Inhibiting redox-mediated endothelial migration by gadofullerenes for inducing tumor vascular normalization and improving chemotherapy.

Tumor vascular normalization (TVN) reverses abnormal tumor vasculatures, which could boost anti-cancer efficiency and especially increase drug intratumoral delivery. Endothelial cells play a vital role in angiogenesis, yet continuous modulating endothelial cell migration to improve TVN is ingenious but challenging. Here we propose a potential strategy for TVN based on inhibiting endothelial migration using antioxidative fullerene nanoparticles (FNPs). We demonstrate that FNPs inhibit cell migration upon their anti-oxidation effects in vitro. The optimized alanine-modified gadofullerene (GFA) exhibits superior TVN ability and inhibits tumor growth in vivo. Mechanically, facilitated with the protein microarray, we confirm that GFA could suppress the focal adhesion pathway to restrain endothelial migration. Subsequently, remarkable anti-tumor efficacy of chemotherapy synergy was obtained, which benefited from a more normalized vascular network by GFA. Together, our study introduces the potential of FNPs as promising TVN boosters to consider in cancer nanomedicine design.

Liver mesenchymal neoplasms: something old, something new.

Histological examination of liver biopsies and resection specimens remains the gold standard to establish a definitive diagnosis of liver lesions. While hepatocellular carcinoma remains the most commonly encountered liver lesion on mass-directed biopsies, surgical pathologists must be aware of other entities that may pose diagnostic challenges, as an accurate diagnosis is key for patient management. Mesenchymal tumours of the liver are relatively uncommon, therefore many pathologists are unfamiliar with these tumours. While the clinical presentation and radiological features of these lesions often overlap, careful attention to histological clues can assist in weeding out various congeners to arrive at the most accurate diagnosis. An additional challenge when diagnosing mesenchymal tumours is the specimen type, as mass-directed core biopsies are limited and have become standard clinical practice. Besides careful attention to histological features, radiological findings and clinical history, immunohistochemical analysis and molecular studies have become of immense diagnostic value. In this review, we discuss several common and rare mesenchymal hepatic lesions as defined in the current World Health Organization (WHO) classification and most up-to-date literature. We also discuss immunohistochemistry panels and relevant molecular findings that may assist in rendering an accurate diagnosis when encountering these lesions in daily practice.

Hexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities.

Defective pericyte-endothelial cell interaction in tumors leads to a chaotic, poorly organized and dysfunctional vasculature. However, the underlying mechanism behind this is poorly studied. Herein, we develop a method that combines magnetic beads and flow cytometry cell sorting to isolate pericytes from tumors and normal adjacent tissues from patients with non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC). Pericytes from tumors show defective blood vessel supporting functions when comparing to those obtained from normal tissues. Mechanistically, combined proteomics and metabolic flux analysis reveals elevated hexokinase 2(HK2)-driven glycolysis in tumor pericytes, which up-regulates their ROCK2-MLC2 mediated contractility leading to impaired blood vessel supporting function. Clinically, high percentage of HK2 positive pericytes in blood vessels correlates with poor patient overall survival in NSCLC and HCC. Administration of a HK2 inhibitor induces pericyte-MLC2 driven tumor vasculature remodeling leading to enhanced drug delivery and efficacy against tumor growth. Overall, these data suggest that glycolysis in tumor pericytes regulates their blood vessel supporting role.

A unique epithelioid vascular neoplasm of bone characterized by EWSR1/FUS-NFATC1/2 fusions.

An increasing number of epithelioid vascular lesions, in particular tumors from the benign and low-grade end of the spectrum, have been characterized by recurrent gene fusions. As a result, the detection of these molecular markers have improved the classification of diagnostically challenging cases. However, despite the significant progress, there are occasional lesions that do not fit in known histologic or molecular groups. Herein, we present five such unclassified epithelioid vascular lesions, which occurred in the bone and showed a distinct morphology composed of alternating vasoformative and solid growth and mild to moderate nuclear pleomorphism. The variegated morphologic appearance resembled that of composite hemangioendothelioma, being distinct from both epithelioid hemangioma and epithelioid hemangioendothelioma, and consistently showed cytologic atypia. Due to their unusual morphologic appearance and negative molecular work-up, targeted transcriptome sequencing was performed in two cases showing the presence of NFATC2 fusions with either EWSR1 or FUS genes. Three additional bone tumors with EWSR1 gene rearrangements were identified by FISH screening of a large cohort of 45 fusion-negative epithelioid vascular neoplasms, one fused to NFATC2 while two others to NFATC1. There were three females and two males, with a wide age range at presentation, mean of 44 years. The lesions occurred in the pelvis, maxillary sinus, and humerus. Two patients presented with polyostotic disease, both located in the pelvic bones. Two patients had available follow-up, one developed two local recurrences in the humerus over a 15-year period, while the other showed no recurrence 4 years subsequent to an en-bloc resection. Tumors were positive for CD31 and ERG, while negative for EMA, CK, synaptophysin, and chromogranin. FISH confirmed this abnormality in all cases, none of them being associated with gene amplifications. Further studies are needed to establish the pathogenetic relationship of this rare molecular subset with other epithelioid vascular tumors and to determine its clinical behavior.

