a time- and dose-dependent manner (p<0.001). No cell-cycle arrest was found, but ethacridine dose-dependently induced apoptosis of thyroid cancer cells (p<0.001). The PAX8 and NIS expressions were significantly increased in SW1736 (3.41-fold and 1.53-fold, respectively) and Nthy-ori 3-1 cells (2.73-fold and 4.12-fold, respectively).
CONCLUSION: Ethacridine elicits apoptotic cell death in thyroid cancer cells and promotes differentiation in a subset of thyroid follicular cells.

Pawelczyk K, Piotrowska A, Ciesielska U, et al.
Role of PD-L1 Expression in Non-Small Cell Lung Cancer and Their Prognostic Significance according to Clinicopathological Factors and Diagnostic Markers.
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The latest immunotherapy, used in the treatment of non-small cell lung cancer (NSCLC), uses monoclonal antibodies directed against programmed death ligand 1 (PD-L1) to inhibit its interaction with the PD-1 receptor. Elevated levels of PD-L1 expression were observed on NSCLC cells. The association between PD-L1 expression and clinicopathological features is still unclear. Therefore, we examined this relationship and also compare PD-L1 expression levels with Ki-67, p63 and TTF-1.
METHODS: 866 samples of NSCLCs were used to prepare tissue microarrays (TMAs) on which immunohistochemical (IHC) reactions were performed. Changes in the level of
RESULTS: PD-L1 expression was observed in 32.6% of NSCLCs. PD-L1 expression was increased in higher malignancy grades (G) (
CONCLUSIONS: PD-L1 expression seems to be associated with increased tumor proliferation and aggressiveness as well as shorter patient survival in NSCLC, predominantly in the AC group.

D'Almeida O, Mothar O, Bondzie EA, et al.
Encapsulated miR-200c and Nkx2.1 in a nuclear/mitochondria transcriptional regulatory network of non-metastatic and metastatic lung cancer cells.
BMC Cancer. 2019; 19(1):136 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNAs are noncoding RNA molecules of ~ 22 nucleotides with diagnostic and therapeutic action [Curr Drug Targets, 2015. 16(12): p. 1381-403], affecting the expression of mRNAs involved in invasion, migration, and development [Oncotarget, 2015. 6(9): p. 6472-98, Cancer Manag Res, 2014. 6: p. 205-16]. miR-200c is part of the miR-200c/141 cluster on chromosome 12p13. Its mechanism of action when encapsulated is critical in lung cancer when patients express changes in miRNAs. miR-200c be a potential biomarkers for various lung diseases. As a potential therapy, miR-200c can impacts lives as target lung cancer is a leading cause of death with about 234,000 cases annually, high heterogeneity, complex screening, and a 5-year survival rate of 16% [CA Cancer J Clin, 2016.66(1): p. 7-30]. Encapsulated miR-200c efficiently enhances bioavailability, pharmacokinetics of therapeutics and targeting to cells, improves efficacy and provides potential cure.
METHODS: The functions of miR-200c were determined in non-metastatic KW-634 and metastatic 821-T4 and 821-LN mouse lung cancer cell lines after various Nano vehicle treatments. Viability and cytotoxicity were determined by cell cycle and quantitative real-time PCR analyses were used to quantify levels of miR-200c and its target genes. In situ hybridization was used to visualize patterns of expression of miR-200c and others in the lung and many organs. Next-generation sequencing accession number GSE125000, invasion and migration assays using transwell chambers, and ActivSignal were used to elucidate the activation and inhibition profiles and perform direct expression measurements and modification of cellular components.
RESULTS: Due to their effectiveness as intracellular vesicles transporting miR-200c into, out, and between parts of the cells, miR-200c is encapsulated with cholesterol, an integral part of the biological membranes with very important physical properties of the vehicle. Nano miR-200c showed efficient cellular uptake in KW-634, 821-T4, and 821-LN cells with important changes in gene expression and new isoforms. In KW-634, when treated with encapsulated miR-200c and compare to the non-encapsulated control; miR-29b increased by 5261-fold, and in 821-T4/LN, miR-1247 increased by 150-fold. Conversely, miR-1247 and miR-675 decreased by 348 and 1029.5-fold, respectively. miR-189 decreased by 34-fold in treated 821-T4 cells. A reduction of growth was observed only after 48 h of treatment with Nano miR-200c. Moreover, labeling the vehicle with carboxy-fluorescein showed that the encapsulated particles enter the nucleus and mitochondria. Encapsulated miR-200c by entering the cells, the nucleus and mitochondria, trigger changes in cell cycle phases with 4 up to 12 fold percentage in G2 and S phase respectively compare to miR-200c. Endogenous expression of Nkx2.1, miR-200c, and their targets Myb, Nfib, Six4 and Six1 showed an inverse correlation, as observed in development.
CONCLUSIONS: Little is known about miR-200c involvement in regulatory processes. Nano miR-200c affects invasion and migration mechanisms. The expression of encapsulated miR-200c contributes to the inhibition/activation of Kras, EMT, Hippo, regulatory pathways and blockers of metastasis. Delivery of miR-200c increases the expression of miR-29b, an EMY regulator, and miR-1247, an inhibitor of cancer genes, both tumor suppressors involved in lung metastasis. Encapsulated miR-200c act on different proteins that regulates cell cycle pathways. These findings represent a part of a regulatory network providing new insights towards improvement of therapy.

