Cytokeratin 5 and cytokeratin 6 expressions are unconnected in normal and cancerous tissues and have separate diagnostic implications

Abstract Cytokeratins (CKs) 5 and 6 are functionally unrelated but often analyzed together using bispecific antibodies in diagnostic immunohistochemistry. To better understand the diagnostic utility of CK5 or CK6 alone, tissue microarrays with > 15,000 samples from 120 different tumor types as well as 608 samples of 76 different normal tissues were analyzed by immunohistochemistry. In normal tissues, both CKs occurred in the squamous epithelium; CK5 dominated in basal and CK6 in suprabasal layers. CK5 (not CK6) stained basal cells in various other organs. Within tumors, both CK5 and CK6 were seen in > 95% of squamous cell carcinomas, but other tumor entities showed different results: CK5 predominated in urothelial carcinoma and mesothelioma, but CK6 in adenocarcinomas. Joint analysis of both CK5 and CK6 obscured the discrimination of epithelioid mesothelioma (100% positive for CK5 alone and for CK5/6) from adenocarcinoma of the lung (12.8% positive for CK5 alone; 23.7% positive for CK5/6). CK5 and CK6 expressions were both linked to high grade, estrogen receptor, and progesterone receptor negativity in breast cancer (p < 0.0001 each), grade/stage progression in urothelial cancer (p < 0.0001), and RAS mutations in colorectal cancer (p < 0.01). Useful diagnostic properties which are commonly attributed to CK5/6 antibodies such as basal cell staining in the prostate, distinction of adenocarcinoma of the lung from squamous cell carcinoma and epithelioid mesothelioma, and identification of basal-type features in urothelial cancer are solely driven by CK5. At least for the purpose of distinguishing thoracic tumors, monospecific CK5 antibodies may be better suited than bispecific CK5/6 antibodies.

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Prevalence of Syndecan-1 (CD138) Expression in Different Kinds of Human Tumors and Normal Tissues

Disease Markers ◽

10.1155/2019/4928315 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Simon Kind ◽

Christina Merenkow ◽

Franziska Büscheck ◽

Katharina Möller ◽

David Dum ◽

...

Keyword(s):

Squamous Cell ◽

Human Cancer ◽

Germ Cell Tumors ◽

Tissue Microarrays ◽

Squamous Cell Carcinomas ◽

Cervix Uteri ◽

Endocrine Tumors ◽

Tissue Samples ◽

Preferential Expression ◽

Normal Tissues

Syndecan-1 (CD138) is a transmembrane proteoglycan known to be expressed in various normal and malignant tissues. It is of interest because of a possible prognostic role of differential expression in tumors and its role as a target for indatuximab, a monoclonal antibody coupled with a cytotoxic agent. To comprehensively analyze CD138 in normal and neoplastic tissues, we used tissue microarrays (TMAs) for analyzing immunohistochemically detectable CD138 expression in 2,518 tissue samples from 85 different tumor entities and 76 different normal tissue types. The data showed that CD138 expression is abundant in tumors. At least an occasional weak CD138 immunostaining could be detected in 71 of 82 (87%) different tumor types, and 58 entities (71%) had at least one tumor with a strong positivity. In normal tissues, a particularly strong expression was found in normal squamous epithelium of various organs, goblet and columnar cells of the gastrointestinal tract, and in hepatocytes. The highly standardized analysis of most human cancer types resulted in a ranking order of tumors according to the frequency and levels of CD138 expression. CD138 immunostaining was highest in squamous cell carcinomas such as from the esophagus (100%), cervix uteri (79.5%), lung (85.7%), vagina (89.7%) or vulva (73.3%), and in invasive urothelial cancer (76.2%). In adenocarcinomas, CD138 was also high in lung (82.9%) and colorectal cancer (85.3%) but often lower in pancreas (73.3%), stomach (54.2% in intestinal type), or prostate carcinomas (16.3%). CD138 expression was usually low or absent in germ cell tumors, sarcomas, endocrine tumors including thyroid cancer, and neuroendocrine tumors. In summary, the preferential expression in squamous cell carcinomas of various sites makes these cancers prime targets for anti-CD138 treatments once these might become available. Abundant expression in many different normal tissues might pose obstacles to exploiting CD138 as a therapeutic target, however.