Vascular Tumor Recapitulated in Endothelial Cells from hiPSCs Engineered to Express the SERPINE1-FOSB Translocation.

Chromosomal translocations are prevalent among soft tissue tumors, including those of the vasculature such as pseudomyogenic hemangioendothelioma (PHE). PHE shows endothelial cell (EC) features and has a tumor-specific t(7;19)(q22;q13) SERPINE1-FOSB translocation, but is difficult to study as no primary tumor cell lines have yet been derived. Here, we engineer the PHE chromosomal translocation into human induced pluripotent stem cells (hiPSCs) using CRISPR/Cas9 and differentiate these into ECs (hiPSC-ECs) to address this. Comparison of parental with PHE hiPSC-ECs shows (1) elevated expression of FOSB, (2) higher proliferation and more tube formation but lower endothelial barrier function, (3) invasive growth and abnormal vessel formation in mice after transplantation, and (4) specific transcriptome alterations reflecting PHE and indicating PI3K-Akt and MAPK signaling pathways as possible therapeutic targets. The modified hiPSC-ECs thus recapitulate functional features of PHE and demonstrate how these translocation models can be used to understand tumorigenic mechanisms and identify therapeutic targets.

[Characteristics of ERG, Fli-1, CD34, CD31 and Fâ §RAg expression in hepatic malignant vascular tumors].

Objective: To investigate the expression of ERG, Fli-1, CD34, CD31 and factor Ⅷ-related antigen(FⅧRAg) in hepatic malignant vascular tumors. Methods: A retrospective analysis was conducted on 63 cases of primary hepatic malignant vascular tumors and 31 cases of hepatic other malignant spindle cell tumors collected during January 1986 to January 2014. EnVision method was used to detect the expression of ERG, Fli-1, CD34, CD31, FⅧRAg. Results: Sixty-three cases of malignant vascular tumors, including 24 cases of angiosarcoma, 38 cases of epithelioid hemangioendothelioma and 1 case of hepatic Kaposi's sarcoma. All of the cases were positive for ERG(100.0%, 63/63). Positive rate of Fli-1, CD34, CD31, FⅧRAg was 96.8% (61/63), 87.3% (55/63), 81.0% (51/63) and 41.3% (26/63), respectively. In other hepatic malignant spindle cell tumors, the positive rate of ERG, Fli-1, CD34, CD31 and FⅧRAg was 3.2% (1/31), 19.4% (6/31), 19.4% (6/31), 9.7%(3/31) and 3.2%(1/31), respectively.The sensitivity of ERG, Fli-1, CD34, CD31, FⅧRAg was 100.0%, 96.8%, 87.3%, 81.0% and 41.3%, respectively.The specificity was 96.8%, 80.6%, 80.6%, 90.3% and 96.8%, respectively. Conclusion: ERG is a more sensitive and specific diagnostic marker for hepatic malignant vascular tumors in comparison to Fli-1, CD34, CD31 and FⅧRAg.

Expression of Vascular Endothelial Growth Factor Receptors in Benign Vascular Lesions of the Orbit: A Case Series.