Kim HS, Kim JH, Han B, Choi DR
Correlation of Thyroid Transcription Factor-1 Expression with
Medicina (Kaunas). 2019; 55(2) [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: This meta-analysis investigated the relationship between thyroid transcription factor-1 (TTF-1) expression and epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) to clarify whether TTF-1 can be a potential surrogate marker for EGFR mutation status in advanced NSLCL.
METHODS: A systematic searching of databases, including PubMed, EMBASE, Cochrane Library, and Google Scholar, was performed to identify studies assessing the correlation of TTF-1 expression with EGFR mutations. From 17 studies, 9764 patients were included in the combined analysis of odds ratio (OR) for the correlation between TTF-1 expression and
RESULTS: Compared with NSCLCs showing negative TTF-1 expression, tumors harboring TTF-1 overexpression showed a significantly higher rate of EGFR mutations (OR = 5.19, 95% confidence interval: 3.60⁻7.47, p < 0.00001). This correlation was observed in both subgroups of East Asian (OR = 4.33, 95% CI: 3.46⁻5.41, p < 0.00001) and European patients (OR = 4.64, 95% CI: 1.41⁻15.28, p < 0.01). In addition, TTF-1 expression was significantly associated with EGFR mutations in exon 19 (OR = 4.63, 95% CI: 2.89⁻7.41, p < 0.00001) as well as exon 21 (OR = 3.16, 95% CI: 1.04⁻9.60, p = 0.04).
CONCLUSIONS: This meta-analysis demonstrates a significant correlation between TTF-1 expression and EGFR mutations in patients with NSCLC. The status of TTF-1 expression may be a biomarker to guide anticancer treatment in patients with NSCLC and unknown EGFR mutation status.

Mitchell A, Wanczyk H, Jensen T, Finck C
Assessment of iPSC teratogenicity throughout directed differentiation toward an alveolar-like phenotype.
Differentiation. 2019 Jan - Feb; 105:45-53 [PubMed] Related Publications
Considerable work has gone into creating cell therapies from induced pluripotent stem cells (iPSCs) since their discovery just over a decade ago. However, comparatively little research has been done concerning the safety of iPSCs and their progeny and specifically the mechanisms governing teratogenicity. The aim of this study was to ascertain at what developmental phase iPSCs undergoing differentiation to an alveolar-like phenotype lose their capacity to form a teratoma and uncover potential mechanisms responsible. iPSCs were differentiated using a previously published directed differentiation protocol mirroring alveolar embryogenesis. At each developmental phase cell phenotype was assessed and cells mixed with Matrigel and injected subcutaneously above the hind limbs of NSG mice to determine teratogenicity. A genetic screen of 42 genes commonly associated with teratoma formation was conducted on all the cells and any resulting teratoma. It was found that neither NKX2-1 lung progenitors nor terminally differentiated alveolar-like cells formed teratomas. As expected the expression of pluripotency markers was diminished over differentiation. However, the expression of two proteoglycans, decorin and lumican, was increased more than 3000x during differentiation. Both decorin and lumican are putative tumor suppressors with additional functions in angiogenesis, fibrosis, inflammation and autophagy. We hypothesize that the increasing expression of these proteoglycans by iPSCs as they differentiate may act to inhibit host endothelial cell recruitment when implanted resulting in the inhibition of any teratoma formation by any remaining undifferentiated iPSCs.

Oktay E, Oflazoglu U, Varol Y, et al.
The prognostic role of thyroid transcription factor-1 in lung adenocarcinoma.
J Cancer Res Ther. 2018; 14(Supplement):S1201-S1208 [PubMed] Related Publications
Aims: In this study, we investigated the expression of thyroid transcription factor-1 (TTF-1) in lung adenocarcinoma patients' samples and analyzed the association of TTF-1 with clinicopathological parameters, prognosis, and treatment options in patients with lung adenocarcinoma.
Subjects and Methods: This retrospective study enrolled 200 patients who were histologically confirmed lung adenocarcinoma with Stage I-IV disease, between 2008 and 2015 years. The cytological archive of these hospitals' Pathology Department was searched. The available slides and the clinical information were reviewed and correlated. All analyses were conducted by SPSS version 15.0 statistical software.
Results: Sixty-five (32.5%) of the patients showed TTF-1 negativity and 135 (67.5%) of them showed TTF-1 positivity. The median survival for TTF-1 positive and negative patients was 19.6 and 12.2 months, respectively. We did not find any statistical significance in-between the parameters in terms of the survival data. In TTF-1-negative group, the survival time of epidermal growth factor receptor mutation positive (P = 0.049), cytokeratin 7 (CK7) positive (P = 0.009) patients and those who had received curative radiotherapy (P = 0.028) was significantly better as compared to TTF-1-positive group. We also analyzed the relation between TTF-1 and survival outcome or chemotherapy selection in Stage IV disease. We could not identify any correlation between TTF-1 and survival outcome or treatment selection.
Conclusions: This study suggests that TTF-1 is not a favorable prognostic factor in lung adenocarcinoma patients. The prognostic role of CK7 and relationship between TFF-1 expression in lung adenocarcinoma and predictive role of TTF-1 expression for the selection of first-line treatment in Stage IV lung adenocarcinoma should be validated in prospective and randomized studies.

Camolotto SA, Pattabiraman S, Mosbruger TL, et al.
FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer.
Elife. 2018; 7 [PubMed] Free Access to Full Article Related Publications
Changes in cancer cell identity can alter malignant potential and therapeutic response. Loss of the pulmonary lineage specifier NKX2-1 augments the growth of KRAS-driven lung adenocarcinoma and causes pulmonary to gastric transdifferentiation. Here, we show that the transcription factors FoxA1 and FoxA2 are required for initiation of mucinous NKX2-1-negative lung adenocarcinomas in the mouse and for activation of their gastric differentiation program.