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p63 expression in human tumors and normal tissues: a tissue microarray study on 10,200 tumors

Biomarker Research ◽

10.1186/s40364-021-00260-5 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Stefan Steurer ◽

Claudia Riemann ◽

Franziska Büscheck ◽

Andreas M. Luebke ◽

Martina Kluth ◽

...

Keyword(s):

Squamous Epithelium ◽

P53 Gene ◽

Tissue Microarrays ◽

Published Data ◽

Tissue Samples ◽

Normal Tissues ◽

Pancreatic Cancers ◽

Urothelial Carcinomas ◽

Specific Tumor ◽

Tumor Types

Abstract Background Tumor protein 63 (p63) is a transcription factor of the p53 gene family involved in differentiation of several tissues including squamous epithelium. p63 immunohistochemistry is broadly used for tumor classification but published data on its expression in cancer is conflicting. Methods To comprehensively catalogue p63 expression, tissue microarrays (TMAs) containing 12,620 tissue samples from 115 tumor entities and 76 normal tissue types were analyzed. Results p63 expression was seen in various normal tissues including squamous epithelium and urothelium. At least occasional weak p63 positivity could be detected in 61 (53%) of 115 different tumor types. The frequencies of p63 positivity was highest in squamous cell carcinomas irrespective of their origin (96–100%), thymic tumors (100%), urothelial carcinomas (81–100%), basal type tumors such as basal cell carcinomas (100%), and various salivary gland neoplasias (81–100%). As a rule, p63 was mostly expressed in cancers derived from p63 positive normal tissues and mostly not detectable in tumors derived from p63 negative cancers. However, exceptions from this rule occurred. A positive p63 immunostaining in cancers derived from p63 negative tissues was unrelated to aggressive phenotype in 422 pancreatic cancers, 160 endometrium cancers and 374 ovarian cancers and might be caused by aberrant squamous differentiation or represent stem cell properties. In 355 gastric cancers, aberrant p63 expression occurred in 4% and was linked to lymph node metastasis (p = 0.0208). Loss of p63 in urothelial carcinomas - derived from p63 positive urothelium - was significantly linked to advanced stage, high grade (p < 0.0001 each) and poor survival (p < 0.0001) and might reflect clinically relevant tumor dedifferentiation. Conclusion The high prevalence of p63 expression in specific tumor types makes p63 immunohistochemistry a suitable diagnostic tool. Loss of p63 expression might constitute a feature of aggressive cancers.

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Glucose transporter Glut-1 is detectable in peri-necrotic regions in many human tumor types but not normal tissues: Study using tissue microarrays

Annals of Anatomy - Anatomischer Anzeiger ◽

10.1016/j.aanat.2010.03.001 ◽

2010 ◽

Vol 192 (3) ◽

pp. 133-138 ◽

Cited By ~ 28

Author(s):

Rachel Airley ◽

Andrew Evans ◽

Ali Mobasheri ◽

Stephen M. Hewitt

Keyword(s):

Glucose Transporter ◽

Human Tumor ◽

Tissue Microarrays ◽

Glut 1 ◽

Normal Tissues ◽

Tumor Types

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Large-Scale Tissue Microarray Evaluation Corroborates High Specificity of High-Level Arginase-1 Immunostaining for Hepatocellular Carcinoma

Diagnostics ◽

10.3390/diagnostics11122351 ◽

2021 ◽

Vol 11 (12) ◽

pp. 2351

Author(s):