PURPOSE: Vascular lesions of the orbit, although not malignant, can cause morbidity because of their location near critical structures in the orbit. For the same reason, they can be challenging to remove surgically. Anti-vascular endothelial growth factor (VEGF) drugs are increasingly being used to treat diseases with prominent angiogenesis. Our study aimed to determine to what extent VEGF receptors and their subtypes are expressed on selected vascular lesions of the orbit. DESIGN: Retrospective case series of all orbital vascular lesions removed by one of the authors (JAG) at the Mayo Clinic. PARTICIPANTS: A total of 52 patients who underwent removal of vascular orbital lesions. METHODS: The pathology specimens from the patients were retrieved, their pathologic diagnosis was confirmed, demographic and clinical information were gathered, and sections from vascular tumors were stained with vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor type 1 (VEGFR1), vascular endothelial growth factor receptor type 2 (VEGFR2), and vascular endothelial growth factor receptor type 3 (VEGFR3). MAIN OUTCOME MEASURES: The existence and pattern of staining with VEGF and its subtypes on these lesions. RESULTS: There were 28 specimens of venous malformations, 4 capillary hemangiomas, 7 lymphatic malformations, and 6 lymphaticovenous malformations. All samples stained with VEGF, 55% stained with VEGFR1, 98% stained with VEGFR2, and 96% stained with VEGFR3. Most (94%) of the VEGFR2 staining was diffuse. CONCLUSIONS: Most orbital vascular lesions express VEGF receptors, which may suggest a future target for nonsurgical treatment.

CD30 expression in malignant vascular tumors and its diagnostic and clinical implications: a study of 146 cases.

Angiosarcoma (AS) is a rare malignant vascular tumor, whereas epithelioid hemangioendothelioma (EHE) is a vascular tumor of low-grade malignancy. CD30 is a member of the tumor necrosis factor receptor superfamily, member 8 (TNFRSF8). Although the expression of CD30 is most commonly associated with lymphoid malignancies or germ cell tumors, occasional ASs have been reported as CD30 positive. However, there are limited data to evaluate its role definitively in malignant vascular tumors. In this study, we evaluated 91 ASs, 30 EHEs from various sites, and 25 Kaposi sarcomas. Overall, CD30 was expressed in 31/91 cases (34%) of AS, in 7/30 cases (30%) of EHE, but in none of the Kaposi sarcomas. CD30 was expressed in a membranous staining pattern and positivity in tumor cells varied from focal to diffuse. The positive ASs included vasoformative more differentiated tumors and also solid, undifferentiated, lymphoma-like examples, one of which was classified as lymphoma before the era of immunohistochemistry. The CD30 expression was seen in >50% of tumor cells in a majority of ASs but only in 7% of EHEs. None of the 55 ASs studied were immunohistochemically positive for TIA-1 or Granzyme B, antigens used as more specific markers for anaplastic large-cell lymphoma. Compared with AS, normal vascular endothelia of capillaries and muscular vessels showed variable positivity. Among hemangiomas, cavernous and spindle cell hemangiomas showed most frequent endothelial CD30 positivity, whereas in most other hemangiomas, CD30 positivity was scant. In conclusion, CD30 expression occurs in a significant subset of ASs and EHEs and needs to be included in the differential diagnosis with other CD30-positive malignancies to avoid a diagnostic pitfall. It remains to be determined whether patients with strongly CD30-positive ASs could be candidates for targeted therapy using the recently introduced CD30 antibody drug conjugates.

c-myc and cutaneous vascular neoplasms.

The c-myc proto-oncogene is involved in various cellular processes including cell growth, proliferation, and apoptosis. Overexpression and deregulated expression of the gene have been previously linked to several lineage-unrelated, aggressive, and poorly differentiated tumors. The expression of c-myc has also been implicated in hematopoiesis and has been shown to play a crucial role in angiogenesis via a vascular endothelial growth factor-dependent mechanism. This gives c-myc a dual oncogenic function in that tumor growth requires both cell proliferation and angiogenesis to ensure survival and confer an effective malignancy. Amplification of c-myc has been recently reported to be a recurrent genetic alteration in angiosarcomas secondary to irradiation and/or chronic lymphedema. Of note, however, no c-myc gene abnormalities have been demonstrated in cases of primary angiosarcomas or postradiation atypical vascular lesions. More recently, our own experience indicates that c-myc amplification is not normally found in the Kaposi sarcoma and cannot be correlated with expression of the c-Myc protein. This comprehensive review outlines the structure, normal functions, and effects of the deregulated expression of c-myc with particular emphasis on its role in angiogenesis and select cutaneous vascular neoplasms.

Update on vascular neoplasms.

This article provides an update on vascular neoplasms. New immunohistochemical markers for the diagnosis of vascular neoplasms tumor 1, infantile hemangiomas, myopericytomas, perivascular epithelial cell tumors, acquired elastotic hemangiomas, vascular proliferations in radiated skin, and new histopathologic variants of AIDS-related Kaposi sarcoma are explored.