TLE1, a transcriptional repressor essential in hematopoiesis, neuronal differentiation and terminal epithelial differentiation, has recently been shown in a single tissue microarray study to be a highly sensitive and relatively specific marker of synovial sarcomas. Expression of TLE1 has not, however, been studied in standard sections of soft tissue and bone tumors. We investigated TLE1 expression in a large series of well-characterized mesenchymal tumors, to more fully characterize the range of TLE1 expression. Standard sections of 163 bone and soft tissue tumors were immunostained for TLE1 (sc-9121, 1:100; Santa Cruz Biochemicals) using the Dako Dual Envision þ detection system. Nuclear positivity was scored as negative (o5% of cell positive), 1 þ (5-25% of cells positive), 2 þ (25-50% of cells positive), and 3 þ (450% of cells positive). Overall, TLE1 was expressed by 18 of 20 (90%) of synovial sarcoma, with 16 cases (89%) showing 2-3 þ positivity. However, TLE1 expression was also seen in 53 of 143 (37%) non-synovial sarcoma, with 36 such cases (25%) showing 2-3 þ positivity. TLE1 expression was commonly seen in peripheral nerve sheath tumors, including 33% of neurofibromas, 100% of schwannomas, and 30% of malignant peripheral nerve sheath tumors. Among non-neoplastic tissues, nuclear TLE1 expression was variably present in basal keratinocytes, adipocytes, perineurial cells, endothelial cells and mesothelial cells. Our study confirms the excellent sensitivity of TLE1 for synovial sarcoma. However, TLE1 expression is by no means specific for synovial sarcoma, being present in a number of tumors, which enter its differential diagnosis, in particular tumors of peripheral nerve sheath origin. Heterogeneity of TLE1 expression likely explains the differences between the present standard section study and the earlier TMA study. TLE1 may be of value in the differential diagnosis of synovial sarcoma, but should be used only in the context of a panel of antibodies. Morphology, ancillary immunohistochemistry for traditional markers such as cytokeratins and CD34, and molecular confirmation of synovial sarcoma-associated fusion genes should remain the 'gold standards' for this diagnosis.
Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumour microenvironment. CAFs have recently attracted attention for their function as a regulator of immune cell recruitment and function in addition to their tumour-promoting roles. In this study, we aimed to determine the role of CAFs on monocyte recruitment and macrophage polarization in breast cancer. CAFs, which were α-SMA expressing fibroblasts in contrast to normal fibroblasts (NFs), effectively recruited monocytes. Recruitment of monocytes by CAFs might be mediated by monocyte chemotactic protein-1 (MCP-1) as well as stromal cell-derived factor-1 (SDF-1) cytokines. CAFs differentiated the recruited monocytes into M2-like macrophages which are capable of exerting their immunosuppressive roles via the PD-1 axis. CAF-educated monocytes exhibited strong immune suppression unlike NF-educated monocytes and enhanced the motility/invasion of breast cancer cells in addition to increasing the expressions of epithelial–mesenchymal transition (EMT)-related genes and vimentin protein in cancer cells. CAF-educated M1 macrophages displayed increased expression of M2 markers and production of anti-inflammatory cytokine IL-10 in contrast to decreased production of pro-inflammatory cytokine IL-12 compared with control M1 macrophages; suggesting that CAFs were also able to induce the trans-differentiation of M1 macrophages to M2 macrophages. We then investigated the relationship between the infiltration of CAFs and tumour associated macrophages (TAMs) using tissue samples obtained from breast cancer patients. High grade of CAFs significantly correlated with the number of TAMs in human breast cancer tissue samples. It was also associated with higher Ki-67 proliferation index, and higher tumour volume. This result is in line with our finding of increased breast cancer cell proliferation due to the effects of CAF-educated monocytes in vitro . Our results concluded that CAFs play pivotal roles in sculpturing the tumour microenvironment in breast cancer, and therapeutic strategies to reverse the CAF-mediated immunosuppressive microenvironment should be taken into consideration.
Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxiarepressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.
