EWSR1-CREB1 and EWSR1-ATF1 are gene fusions of which one or both have now been consistently described in 5 histopathologically and behaviorally diverse neoplasms: angiomatoid fibrous histiocytoma, conventional clear cell sarcoma (of tendons and aponeuroses), clear cell sarcoma-like tumor of the gastrointestinal tract, hyalinizing clear cell carcinoma of the salivary gland, and primary pulmonary myxoid sarcoma. Some of the tumors in this group have been described only recently, and others have been the subject of recent genetic insights contributing to their characterization. These neoplasms are all rare; yet, the increasing frequency with which EWSR1-CREB1 and EWSR1-ATF1 fusions are being described in separate entities is noteworthy. The additional molecular mechanisms by which tumors with such variable morphologic, immunohistochemical, and clinical phenotypes are generated are yet to be understood. We review the clinicopathologic and molecular features of this group of neoplasms unified by the presence of EWSR1-CREB1 and EWSR1-ATF1 genetic fusions.

Tumors With EWSR1-CREB1 and EWSR1-ATF1 Fusions: The Current Status

CD10 is a remarkable member of the major class of widely expressed cell surface proteins, endopeptidases. First identified in leukemia as a tumor-specific antigen (common acute lymphoblastic leukemia antigen), CD10 has become largely used in cancer diagnosis. However, its function in oncogenesis remains unclear. We previously identified CD10 as a tool to access sphere-forming cells and showed its involvement in mammary stem cell (SC) regulation. We further illustrated that its enzymatic activity is involved, through signaling peptides, in SC maintenance. Therefore, CD10 is not only a cell surface marker in normal and malignant contexts but also affects the extracellular environment and plays a key role in regulation of a number of biological functions and likely in SC. In tumors, the "niche" favors the survival of sheltered cancer SC whose eradication has become the new challenge in oncology. This highlights the importance of understanding the role of CD10 in cancer SC. We will review the characteristics, main functions, and mechanism of action of CD10. Finally, we will review its clinical use and involvement in cancer.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/stem.592

Concise review: neutral endopeptidase (CD10): a multifaceted environment actor in stem cells, physiological mechanisms, and cancer.

CD10+ Pancreatic Stellate Cells Enhance the Progression of Pancreatic Cancer

Many soft tissue sarcomas have chromosomal translocations with resultant formation of new fusion genes. Among the genes that can be rearranged, the EWSR1 gene has been identified as a partner in a wide variety of clinically and pathologically diverse sarcomas as well as some non-mesenchymal tumours. The former include Ewing sarcoma and similar (Ewing-like) small round cell sarcomas, desmoplastic small round cell tumour, myxoid liposarcoma, extraskeletal myxoid chondrosarcoma, angiomatoid fibrous histiocytoma, clear cell sarcoma of soft tissue and clear cell sarcoma-like tumours of the gastrointestinal tract, primary pulmonary myxoid sarcoma, extrasalivary myoepithelial tumours and sporadic examples of low-grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma and mesothelioma. EWSR1 is a 'promiscuous' gene that can fuse with many different partner genes, but sometimes this results in phenotypically identical tumours. EWSR1 can, conversely, partner with the same genes in morphologically and behaviourally different neoplasms. This paper reviews the diversity of the several soft tissue tumour types that are associated with rearrangement of the EWSR1 gene.

The diversity of soft tissue tumours with EWSR1 gene rearrangements: a review

We present clinicopathologic data on 10 pulmonary myxoid sarcomas, which are defined by distinctive histomorphologic features and characterized by a recurrent fusion gene, that appear to represent a distinct tumor entity at this site. The patients [7 female, 3 male; aged 27 to 67 y (mean, 45 y)] presented with local or systemic symptoms (n=5), symptoms from cerebral metastasis (1), or incidentally (2). Follow-up of 6 patients showed that 1 with brain metastasis died shortly after primary tumor resection, 1 developed a renal metastasis but is alive and well, and 4 are disease free after 1 to 15 years. All tumors involved pulmonary parenchyma, with a predominant endobronchial component in 8 and ranged from 1.5 to 4 cm. Microscopically, they were lobulated and composed of cords of polygonal, spindle, or stellate cells within myxoid stroma, morphologically reminiscent of extraskeletal myxoid chondrosarcoma. Four cases showed no or minimal atypia, 6 showed focal pleomorphism, and 5 had necrosis. Mitotic indices varied, with most tumors not exceeding 5/10 high-power fields. Tumors were immunoreactive for only vimentin and weakly focal for epithelial membrane antigen. Of 9 tumors, 7 were shown to harbor a specific EWSR1-CREB1 fusion by reverse transcription-polymerase chain reaction and direct sequencing, with 7 of 10 showing EWSR1 rearrangement by fluorescence in situ hybridization. This gene fusion has been described previously in 2 histologically and behaviorally different sarcomas: clear cell sarcoma-like tumors of the gastrointestinal tract and angiomatoid fibrous histiocytomas; however, this is a novel finding in tumors with the morphology we describe and that occur in the pulmonary region.