Maximilian Lennartz ◽

Eva Gehrig ◽

Sören Weidemann ◽

Natalia Gorbokon ◽

Anne Menz ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Squamous Cell ◽

Large Scale ◽

High Specificity ◽

Tissue Microarrays ◽

Squamous Cell Carcinomas ◽

Low Grade ◽

Normal Tissues ◽

Arginase 1 ◽

High Level

Arginase-1 catalyzes the conversion of arginine to ornithine and urea. Because of its predominant expression in hepatocytes, it serves as a marker for hepatocellular carcinoma, although other tumor entities can also express arginase-1. To comprehensively determine arginase-1 expression in normal and neoplastic tissues, tissue microarrays containing 14,912 samples from 117 different tumor types and 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry. In normal tissues, arginase-1 was expressed in the liver, the granular layer of the epidermis, and in granulocytes. Among tumors, a nuclear and cytoplasmic arginase-1 immunostaining was predominantly observed in hepatocellular carcinoma, where 96% of 49 cancers were at least moderately positive. Although 22 additional tumor categories showed occasional arginase immunostaining, strong staining was exceedingly rare in these entities. Staining of a few tumor cells was observed in squamous cell carcinomas of various sites. Staining typically involved maturing cells with the beginning of keratinization in these tumors and was significantly associated with a low grade in 635 squamous cell carcinomas of various sites (p = 0.003). Teratoma, urothelial carcinoma and pleomorphic adenomas sometimes also showed arginase expression in areas with squamous differentiation. In summary, arginase-1 immunohistochemistry is highly sensitive and specific for hepatocellular carcinoma if weak and focal staining is disregarded.

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Targeting Nodal and Cripto-1: Perspectives Inside Dual Potential Theranostic Cancer Biomarkers

Current Medicinal Chemistry ◽

10.2174/0929867325666180912104707 ◽

2019 ◽

Vol 26 (11) ◽

pp. 1994-2050 ◽

Cited By ~ 4

Author(s):

Annamaria Sandomenico ◽

Menotti Ruvo

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Normal Development ◽

Cancer Biomarkers ◽

Normal Tissues ◽

Tumor Relapse ◽

Developmental Factors ◽

Theranostic Agents ◽

Tumor Types ◽

Embryonic Signaling

Background:Elucidating the mechanisms of recurrence of embryonic signaling pathways in tumorigenesis has led to the discovery of onco-fetal players which have physiological roles during normal development but result aberrantly re-activated in tumors. In this context, Nodal and Cripto-1 are recognized as onco-developmental factors, which are absent in normal tissues but are overexpressed in several solid tumors where they can serve as theranostic agents.Objective:To collect, review and discuss the most relevant papers related to the involvement of Nodal and Cripto-1 in the development, progression, recurrence and metastasis of several tumors where they are over-expressed, with a particular attention to their occurrence on the surface of the corresponding sub-populations of cancer stem cells (CSC).Results:We have gathered, rationalized and discussed the most interesting findings extracted from some 370 papers related to the involvement of Cripto-1 and Nodal in all tumor types where they have been detected. Data demonstrate the clear connection between Nodal and Cripto-1 presence and their multiple oncogenic activities across different tumors. We have also reviewed and highlighted the potential of targeting Nodal, Cripto-1 and the complexes that they form on the surface of tumor cells, especially of CSC, as an innovative approach to detect and suppress tumors with molecules that block one or more mechanisms that they regulate.Conclusion:Overall, Nodal and Cripto-1 represent two innovative and effective biomarkers for developing potential theranostic anti-tumor agents that target normal as well as CSC subpopulations and overcome both pharmacological resistance and tumor relapse.