Clear cell sarcoma (CCS) is a rare, distinctive soft tissue neoplasm, typically occurring in the distal extremities of young adult patients. Although CCS shows melanocytic differentiation, it is now clear that it is clinicopathologically and genetically distinct from conventional malignant melanoma. The 'osteoclast-rich tumour of the gastrointestinal tract with features resembling clear cell sarcoma of soft parts' is an extraordinarily rare gastrointestinal neoplasm that shares some features of CCS, but differs from it in other ways. The historical, histopathological, ultrastructural, immunohistochemical and genetic aspects of these two tumours are reviewed in this article.
Our results showed that denosumab provided a meaningful clinical and radiological improvement in ABC. It may be a treatment option, especially in spinal and pelvic tumors with potentially high surgical morbidity. However, late rebound hypercalcemia may restrict its use. Studies with more cases are required for routine use of denosumab in ABC.
Giant cell tumors of soft tissue (GCT-ST) are rare low-grade neoplasms that were at one time thought to represent the soft tissue counterparts of GCT of bone (GCT-B) but are now known to lack the H3F3 mutations characteristic of osseous GCT. We present six distinctive giant cell-rich soft tissue neoplasms that expressed keratins and carried a recurrent HMGA2-NCOR2 gene fusion. Patients were five females and one male aged 14–60 years (median, 29). All presented with superficial (subcutaneous) masses that were removed by conservative marginal (3) or wide (2) local excision. The tumors originated in the upper extremity (2), lower extremity (2), head/neck (1), and trunk (1). Five patients with follow-up (median, 21 months; range, 14–168) remained disease-free. Grossly, all tumors were well-demarcated but not encapsulated with variable lobulation. Histologically, they were composed of bland plump epithelioid or ovoid to spindled mononuclear cells admixed with evenly distributed multinucleated osteoclast-type giant cells. Foci of stromal hemorrhage and hemosiderin were seen in all cases. The mitotic activity ranged from 2 to 14/10 high power fields (median: 10). Foci of necrosis and vascular invasion were seen in one case each. The mononuclear cells were immunoreactive with the AE1/AE3 keratin cocktail and less frequently/less diffusely for K7 and K19 but lacked expression of other lineage-associated markers. RNA-based next-generation sequencing revealed an HMGA2-NCOR2 fusion in all tumors. None of the keratin-negative conventional GCT-ST showed the HMGA2-NCOR2 fusion (0/7). Metaplastic bone (4/9) and SATB2 expression (3/4) were frequent in keratin-negative conventional GCT-ST but were lacking in keratin-positive HMGA2-NCOR2 fusion-positive tumors. The distinctive immunophenotype and genotype of these tumors strongly suggest that they represent a discrete entity, differing from conventional GCT-ST and other osteoclast-rich morphologic mimics. Their natural history appears favorable, although a study of additional cases and longer follow-up are warranted.
The protective effect of quercetin on cisplatin-induced renal and testicular tissue damage was investigated using biochemical, histopathological and histological approaches. A total of 40 male rats were divided into 5 groups as follows: control; cisplatin alone; quercetin alone; cisplatin + quercetin; and quercetin + cisplatin. Cisplatin was administered to rats at a single dose of 7 mg kg(-1) intraperitoneal. Quercetin was administered by gavage daily for 10 days at dosage 50 mg kg(-1) . At the end of the study serum, total antioxidant capacity (TAC) levels and total oxidant status (TOS) were determined. Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and xanthine oxidase (XO) were studied separately in serum, renal tissue and testicular tissue. Renal and testicular morphological alterations were assessed, histopathologically. Epididymal sperm concentration, motility and morphology were investigated. Testicular and renal TAC and TOS values did not alter significantly. Renal CAT levels were increased by cisplatin and cisplatin plus quercetin groups that is reversed by administration of quercetin before cisplatin. MDA, CAT, SOD ve XO levels of testicular tissue did not differ significantly. Cisplatin and cisplatin plus quercetin groups had decreased sperm motility ratio and increased abnormal spermatozoa. Quercetin partially reverses some of the cisplatin-related pathological effects on kidney and testis.
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