Selberherr A, Koperek O, Riss P, et al.
Neuroendocrine Liver Metastasis-a Specific Set of Markers to Detect Primary Tumor Sites.
Endocr Pathol. 2019; 30(1):31-34 [PubMed] Related Publications
The diagnosis of neuroendocrine neoplasia (NEN) is often made at an advanced stage of disease, including hepatic metastasis. At this point, the primary may still be unknown and sometimes cannot even be detected by functional imaging, especially in very small tumors of the pancreas (pan) and small intestinal (si) entities. The site of the primary may be based on biopsy specimens of the liver applying a specific set of markers. Specimens of liver metastases from 87 patients with NENs were studied. In retrospect, 50 patients had si and 37 pan NENs. Tissue samples were evaluated by immunohistochemistry. The markers applied were insulin gene enhancer protein Islet-1 (ISL-1), homeobox protein CDX-2 (CDX2), thyroid transcription factor 1 (TTF-1), and serotonin. Positive stains for CDX2 were documented in 43 (86%) and for serotonin in 45 (90%) of 50 siNENs. Three panNENs were positive for CDX2 and one for serotonin, respectively. ISL-1 was negative throughout in siNENs and also negative in 8 of 50 panNENs (21.6%). TTF-1 was negative in more than 90% of the specimens of either entity. Immunohistochemical markers in liver metastasis can lead the way to the site of the primary NEN. They should always be used in combined clusters.

Mollaoglu G, Jones A, Wait SJ, et al.
The Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment.
Immunity. 2018; 49(4):764-779.e9 [PubMed] Article available free on PMC after 16/10/2019 Related Publications
The major types of non-small-cell lung cancer (NSCLC)-squamous cell carcinoma and adenocarcinoma-have distinct immune microenvironments. We developed a genetic model of squamous NSCLC on the basis of overexpression of the transcription factor Sox2, which specifies lung basal cell fate, and loss of the tumor suppressor Lkb1 (SL mice). SL tumors recapitulated gene-expression and immune-infiltrate features of human squamous NSCLC; such features included enrichment of tumor-associated neutrophils (TANs) and decreased expression of NKX2-1, a transcriptional regulator that specifies alveolar cell fate. In Kras-driven adenocarcinomas, mis-expression of Sox2 or loss of Nkx2-1 led to TAN recruitment. TAN recruitment involved SOX2-mediated production of the chemokine CXCL5. Deletion of Nkx2-1 in SL mice (SNL) revealed that NKX2-1 suppresses SOX2-driven squamous tumorigenesis by repressing adeno-to-squamous transdifferentiation. Depletion of TANs in SNL mice reduced squamous tumors, suggesting that TANs foster squamous cell fate. Thus, lineage-defining transcription factors determine the tumor immune microenvironment, which in turn might impact the nature of the tumor.

Zamboni M, Civitareale D
TTF-1/Nkx2.1 functional connection with mutated EGFR relies on LRIG1 and β-catenin pathways in lung cancer cells.
Biochem Biophys Res Commun. 2018; 505(4):1027-1031 [PubMed] Related Publications
In non-small lung cancer, the expression of the transcription factor TTF-1/Nkx2.1 correlates with the presence of EGFR mutations, therefore TTF-1/Nkx2.1 expression is used to optimize an EGFR testing strategy and to guide clinical treatment. We investigate the molecular mechanisms underlying the functional connection between EGFR and TTF-1/Nkx2.1 gene expression in lung adenocarcinoma. Using the H1975 cell line as a non-small cell lung cancer model system and short hairpin RNA, we have selected clones with TTF-1/Nkx2.1 silenced expression. We have found that Leucine-rich immunoglobulin repeats-1 (LRIG1) gene is a direct target of TTF-1/Nkx2.1 and the transcription factor binding to the LRIG1 genomic sequence inhibits its gene expression. In TTF-1/Nkx2.1 depleted clones, we have found high levels of LRIG1 and decreased presence of EGFR protein. Furthermore, in TTF-1/Nkx2.1 depleted clones we detected a reduced β-catenin level and we provide experimental evidence indicating that TTF-1/Nkx2.1 gene expression is regulated by β-catenin. Published studies indicate that LRIG1 triggers EGFR degradation and that mutated EGFR induces β-catenin activity. Hence, with the present study we show that mutated EGFR, enhancing β-catenin, stimulates TTF-1/Nkx2.1 gene expression and, at the same time, TTF-1/Nkx2.1, down-regulating LRIG1, sustains EGFR pathway. Therefore, LRIG1 and β-catenin mediate the functional connection between TTF-1/Nkx2.1 and mutated EGFR.

Ren Y, Zhang L, Xie H, et al.
Lymph Node Micrometastasis Prognosticates Survival for Patients with Stage 1 Bronchogenic Adenocarcinoma.
Ann Surg Oncol. 2018; 25(13):3812-3819 [PubMed] Related Publications
BACKGROUND: This study aimed to investigate the significance of lymph node micrometastasis (LNMM) in the lung cancer nodal categories.
METHODS: Between 1 January 2009 and 31 December 2013, 589 patients with suspected c-stage 1 and p-T1-2aN0-1M0 lung adenocarcinoma were enrolled in this study. The study evaluated LNMM with cytokeratin (AE1/AE3) and transcription factor-1 (TTF1) (8G7G3/1) expression by immunohistochemistry. Recurrence-free survival (RFS) and overall survival (OS) were compared among the T1-2aN0-1M0 patients stratified by the new N categories.
RESULTS: From 589 patients, 7892 removed lymph nodes were examined, and LNMM was observed in 55 (9.3%) of the patients. The patients without LNMM or N1 had the best RFS (5-year rate: 80% vs 25%; P < 0.001) and OS (5-year rate: 87% vs 43%; P < 0.001), followed by the patients with LNMM, compared with those in the N1 category (RFS: 5-year rate, 25% vs 8%; P = 0.010; OS: 5-year rate, 43% vs 20%; P = 0.009). Similarly, this trend was observed when patients were subdivided into the T1 and T2a categories. Multivariate analysis showed that the new N categories with the addition of LNMM were an independent prognostic factor. This result also was noticed in all subgroups.
CONCLUSIONS: The findings showed LNMM to be clinically significant as a risk factor for lung cancer. Clinicians should consider LNMM when estimating N categories to determine prognosis and the best treatment strategy.