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PD-L1 Testing and Squamous Cell Carcinoma of the Head and Neck: A Multicenter Study on the Diagnostic Reproducibility of Different Protocols

Cancers ◽

10.3390/cancers13020292 ◽

2021 ◽

Vol 13 (2) ◽

pp. 292

Author(s):

Simona Crosta ◽

Renzo Boldorini ◽

Francesca Bono ◽

Virginia Brambilla ◽

Emanuele Dainese ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Checkpoint Inhibitors ◽

Interobserver Reliability ◽

Tissue Microarrays ◽

Observer Agreement ◽

Alternative Methods ◽

Observer Reliability

Immune checkpoint inhibitors for blocking the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis are now available for squamous cell carcinoma of the head and neck (HNSCC) in relapsing and/or metastatic settings. In this work, we compared the resulting combined positive score (CPS) of PD-L1 using alternative methods adopted in routine clinical practice and determined the level of diagnostic agreement and inter-observer reliability in this setting. The study applied 5 different protocols on 40 tissue microarrays from HNSCC. The error rate of the individual protocols ranged from a minimum of 7% to a maximum of 21%, the sensitivity from 79% to 96%, and the specificity from 50% to 100%. In the intermediate group (1 ≤ CPS < 20), the majority of errors consisted of an underestimation of PD-L1 expression. In strong expressors, 5 out of 14 samples (36%) were correctly evaluated by all the protocols, but no protocol was able to correctly identify all the “strong expressors”. The overall inter-observer agreement in PD-L1 CPS reached 87%. The inter-observer reliability was moderate, with an ICC of 0.774 (95% CI (0.651; 0.871)). In conclusion, our study showed moderate interobserver reliability among different protocols. In order to improve the performances, adequate specific training to evaluate PD-L1 by CPS in the HNSCC setting should be coordinated.

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Coexisting macrophage-associated fibrin formation and tumor cell urokinase in squamous cell and adenocarcinoma of the lung tissues

Cancer ◽

10.1002/1097-0142(19910901)68:5<1061::aid-cncr2820680525>3.0.co;2-d ◽

1991 ◽

Vol 68 (5) ◽

pp. 1061-1067 ◽

Cited By ~ 33

Author(s):

Deborah L. Ornstein ◽

Leo R. Zacharski ◽

Vincent A. Memoli ◽

Walter Kisiel ◽

Bohdan J. Kudryk ◽

...

Keyword(s):

Tumor Cell ◽

Squamous Cell ◽

Adenocarcinoma Of The Lung ◽

Fibrin Formation

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High expression of DNA damage-inducible transcript 4 (DDIT4) is associated with advanced pathological features in the patients with colorectal cancer

Scientific Reports ◽

10.1038/s41598-021-92720-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Fahimeh Fattahi ◽

Leili Saeednejad Zanjani ◽

Zohreh Habibi Shams ◽

Jafar Kiani ◽

Mitra Mehrazma ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Damage ◽

Prognostic Significance ◽

Tissue Microarrays ◽

Survival Outcomes ◽

Hub Genes ◽

Kegg Pathways ◽

Normal Tissues ◽

Nuclear Expression ◽

Pathways Analysis

AbstractDNA damage-inducible transcript 4 (DDIT4) is induced in various cellular stress conditions. This study was conducted to investigate expression and prognostic significance of DDIT4 protein as a biomarker in the patients with colorectal cancer (CRC). PPI network and KEGG pathway analysis were applied to identify hub genes among obtained differentially expressed genes in CRC tissues from three GEO Series. In clinical, expression of DDIT4 as one of hub genes in three subcellular locations was evaluated in 198 CRC tissues using immunohistochemistry method on tissue microarrays. The association between DDIT4 expression and clinicopathological features as well as survival outcomes were analyzed. Results of bioinformatics analysis indicated 14 hub genes enriched in significant pathways according to KEGG pathways analysis among which DDIT4 was selected to evaluate CRC tissues. Overexpression of nuclear DDIT4 protein was found in CRC tissues compared to adjacent normal tissues (P = 0.003). Furthermore, higher nuclear expression of DDIT4 was found to be significantly associated with the reduced tumor differentiation and advanced TNM stages (all, P = 0.009). No significant association was observed between survival outcomes and nuclear expression of DDIT4 in CRC cases. Our findings indicated higher nuclear expression of DDIT4 was significantly associated with more aggressive tumor behavior and more advanced stage of disease in the patients with CRC.

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