Islet-1 is a sensitive but not entirely specific marker for pancreatic neuroendocrine neoplasms and their metastases.
Graham Rondell P,Shrestha Bijayee,Caron Bolette L,Smyrk Thomas C,Grogg Karen L,Lloyd Ricardo V,Zhang Lizhi
The American journal of surgical pathology
Islet-1 (Isl1) is a transcription factor involved in the embryogenesis of islets of Langerhans. Immunohistochemically, Isl1 is a sensitive lineage-specific marker for pancreatic neuroendocrine neoplasms (NENs) and their metastases. Its specificity has not been documented, nor have large numbers of NENs from other parts of the gut or other organs been studied. We examined Isl1 expression in 203 primary NENs (gastroenteropancreatic, lung, breast, and ovarian neoplasms) and 40 hepatic NEN metastases (enteropancreatic and lung neoplasms) from known primaries. The correlation between Isl1 and CDX2 expression was studied using a tissue microarray containing 46 pancreatic NENs. Immunostaining for Isl1 and CDX2 was also performed in selected NENs from other sites. Isl1 was positive in 90% of pancreatic, 89% of duodenal, 100% of rectal, 38% of colonic, 14% of appendiceal, and 6% of ileal primaries. Isl1 was negative in all other NENs. Among metastatic neoplasms, 76% of pancreatic and 2 of 2 rectal NEN metastases were Isl1 positive, whereas all other tested metastases were negative. The overall sensitivity and specificity of Isl1 in identifying primary pancreatic NENs was 88% and 80%, respectively. Thirty-six of 46 pancreatic NENs in the tissue microarray were Isl1 positive; 4 were Isl1 negative but CDX2 positive. Our findings confirm that Isl1 is a sensitive marker of pancreatic origin in cases of metastatic NEN. However, Isl1 does not distinguish pancreatic NEN from duodenal and colorectal NEN, even when used in association with CDX2.
10.1097/PAS.0b013e31826f042c
ISL1 is upregulated in breast cancer and promotes cell proliferation, invasion, and angiogenesis.
Li Lin,Sun Fuwen,Chen Xiaoyan,Zhang Minghui
OncoTargets and therapy
ISL1 plays a key role in several cancers, including pheochromocytoma, gastrointestinal, pancreatic, and lung tumors and bile duct carcinoma. In order to elucidate the role of ISL1 in breast cancer, we performed quantitative real-time polymerase chain reaction and Western blotting analysis, and we found that ISL1 was upregulated in breast cancer cells and tissues. Moreover, high expression of ISL1 was correlated with tumor size, metastasis, and poor prognosis. Colony formation analysis and CCK-8 analysis revealed that ISL1 facilitated breast cancer cell proliferation. In addition, wound healing analysis and transwell invasion analysis demonstrated that ISL1 played a role in cell migration and invasion. Interestingly, the expression of ISL1 was also associated with the expression of vascular endothelial growth factor (VEGF) in breast cancer, and ISL1 promoted angiogenesis in breast cancer. In conclusion, reducing the expression of ISL1 suppresses proliferation, migration, invasion, and angiogenesis in breast cancer, suggesting that ISL1 might serve as a novel molecular therapy target in breast cancer.
10.2147/OTT.S144241
The expression of TTF1, CDX2 and ISL1 in 74 poorly differentiated neuroendocrine carcinomas.