Rodriguez EF, VandenBussche CJ, Chowsilpa S, Maleki Z
Molecular genetic alterations in thyroid transcription factor 1-negative lung adenocarcinoma in cytology specimens: A subset with aggressive behavior and a poor prognosis.
Cancer Cytopathol. 2018; 126(10):853-859 [PubMed] Related Publications
BACKGROUND: Patients with thyroid transcription factor 1 (TTF1)-negative pulmonary adenocarcinoma (ADC) have been reported to have a worse prognosis and to lack epidermal growth factor receptor (EGFR) mutations. This study describes a series of cytology specimens from patients with clinically confirmed pulmonary carcinoma negative for TTF1.
METHODS: A search for TTF1-negative ADC from 2010 to 2017 was performed. Each patient's clinical history, pathology specimens, and molecular results were noted. Two hundred ten patients with TTF1-positive pulmonary ADC formed the control group.
RESULTS: Fifty specimens were identified from 50 patients (26 females and 24 males). The median age was 58.5 years. The smoking history was as follows: 38 smokers/former smokers (76%), 10 nonsmokers (20%), and 2 patients with an unknown status (4%). Thirty-nine patients (78%) had no previous history of malignancy. The clinical stages were as follows: stage I or II (n = 2 [4%]), stage III (n = 9 [18%]), stage IV (n = 37 [74%]), and unknown (n = 2 [4%]). Patients' mean survival was 10.3 months. Molecular results were available in 43 cases. Twenty-seven cases (63%) had no mutation identified; when they were compared with the control group, TTF1-negative patients had overall shorter survival (P = .0047), even though no statistically significant difference was seen on the clinical stage. Known mutations were less frequent (P = .0095) in TTF-negative tumors (KRAS mutations, n = 11 [25%]; anaplastic lymphoma kinase [ALK], n = 3 [7%]; and EGFR, n = 2 [5%]). This was particularly true for EGFR mutations (P = .047). However, ALK rearrangements were present at an increased frequency in the TTF1-negative group (P = .018).
CONCLUSIONS: Patients with TTF1-negative lung ADC have worse overall survival, a lower frequency of known mutations, and a higher frequency of ALK alterations.

Takeuchi A, Oguri T, Yamashita Y, et al.
TTF-1 Expression Predicts the Merit of Additional Antiangiogenic Treatment in Non-squamous Non-small Cell Lung Cancer.
Anticancer Res. 2018; 38(9):5489-5495 [PubMed] Related Publications
BACKGROUND/AIM: To investigate whether TTF-1 expression predicts a beneficial response of non-squamous non-small-cell lung cancer (NS-NSCLC) patients to bevacizumab.
PATIENTS AND METHODS: We retrospectively screened 118 advanced NS-NSCLC patients who were treated with pemetrexed plus platinum derivatives alone (Bev(-)) or with bevacizumab (Bev(+)), and investigated the relationship between expression of TTF-1 and treatment outcomes.
RESULTS: Among the 92 TTF-1-positive patients, clinical outcomes in the Bev(+) group were significantly better than those in the Bev(-) group (response rate, 51.4% vs. 27.3%, p=0.027; median progression-free survival, 216 days vs. 137 days, p=0.012). Overall survival in the Bev(+) group tended to be longer than that in the Bev(-) group. However, the addition of bevacizumab to the standard treatment of 26 TTF-1-negative patients offered no clinical benefit.
CONCLUSION: TTF-1 expression may serve as a predictive marker to identify patients who may benefit from the addition of bevacizumab to platinum doublet therapy.

Vidarsdottir H, Tran L, Nodin B, et al.
Comparison of Three Different TTF-1 Clones in Resected Primary Lung Cancer and Epithelial Pulmonary Metastases.
Am J Clin Pathol. 2018; 150(6):533-544 [PubMed] Related Publications
Objectives: Immunohistochemical staining against thyroid transcription factor 1 (TTF-1) is often used to distinguish lung adenocarcinoma from squamous cell carcinoma and pulmonary metastasis.
Methods: TTF-1 expression was examined using the antibody clones 8G7G3/1, SPT24, and SP141 on tissue microarrays from 665 cases of resected lung cancers and 428 pulmonary metastases.
Results: Most lung adenocarcinomas, 89%, 93%, and 93%, were positive with TTF-1 clones 8G7G3/1, SPT24, and SP141, respectively. The corresponding figures for lung squamous cell carcinomas were 0%, 6%, and 8%. In total, five (2%), 19 (7%), and 21 (8%) of the pulmonary metastases from colorectal adenocarcinomas were positive with clones 8G7G3/1, SPT24, and SP141, respectively. Other TTF-1-positive pulmonary metastases (n = 8) were thyroid, urothelial, pancreatic, small bowel, and cervix carcinomas.
Conclusions: TTF-1 expression in lung cancer and pulmonary metastases differs between clones, with 8G7G3/1 being more specific but less sensitive compared with SPT24 and SP141.

Liu H, Zhang Y, Chang J, et al.
Differential expression of neuroendocrine markers, TTF-1, p53, and Ki-67 in cervical and pulmonary small cell carcinoma.
Medicine (Baltimore). 2018; 97(30):e11604 [PubMed] Article available free on PMC after 16/10/2019 Related Publications
Small cell carcinoma (SCC) is a highly malignant neuroendocrine tumor that may occur in many anatomic sites of the body.In this study, we compared the different expression of neuroendocrine markers, thyroid transcription factor 1 (TTF-1), p53, and Ki-67 in 23 cases of cervical SCC and 56 cases of pulmonary SCC using immunohistochemistry.Our study showed that cervical SCC had a younger onset age than pulmonary counterpart. Although both had the similar morphological features, different immunohistochemical expression panel was observed in this study. As neuroendocrine tumors, SCC of cervix and lung had similar immunoreactive staining for CD56 and chromogranin A, but the expression of the synaptophysin in cervical SCC was significantly higher than that in pulmonary SCC (P = .007). The TTF-1 expression of pulmonary SCC illustrating diffuse and strong positivity in tumor cell nuclei was significantly higher than that of the cervical SCC (P = .003). There was only 1 case showing p53 protein over-expression in the 23 cases of cervical SCC, and p53 over-expression was observed in 42.9% of pulmonary SCC (P = .001). Only 9 cases of cervical SCC showed ≥80% of the Ki-67 proliferation index, while it was found in 94.6% of pulmonary SCC (P < .001).The different immunohistochemical expressions of these 2 kinds of SCCs may be related with their pathogenetic mechanism, and these differences may be helpful in the identification of the origins of the metastatic SCC with unknown primary site.