Primary Pulmonary Myxoid Sarcoma With EWSR1-CREB1 Fusion: A New Tumor Entity

Background: CD10 is a cell surface metalloproteinase expressed by a variety of normal cell types, including lymphoid precursor cells, germinal center B lymphocytes and some epithelial cells. Although accumulating data indicate that CD10 expression by stromal cells is involved in colorectal carcinogenesis and it is a novel prognostic factor in breast carcinoma, CD10-positive stromal cells and their correlation with invasion and metastasis have not been studied in gastric carcinoma. The aim of this study was to immunohistochemically investigate the rate of CD10 production in the stromal cells in our gastric carcinoma collection and clarify its correlation with invasion and metastasis. Methods: One hundred and sixteen cases of gastric carcinoma were analyzed immunohistochemically using a monoclonal CD10 antibody (clone 56C6). Results: The expression of CD10 by stromal cells was significantly higher in the primary gastric carcinomasthaninnormalanddysplasiamucosas(P =0.014).MorefrequentexpressionofCD10 by stromal cells was detected in differentiated carcinoma than in undifferentiated carcinoma (P < 0.001). CD10 expression by the stromal cells was associated with depth of invasion and lymph node metastasis (P < 0.05). Stromal CD10 expression was lower in gastric carcinoma without vessel invasion than in those with vessel invasion (P = 0.001). However, no association was observed between stromal CD10 expression and TNM stage. In differentiated carcinoma, stromal CD10 expression was associated with the depth of invasion, lymph node metastasis, vessel invasion and TNM stage (P < 0.01). Conclusion: These results indicate that stromal cells expressing CD10 may play an important role in gastric carcinogenesis. CD10 expression by stromal cells seems to promote invasion and metastasis of differentiated gastric carcinoma.

CD10-positive stromal cells in gastric carcinoma: correlation with invasion and metastasis.

Objective: To investigate the expression of gene BRG1 in prostatic intraepithelial neoplasia and adenocarcinoma,and the relationship between gene BRG1 expression and the clinicopathological features of prostate carcinoma.Methods: Gene BRG1 expression was evaluated in 37 cases of human prostate carcinoma,13 human prostatic intraepithelial neoplasia(PIN) and 14 human benign prostatic hyperplasia(BPH) by using immunohistochemistry(EnVision method) and tissue microarray.Results: The positive rates of BRG1 protein were(81.08)%(30/37),(38.46)%(5/13) and(14.28)%(2/14)in prostate carcinoma,PIN and BPH,respectively,significantly higher in the first group than in the latter two(P(0.05)).There was no statistically significant difference in BRG1 gene expression either between PIN and BPH(P(0.05)) or between the groups of the moderate differentiation(the Gleason histologic grading: 5～7) and the lower one(the Gleason histologic grading: 8～10)(P(0.05)).Conclusion: BRG1 may play an important role in the development of prostate carcinoma.Tissue microarray technology,with the advantages of high throughput,conciseness,rapidity,high efficiency,low cost,and nice reproducibility,has significant practical value and broad application prospects in pathology.

BRG1 expression in prostate carcinoma by application of tissue microarray

OBJECTIVE To study the Gleason histologic grading of prostate carcinoma in relation to the serum prostate-specific antigen (PSA) level and the PSA in situ of the tumor, and the immunohistochemical staining of basal cell-specific cytokertain(34 beta E12) and alpha-Methylacyl-CoA racemase(P504S) of the tumor. METHODS The serum PSA levels were measured in 40 cases of prostate carcinoma. The Gleason histologic grading was based on histopathologic examination of the tumors, and the immunohistochemical staining including PSA in situ (35 cases), 34 beta E12(12 cases) and P504S(10 cases) was examined. RESULTS The higher the Gleason histologic grading of prostate carcinoma, the higher the serum PSA level(P < 0.01), and the weaker the positive reaction of the immunohistochemical staining of PSA of the tumor(P < 0.05). And the tumor cells displayed positive reaction for P504S and negative for 34 beta E12. CONCLUSION The Gleason histologic grading of prostate carcinoma is positively related to the serum PSA level and negatively to PSA in situ of the tumor immunohistochemically. It is important to use immunohistochemical staining for 34 beta E12 and P504S in the pathologic diagnosis of prostate carcinoma.