Lee Hwajeong,Fu Zhiyan,Koo Brandon H,Sheehan Christine E,Young Gloria Q,Lin Jingmei,Patil Deepa T,Yang Zhaohai
Annals of diagnostic pathology
BACKGROUND:The expression profile of immunohistochemical markers of origin in poorly differentiated neuroendocrine carcinoma (PDNEC) is not well studied. MATERIALS AND METHODS:Seventy-four PDNECs from gastroenteropancreatic (GEP) organs and the lung, including 48 large cell NEC (LCNEC) and 26 small cell carcinomas (SmCC), were subject to immunohistochemical staining for CDX2, TTF1 and ISL1. The staining intensity (1 to 3) and percentage of positive tumor cells [0 (negative), 1 (<50%) and 2 (≥50%)] were assessed. The multiplicative index (maximum 6) was calculated and the average total score (aTS) was determined for each primary site and histologic subtype. RESULTS:In the 38 GEP and 36 lung PDNECs, CDX2, TTF1 and ISL1 staining was observed in 71% (aTS 2.8), 16% (aTS 0.4), 63% (aTS 1.9), and 22% (aTS 0.6), 72% (aTS 2.9) and 92% (aTS 3.8), respectively. GEP PDNECs showed a higher aTS for CDX2 and lower aTS for TTF1 and ISL1, compared to that of lung PDNECs (Student's t-test, p < 0.001). SmCC had a higher aTS for TTF1 and ISL1 (p < 0.001) and lower aTS for CDX2 (p < 0.002) than that of LCNEC. CONCLUSIONS:CDX2 and TTF1 demonstrate potential utility in suggesting the primary site of PDNEC. In addition, CDX2 may be useful in supporting the diagnosis of LCNEC in cases with overlapping or borderline morphology. Utility of ISL1 as an adjunctive diagnostic marker of SmCC remains to be studied.
10.1016/j.anndiagpath.2018.09.005
Value of SATB2, ISL1, and TTF1 to differentiate rectal from other gastrointestinal and lung well-differentiated neuroendocrine tumors.
Zhao Lian-Hua,Chen Chuan,Mao Cheng-Yi,Xiao He,Fu Ping,Xiao Hua-Liang,Wang Ge
Pathology, research and practice
BACKGROUND:Management of neuroendocrine tumors (NETs) depends on the primary site, but the location of many well-differentiated (WD) NETs is elusive. Organ-specific markers are required for pathological diagnosis from biopsy. Transcription factors with good organ specificity include TTF1 (thyroid transcription factor 1; lung), CDX2 (caudal type homeobox transcription factor 2; midgut), and ISL1 (ISL LIM homeobox 1) and PAX8 (paired box 8) for the pancreas and rectum. SATB2 (SATB homeobox 2) has shown high sensitivity and specificity in colorectal adenocarcinoma. This study determined the viability of SATB2 and other transcription factors as markers, single or in combination, for WD-NETs of various sites. METHODS:Immunohistochemical staining of 81 WD-NETs from 8 organ sites was performed to identify SATB2, TTF1, CDX2, ISL1, and PAX8. Receiver operating characteristic (ROC) curves were constructed for different combinations of the 5 markers to determine sensitivity and specificity. RESULTS:Among the WD-NETs, SATB2 was predominantly found in those of the rectum; TTF1 in the lung, larynx, and esophagus; and ISL1 in the duodenum and rectum. PAX8 and CDX2 showed poor organ specificity. ROC profiles showed 50% sensitivity and 96% specificity to lung for TTF1 ISL1-; and 65% sensitivity and 100% specificity to rectum for SATB2 ISL1- TTF1-. ISL1 SATB2- TTF1- showed 83% sensitivity and 85% specificity to the duodenum, and 44% sensitivity and 87% specificity to the pancreas. A literature search showed that there was no significant difference in the expression rates of the five transcription factors (TTF1, CDX2, SATB2, PAX8 and ISL1) between primary and metastatic WD-NETs at the same organ when there was a large sample size. CONCLUSION:Among the 5 transcription factors tested, SATB2 may be a viable marker of WE-NETs of the rectum. The combination of SATB2, ISL1, and TTF1 may help estimate the locations of WD-NETs of unknown origin.
10.1016/j.prp.2019.152448
Comparison of lung cancer cell lines representing four histopathological subtypes with gene expression profiling using quantitative real-time PCR.