Wang X, Zhang L, Wang Y, et al.
Sclerosing pneumocytoma with metastasis to the mediastinal and regional lymph nodes.
Indian J Pathol Microbiol. 2018 Jul-Sep; 61(3):407-409 [PubMed] Related Publications
Sclerosing pneumocytoma (SP) is an uncommon benign tumor, and metastasis of SP has been rarely reported. Here, we report the case of a 26-year-old woman with surgically confirmed SP. The tumor diameter was 40 mm, and metastasis to mediastinal and regional lymph nodes was observed. Immunohistochemically, both surface and round cells were positive for epithelial membrane antigen, thyroid transcription factor 1, and vimentin. Only surface cells expressed creatine kinase, carcinoembryonic antigen, napsin A, and cytokeratin 7, and only round cells expressed progesterone receptor. Ki-67 was detected in ~3% of cells, and the rate of weak positive p53 staining was 3%. Both cell types were negative for chromogranin A, synaptophysin, CD3, and CK20. Multiple metastases in a young SP patient are very rare, and potential mechanisms of metastasis may be related to epithelial-mesenchymal transformation.

Doherty MK, O'Connor E, Hannon D, et al.
Absence of thyroid transcription factor-1 expression is associated with poor survival in patients with advanced pulmonary adenocarcinoma treated with pemetrexed-based chemotherapy.
Ir J Med Sci. 2019; 188(1):69-74 [PubMed] Related Publications
INTRODUCTION: Adenocarcinoma is the commonest histologic subtype of lung cancer and is often identified by immunohistochemical staining for thyroid transcription factor-1 (TTF-1). However, up to 20% of lung adenocarcinomas do not express TTF-1, and there is uncertainty regarding the significance of this. We aimed to evaluate the prognostic effect of TTF-1 expression status on survival in patients treated with pemetrexed-based chemotherapy for advanced adenocarcinoma of the lung.
METHODS: This retrospective study included patients treated with pemetrexed-based chemotherapy for stage IIIB/IV lung adenocarcinoma, who had known TTF-1 expression status. Clinical and demographic data were obtained from medical records. Overall survival (OS) was estimated using the Kaplan-Meier method, and differences in survival between groups assessed using the Cox proportional hazards model.
RESULTS: Forty-four patients were identified with documented TTF-1 expression: 35 with TTF-1-positive and 9 with TTF-1-negative disease. Patients in the TTF-1-negative group had poorer performance scores than those in the TTF-1-positive group (ECOG 2: 67 vs 20%, p = 0.008), and received less chemotherapy (median cycles 2 vs 4, p = 0.009), and were fewer in treatment with doublet regimens (22 vs 69%, p = 0.013). OS was significantly shorter in the TTF-1-negative group than in the TTF-1-positive group (2.4 vs 11.5 months, HR 8.38, p < 0.0001).
CONCLUSIONS: In this group of patients treated with pemetrexed-based chemotherapy for advanced pulmonary adenocarcinoma, absence of TTF-1 expression was associated with an aggressive tumor phenotype, poorer performance status, and poor survival. This subgroup of patients should be recognized as having a distinct clinical course, with limited benefit from standard chemotherapy.

Zhang Y, Yang J, Zhang M, et al.
Thyroid follicular carcinoma-like renal tumor: A case report and literature review.
Medicine (Baltimore). 2018; 97(21):e10815 [PubMed] Article available free on PMC after 16/10/2019 Related Publications
RATIONALE: Thyroid follicular carcinoma-like renal tumor (TFCLRT) is a rare primary renal epithelial tumor that was first reported in 2006. We report a case diagnosed of TFCLRT by us to observe the pathological feature and analyze comparatively the clinical and pathologic characteristics with all cases of reviewed literatures.
PATIENT CONCERNS: A 54-year-old female patient had the urinary frequency with the symptom of right flank pain with a history of more than half a year of hypertension and received uterine fibroid resection 12 years ago. B-mode ultrasound examination and renal magnetic resonance showed a right renal sinus nodule.
DIAGNOSES: Histopathology revealed thyroid follicle-like structures of different sizes, containing a colloid-like substance, while the periodic acid-Schiff (PAS) and diastase-resistant PAS staining confirmed that it was mucus protein. Immunohistochemical staining showed that it expresses the transcription factor PAX-8 but does not express the thyroid-specific antibodies TG and TTF-1.
INTERVENTIONS: The patient underwent a tumor enucleation of right kidney. No other treatment was conducted after surgery.
OUTCOMES: No metastases to lymph nodes and other organs were found, and 9-months of follow-up did not reveal any tumor progression.
LESSONS: We should differentially diagnose the renal metastasis of thyroid follicular carcinoma or papillary carcinoma. Some related literatures reported that the tumour cells had significant heteromorphism, several of which metastasized to lymph nodes or distal organs. Its biological behavior need to be studied intensively by further expanding the number of cases.