[Gleason histologic grading of prostate carcinoma in relation to serum PSA, PSA in situ and immunohistochemical expression of 34 beta E12 and P504S].

Chemotherapy-induced adaptive resistance is a significant factor that contributes to low therapeutic efficacy in tumor cells. The unfolded protein response (UPR) is a key mechanism in the development of drug resistance and serves as a critical reactive system for endoplasmic reticulum stress. Cu(II) can reduce the abundance of 60S ribosomal subunits and inhibit rRNA processing, leading to a decrease in the translation efficiency of the GRP78/BiP mRNA, which serves as a primary sensor for UPR activation. In this study, CuET-Lipid@Cela, composed of CuET and tripterine (Cela), demonstrated a significant synergistic antitumor effect on cholangiocarcinoma (CCA) cells. RNA-Seq was used to investigate the underlying mechanism, which suggests that the TMX2 gene may be crucial in Cu(II) regulation of UPR by inhibiting the activation of GRP78/BiP and PERK/eIF2α. The synergistic antitumor efficacy of CuET-Lipid@Cela via inhibition of TMX2 was also confirmed in a myrAKT/YapS127A plasmid-induced primary CCA mouse model, providing new insights into the reversal of acquired chemotherapy-induced resistance in CCA. This article is protected by copyright. All rights reserved.

Copper Increases the Sensitivity of Cholangiocarcinoma Cells to Tripterine by Inhibiting TMX2-Mediated Unfolded Protein Reaction Activation.

Objective: To investigate the expression of glycoprotein non metastatic melanoma protein B (GPNMB) in renal eosinophilic tumors and to compare the value of GPNMB with CK20, CK7 and CD117 in the differential diagnosis of renal eosinophilic tumors. Methods: Traditional renal tumor eosinophil subtypes, including 22 cases of renal clear cell carcinoma eosinophil subtype (e-ccRCC), 19 cases of renal papillary cell carcinoma eosinophil subtype (e-papRCC), 17 cases of renal chromophobe cell carcinoma eosinophil subtype (e-chRCC), 12 cases of renal oncocytoma (RO) and emerging renal tumor types with eosinophil characteristics [3 cases of eosinophilic solid cystic renal cell carcinoma (ESC RCC), 3 cases of renal low-grade eosinophil tumor (LOT), 4 cases of fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) and 5 cases of renal epithelioid angiomyolipoma (E-AML)], were collected at the Affiliated Drum Tower Hospital of Nanjing University Medical School from January 2017 to March 2022. The expression of GPNMB, CK20, CK7 and CD117 was detected by immunohistochemistry and statistically analyzed. Results: GPNMB was expressed in all emerging renal tumor types with eosinophil characteristics (ESC RCC, LOT, FH-dRCC) and E-AML, while the expression rates in traditional renal eosinophil subtypes e-papRCC, e-chRCC, e-ccRCC and RO were very low or zero (1/19, 1/17, 0/22 and 0/12, respectively); the expression rate of CK7 in LOT (3/3), e-chRCC (15/17), e-ccRCC (4/22), e-papRCC (2/19), ESC RCC (0/3), RO (4/12), E-AML(1/5), and FH-dRCC (2/4) variedly; the expression of CK20 was different in ESC RCC (3/3), LOT(3/3), e-chRCC(1/17), RO(9/12), e-papRCC(4/19), FH-dRCC(1/4), e-ccRCC(0/22) and E-AML(0/5), and so did that of CD117 in e-ccRCC(2/22), e-papRCC(1/19), e-chRCC(16/17), RO(10/12), ESC RCC(0/3), LOT(1/3), E-AML(2/5) and FH-dRCC(1/4). GPNMB had 100% sensitivity and 97.1% specificity in distinguishing E-AML and emerging renal tumor types (such as ESC RCC, LOT, FH-dRCC) from traditional renal tumor types (such as e-ccRCC, e-papRCC, e-chRCC, RO),respectively. Compared with CK7, CK20 and CD117 antibodies, GPNMB was more effective in the differential diagnosis (P<0.05). Conclusion: As a new renal tumor marker, GPNMB can effectively distinguish E-AML and emerging renal tumor types with eosinophil characteristics such as ESC RCC, LOT, FH-dRCC from traditional renal tumor eosinophil subtypes such as e-ccRCC, e-papRCC, e-chRCC and RO, which is helpful for the differential diagnosis of renal eosinophilic tumors.

[Expression of GPNMB in renal eosinophilic tumors and its value in differential diagnosis].

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