Watanabe Takashi,Miura Tomohiro,Degawa Yusuke,Fujita Yuna,Inoue Masaaki,Kawaguchi Makoto,Furihata Chie
Cancer cell international
BACKGROUND:Lung cancers are the most common type of human malignancy and are intractable. Lung cancers are generally classified into four histopathological subtypes: adenocarcinoma (AD), squamous cell carcinoma (SQ), large cell carcinoma (LC), and small cell carcinoma (SC). Molecular biological characterization of these subtypes has been performed mainly using DNA microarrays. In this study, we compared the gene expression profiles of these four subtypes using twelve human lung cancer cell lines and the more reliable quantitative real-time PCR (qPCR). RESULTS:We selected 100 genes from public DNA microarray data and examined them by DNA microarray analysis in eight test cell lines (A549, ABC-1, EBC-1, LK-2, LU65, LU99, STC 1, RERF-LC-MA) and a normal control lung cell line (MRC-9). From this, we extracted 19 candidate genes. We quantified the expression of the 19 genes and a housekeeping gene, GAPDH, with qPCR, using the same eight cell lines plus four additional validation lung cancer cell lines (RERF-LC-MS, LC-1/sq, 86-2, and MS-1-L). Finally, we characterized the four subtypes of lung cancer cell lines using principal component analysis (PCA) of gene expression profiling for 12 of the 19 genes (AMY2A, CDH1, FOXG1, IGSF3, ISL1, MALL, PLAU, RAB25, S100P, SLCO4A1, STMN1, and TGM2). The combined PCA and gene pathway analyses suggested that these genes were related to cell adhesion, growth, and invasion. S100P in AD cells and CDH1 in AD and SQ cells were identified as candidate markers of these lung cancer subtypes based on their upregulation and the results of PCA analysis. Immunohistochemistry for S100P and RAB25 was closely correlated to gene expression. CONCLUSIONS:These results show that the four subtypes, represented by 12 lung cancer cell lines, were well characterized using qPCR and PCA for the 12 genes examined. Certain genes, in particular S100P and CDH1, may be especially important for distinguishing the different subtypes. Our results confirm that qPCR and PCA analysis provide a useful tool for characterizing cancer cell subtypes, and we discuss the possible clinical applications of this approach.
10.1186/1475-2867-10-2
Islet 1 (Isl1) expression is a reliable marker for pancreatic endocrine tumors and their metastases.
Schmitt Anja M,Riniker Florian,Anlauf Martin,Schmid Sonja,Soltermann Alex,Moch Holger,Heitz Philipp U,Klöppel Günther,Komminoth Paul,Perren Aurel
The American journal of surgical pathology
BACKGROUND:Tracing the origin of a metastasis of a neuroendocrine carcinoma is a challenge. The transcription factors Cdx2 and TTF1 have been found to be helpful in identifying well-differentiated neuroendocrine tumors of gastrointestinal and pulmonary origin, respectively. So far, such a marker is lacking for pancreatic neuroendocrine tumors (PETs) and metastases thereof. Islet1 (Isl1) is a transcription factor expressed in pancreatic islet cells. The aim of this study was (1) to test the specificity and sensitivity of Isl1 as a marker of PETs, and (2) to test the specificity and sensitivity of a panel of markers, including Isl1, Cdx2, and TTF1, for the localization of the primary. DESIGN:One hundred eighty-eight primary gastroenteropancreatic and pulmonary endocrine tumors and 49 metastases thereof were examined. Immunohistochemistry using antibodies directed against Isl1, Cdx2, and TTF1 was performed and the staining results were scored semiquantitatively. RESULTS:Isl1 proved to be a highly specific marker for pancreatic endocrine tumors. In 84 primary PET its specificity was 78.4% (sensitivity 74.3%) and in 18 metastases of PET the specificity reached 100% (sensitivity 77.8%). Strong Cdx2 staining showed a specificity for gastrointestinal origin of 83.9% (sensitivity 82%) in primary tumors and of 100% (sensitivity 40%) in metastases. Including weakly positive tumors lead to a decreased specificity but an increased sensitivity. TTF1 expression was detected in 2 PET and 1 ileal primary tumor only and was absent in all metastases of gastroenteropancreatic endocrine tumors. CONCLUSIONS:Isl1 is a reliable marker of pancreatic endocrine tumors and metastases thereof. It shows a comparable sensitivity and specificity as Cdx2 as a marker of ileal and appendiceal neuroendocrine tumors and their metastases. TTF1 is very rarely expressed in well-differentiated gastroentero-PETs. Therefore, the panel of Isl1, Cdx2, and TTF1 seems useful for examining metastases of well-differentiated endocrine carcinomas of unknown origin.
10.1097/PAS.0b013e318158a397