Iida Y, Masuda S, Nakanishi Y, et al.
Clinicopathological characteristics of thyroid transcription factor 1-negative small cell lung cancers.
Hum Pathol. 2018; 79:127-134 [PubMed] Related Publications
Limitations in obtaining surgically resected or biopsy samples of small cell lung cancer (SCLC) tumors make comprehensive biological analyses difficult. The loss of thyroid transcription factor 1 (TTF-1) has been associated with the aggressive behavior of non-small cell lung cancer; however, clinicopathological features of TTF-1-negative SCLC remain unclear. This study aimed to elucidate the characteristics of TTF-1-negative SCLC. We studied the associations between the expression of TTF-1 and the clinicopathological factors associated with SCLC, including survival and expression of neuroendocrine markers (synaptophysin, chromogranin A, and CD56), neuroendocrine cell-specific transcription factors (ASCL1, BRN2), a proliferation marker (Ki-67 labeling index), and an oncogene (NF1B). Formalin-fixed and paraffin-embedded sections of SCLC tumors were subjected to immunohistochemistry and quantitative reverse-transcription polymerase chain reaction analyses. In a case-control cohort matched for basic clinical factors, expression of ProGRP, synaptophysin, chromogranin A, and ASCL1 was significantly decreased in TTF-1-negative SCLC samples. In contrast, there was no significant correlation between Ki-67 labeling index and TTF-1. In a larger serial case cohort, TTF-1-negative SCLC cases were older at diagnosis, but there was no significant difference in the overall survival of patients with TTF-1-negative and TTF-1-positive SCLC. In conclusion, TTF-1-negative SCLC showed decreased neuroendocrine differentiation, and significantly worse clinical outcomes were not observed.

Sterlacci W, Fiegl M, Veits L, Tzankov A
Diagnostic and prognostic impact of mucin 1-6 expression in non-small cell lung cancer.
Indian J Pathol Microbiol. 2018 Apr-Jun; 61(2):187-191 [PubMed] Related Publications
Background: The prognostic significance and clinico-pathological characterization of mucin (MUC) expression in non-small cell lung cancer (NSCLC) is controversial and little studied.
Aims: This study aims at elucidating this issue on the largest and most detailed cohort so far.
Settings and Design: We examined the expression of MUC 1, 2, 4, 5AC and 6 on 371, well documented, surgically resected NSCLC cases.
Materials and Methods: Immunohistochemical results were correlated with several of our previously studied, relevant parameters on this cohort including a follow-up period of up to 20 years. An additional point we examined for practical reasons that has not been addressed so far, was the possible assistance of MUC expression for the differentiation between a primary lung adenocarcinoma and metastasis from a known pancreatobiliary primary tumor.
Statistical Analysis Used: Cronbach's Alpha reliability correlation, Spearman's correlation, ANOVA means of comparison with additional Kruskall-Wallis H-test, and Kaplan-Meier survival analysis were employed as statistical analyses in this study.
Results and Conclusions: MUCs were associated with histologic subtypes, tumor differentiation and members of the epidermal growth factor receptor signaling pathway, although they were not found to be significant for prognosis. Expression of MUC1 correlated with certain other markers and may point to a group of patients relevant for upcoming treatment strategies involving MUC1. According to our findings, we also recommend additional MUC5AC staining for a thyroid transcription factor 1-negative adenocarinoma in the lung for the differentiation of a possible metastasis in the presence of a pancreatic ductal adenocarcinoma.

Tata PR, Chow RD, Saladi SV, et al.
Developmental History Provides a Roadmap for the Emergence of Tumor Plasticity.
Dev Cell. 2018; 44(6):679-693.e5 [PubMed] Article available free on PMC after 16/10/2019 Related Publications
We show that the loss or gain of transcription factor programs that govern embryonic cell-fate specification is associated with a form of tumor plasticity characterized by the acquisition of alternative cell fates normally characteristic of adjacent organs. In human non-small cell lung cancers, downregulation of the lung lineage-specifying TF NKX2-1 is associated with tumors bearing features of various gut tissues. Loss of Nkx2-1 from murine alveolar, but not airway, epithelium results in conversion of lung cells to gastric-like cells. Superimposing oncogenic Kras activation enables further plasticity in both alveolar and airway epithelium, producing tumors that adopt midgut and hindgut fates. Conversely, coupling Nkx2-1 loss with foregut lineage-specifying SOX2 overexpression drives the formation of squamous cancers with features of esophageal differentiation. These findings demonstrate that elements of pathologic tumor plasticity mirror the normal developmental history of organs in that cancer cells acquire cell fates associated with developmentally related neighboring organs.

Lai SC, Phelps CA, Short AM, et al.
Thyroid transcription factor 1 enhances cellular statin sensitivity via perturbing cholesterol metabolism.
Oncogene. 2018; 37(24):3290-3300 [PubMed] Article available free on PMC after 16/10/2019 Related Publications
We have discovered an unexpected connection between a critical lung development and cancer gene termed thyroid transcription factor 1 (TTF-1 also known as NKX2-1) and cholesterol metabolism. Our published work implicates that TTF-1 positively regulates miR-33a which is known to repress ATP-binding cassette transporter 1 (ABCA1) and thus its cholesterol efflux activity. We set out to demonstrate that a higher TTF-1 expression would presumably inhibit cholesterol efflux and consequently raise intracellular cholesterol level. Surprisingly, raising TTF-1 expression actually lowers intracellular cholesterol level, which, we believe, is attributed to a direct transactivation of ABCA1 by TTF-1. Subsequently, we show that lung cancer cells primed with a TTF-1-driven decrease of cholesterol were more vulnerable to simvastatin, a frequently prescribed cholesterol biosynthesis inhibitor. In view of the fact that pathologists routinely interrogate human lung cancers for TTF-1 immunopositivity to guide diagnosis and the prevalent use of statins, TTF-1 should be further investigated as a putative biomarker of lung cancer vulnerability to statins.

Zhang Z, Wang H, Ding Q, et al.
Establishment of patient-derived tumor spheroids for non-small cell lung cancer.
PLoS One. 2018; 13(3):e0194016 [PubMed] Article available free on PMC after 16/10/2019 Related Publications
The prognosis of advanced non-small cell lung cancer (NSCLC) patients is poor. One of the reasons for this hampered progress has been a lack of in vitro models that would faithfully recapitulate the heterogeneity of tumors and response to treatment. In this study, surgically resected tumors were obtained from patients with stage I/II NSCLC during curative-intent surgery. Using a 3D patient-derived tumor spheroids culture system, our results demonstrate successful long-term expansion of primary NSCLC cells in vitro (> 120 days). Patient-derived tumor spheroid (PDS) cultures could be established with a success rate of 100% (3 out of 3 samples). Consistent with their growth in culture and their cancer type, many cells within the tumor spheroids were stained positive for Ki67 and thyroid transcription factor-1. The result of this study supports the establishment of an expandable 3D in vitro NSCLC model for drug screening, and enables the potential long term studies such as the establishment of drug resistant models.

Shibuya M
Welcoming the new WHO classification of pituitary tumors 2017: revolution in TTF-1-positive posterior pituitary tumors.
Brain Tumor Pathol. 2018; 35(2):62-70 [PubMed] Related Publications
The fourth edition of the World Health Organization classification of endocrine tumors (EN-WHO2017) was released in 2017. In this new edition, changes in the classification of non-neuroendocrine tumors are proposed particularly in tumors arising in the posterior pituitary. These tumors are a distinct group of low-grade neoplasms of the sellar region that express thyroid transcription factor-1, and include pituicytoma, granular cell tumor of the sellar region, spindle cell oncocytoma, and sellar ependymoma. This short review focuses on the classification of posterior pituitary tumors newly proposed in EN-WHO2017, and controversies in their pathological differential diagnosis are discussed based on recent cases.

Mervai Z, Egedi K, Kovalszky I, Baghy K
Diethylnitrosamine induces lung adenocarcinoma in FVB/N mouse.
BMC Cancer. 2018; 18(1):157 [PubMed] Article available free on PMC after 16/10/2019 Related Publications
BACKGROUND: Diethylnitrosamine is a well known carcinogen that induces cancers of various organs in mice and rats. Using FVB/N mouse strain, here we show that diethylnitrosamine induces primarily lung adenocarcinomas with modest tumor development in the liver, offering a new model to study chemical carcinogenesis in the lung.
METHODS: Animals were exposed to a single high dose of diethylnitrosamine, and more than 70% of the mice developed lung cancer. To obtain a new transplantable tumor line, pieces of primary tumors were inoculated and maintained subcutaneously in the same mouse strain. We used immunohistochemistry to characterize the tumor for main lung adenocarcinoma markers. We searched for mutations in KRAS exon 2 and EGFR exon 19, 21 with Sanger sequencing. We also compared the normal lung tissue with the diethylnitrosamine induced primary adenocarcinoma, and with the subcutaneously maintained adenocarcinoma using Western blot technique for main cell cycle markers and to identify the main pathways.
RESULTS: Primary and subcutaneous tumors express cytokeratin-7 and thyroid transcription factor-1, markers characteristic to lung adenocarcinoma. In addition, no mutations were found in the hot spot regions of KRAS and EGFR genes. We found high mTOR activation, but the level of p-Akt Ser473 and p-Akt Thr308 decreased in the tumorous samples.
CONCLUSIONS: We established a new lung adenocarcinoma model using FVB/N mouse strain and diethylnitrosamine. We believe that this new model system would be highly useful in lung cancer research.

Hayashi T, Takamochi K, Yanai Y, et al.
Non-small cell lung carcinoma with diffuse coexpression of thyroid transcription factor-1 and ΔNp63/p40.
Hum Pathol. 2018; 78:177-181 [PubMed] Related Publications
Here, we present a case of non-small cell lung carcinoma (NSCLC) with widespread and strong nuclear immunopositivity for both thyroid transcription factor-1 (TTF-1) and ΔNp63/p40 (p40). Double immunofluorescence for TTF-1 and p40 showed coexpression of both markers in the tumor cells. Furthermore, PTEN (pHis123Asp) and TP53 (pVal272Leu) mutations were identified as possible mitogenic driver mutations by next-generation sequencing. To the best of our knowledge, this is the first case of NSCLC harboring concurrent PTEN and TP53 mutations with widespread and strong coexpression of TTF-1 and p40, which has been confirmed in the resected specimen, and only the second documented case of NSCLC with TTF-1 and p40 diffuse coexpression in the carcinoma cells from the same individual. Our case illustrates the possibility that poorly differentiated NSCLCs with widespread and strong nuclear positivity for TTF-1 and p40 may be an underrecognized and new entity.

Zhang WL, Ma S, Havrilla L, et al.
Primary thyroid-like low-grade nasopharyngeal papillary adenocarcinoma: A case report and literature review.
Medicine (Baltimore). 2017; 96(47):e8851 [PubMed] Article available free on PMC after 16/10/2019 Related Publications
RATIONALE: Primary thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is an extremely rare malignant nasopharyngeal tumor with features resembling papillary thyroid carcinoma including nuclear positive expression of thyroid transcription factor-1 (TTF-1).
PATIENT CONCERNS: A 64-year-old male presented with nasal bleeding and a foreign body sensation of the nasopharynx. Laryngoscopy revealed a 2.0-cm broad-based mass with a smooth surface on the posterior wall of the nasopharynx. A biopsy was obtained.
DIAGNOSES: Histopathologic examination demonstrated tumor cells arranged in both papillary and glandular architecture. The tumor cells express nuclear immunoreactivity for TTF-1. The diagnosis of TL-LGNPPA was made.
INTERVENTIONS: After the patient was diagnosed with TL-LGNPPA, he underwent complete surgical resection.
OUTCOMES: There was no recurrence or evidence of metastatic disease at the 12-month follow-up.
LESSONS: TL-LGNPPA is easy to misdiagnose as metastatic papillary thyroid carcinoma or other relative primary adenocarcinomas. It is important to have a broad differential diagnosis and know the key features of each entity because the prognosis and clinical treatment of each may differ.

Hanley KZ, Dureau ZJ, Cohen C, et al.
Orthopedia homeobox is preferentially expressed in typical carcinoids of the lung.
Cancer Cytopathol. 2018; 126(4):236-242 [PubMed] Related Publications
BACKGROUND: Twenty-seven percent of neuroendocrine tumors (NETs) are associated with distant metastases, and in some patients, the primary site is unknown. Orthopedia homeobox protein (OTP) has been described as a useful marker for lung carcinoids (LCs) and for separating low-grade typical carcinoids (TCs) from intermediate-grade atypical carcinoids (ACs) in resection specimens. This study evaluated OTP, thyroid transcription factor 1 (TTF-1), and Ki-67 expression in fine-needle aspiration (FNA) samples of various NETs.
METHODS: A search for NETs diagnosed via FNA with subsequent resection was performed. Cell block sections were stained for OTP, TTF-1, and mindbomb E3 ubiquitin protein ligase 1 (Mib-1). Nuclear expression for OTP and TTF-1 was considered positive. Nuclear Ki-67 staining was reported as a percentage. Results were correlated with the grade and primary site for resection specimens.
RESULTS: Sixty-three FNA samples of NETs were identified: 14 liver samples, 14 pancreatic samples, 13 lymph node samples, 12 lung samples, 3 retroperitoneum samples, 2 small intestine samples, and 5 other samples. OTP was positive in 12 of 63 NETs (19%) from the following sites: lung (n = 8), liver (lung primary; n = 2), skin (n = 1), and lymph node (lung primary; n = 1). In well-differentiated NETs, only LCs were OTP-positive, whereas TTF-1 was positive in LCs and nonlung NETs (67% vs 7%). Within the LC category, OTP was positive in 100% of the TCs versus 17% of the ACs.
CONCLUSIONS: OTP is specific for LCs because well-differentiated nonlung NETs are negative for OTP. OTP preferentially stains TCs over ACs. In well-differentiated NETs, OTP staining is highly specific for LCs, and in combination with a low Ki-67 index, it suggests a pulmonary TC. Cancer Cytopathol 2018;126:236-42. © 2018 American Cancer Society.

Okamoto M, Takazawa A, Aoki K, et al.
Initial clinical presentation of single soft tissue metastasis of medullary thyroid carcinoma without primary tumor in the thyroid gland.
World J Surg Oncol. 2017; 15(1):221 [PubMed] Article available free on PMC after 16/10/2019 Related Publications
BACKGROUND: Single soft tissue metastasis of medullary thyroid carcinoma is extremely rare. In addition, several occult medullary thyroid carcinomas with distant metastasis were reported, but undetectable primary lesion at diagnosis was also extremely rare.
CASE PRESENTATION: A 74-year-old man was admitted to our hospital because of a painful nodule in his left buttock for over 1 year. Needle biopsy was performed, and the histological findings revealed adenocarcinoma positive for thyroid transcription factor-1. No evidence of a primary tumor, including the lung and thyroid gland, could be found elsewhere despite detailed examinations, including thyroid echography, chest computed tomography, and fluorodeoxyglucose-positron emission tomography. The soft tissue tumor was resected with a wide margin. Immunohistochemical analysis showed the tumor cells to be positive for cytokeratin-AE1/3, cytokeratin 7, synaptophysin, chromogranin A, calcitonin, and carcinoembryonic antigen, but negative for cytokeratin 20, Napsin A, Pax8, and p40, resulting in a diagnosis of metastasis of medullary thyroid carcinoma.
CONCLUSION: Initial presentation with a single metastasis to soft tissue and undetectable primary tumor in the thyroid gland is an extremely rare clinical manifestation in patients with medullary thyroid carcinoma.

Moisés J, Navarro A, Santasusagna S, et al.
NKX2-1 expression as a prognostic marker in early-stage non-small-cell lung cancer.
BMC Pulm Med. 2017; 17(1):197 [PubMed] Article available free on PMC after 16/10/2019 Related Publications
BACKGROUND: NKX2-1, a key molecule in lung development, is highly expressed in non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma (ADK), where it is a diagnostic marker. Studies of the prognostic role of NKX2-1 in NSCLC have reported contradictory findings. Two microRNAs (miRNAs) have been associated with NKX2-1: miR-365, which targets NKX2-1; and miR-33a, which is downstream of NKX2-1. We have examined the effect of NKX2-1, miR-365 and miR-33a on survival in a cohort of early-stage NSCLC patients and in sub-groups of patients classified according to the mutational status of TP53, KRAS, and EGFR.
METHODS: mRNA and miRNA expression was determined using TaqMan assays in 110 early-stage NSCLC patients. TP53, KRAS, and EGFR mutations were assessed by Sanger sequencing.
RESULTS: NKX2-1 expression was upregulated in never-smokers (P = 0.017), ADK (P < 0.0001) and patients with wild-type TP53 (P = 0.001). A negative correlation between NKX2-1 and miR-365 expression was found (ρ = -0.287; P = 0.003) but there was no correlation between NKX2-1 and miR-33a expression. Overall survival (OS) was longer in patients with high expression of NKX2-1 than in those with low expression (80.8 vs 61.2 months (P = 0.035), while a trend towards longer OS was observed in patients with low miR-365 levels (P = 0.07). The impact of NKX2-1 on OS and DFS was higher in patients with neither TP53 nor KRAS mutations. Higher expression of NKX2-1 was related to higher OS (77.6 vs 54 months; P = 0.017) and DFS (74.6 vs 57.7 months; P = 0.006) compared to low expression. The association between NKX2-1 and OS and DFS was strengthened when the analysis was limited to patients with stage I disease (P = 0.005 and P=0.003 respectively).
CONCLUSIONS: NKX2-1 expression impacts prognosis in early-stage NSCLC patients, particularly in those with neither TP53 nor KRAS mutations.

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