ABSTRACT
Angiosarcoma is a rare, life-threatening soft tissue sarcoma with malignant endothelial cells that is mainly found in the skin. Multidisciplinary approaches are used to treat patients with unresectable metastasized lesions; considering the cellular origin of angiosarcoma, anti-angiogenic therapy has also been used recently. However, these treatments have limited efficacy, and the survival rate remains low. Thus, more effective treatments need to be developed. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in malignant tumors and promotes tumor progression. Thus, NECTIN4 is expected to be a novel therapeutic target for cancer. However, the significance of NECTIN4 in angiosarcoma remains unknown. Using immunohistochemistry, we investigated NECTIN4 expression in 74 tissue samples from angiosarcoma patients, finding variable NECTIN4 expression. In addition, we investigated NECTIN4 expression and function in human angiosarcoma cell lines. NECTIN4 expression was higher in angiosarcoma cells than normal endothelial cells, and angiosarcoma cells were sensitive to monomethyl auristatin E, the cytotoxic part of a NECTIN4-targetting antibody-drug conjugate. NECTIN4 knockdown inhibited the proliferation and angiogenesis of angiosarcoma cells, and Src kinase signaling was shown to be involved in NECTIN4 function, at least in part. NECTIN4-targeted therapy has the potential to be a novel treatment strategy for angiosarcoma.
Subject(s)
Cell Adhesion Molecules , Hemangiosarcoma , Skin Neoplasms , src-Family Kinases , Cell Adhesion Molecules/immunology , Cell Adhesion Molecules/metabolism , Endothelial Cells/metabolism , Hemangiosarcoma/blood supply , Hemangiosarcoma/drug therapy , Hemangiosarcoma/metabolism , Humans , Immunoconjugates/pharmacology , Nectins , Neovascularization, Pathologic/drug therapy , Skin Neoplasms/blood supply , Skin Neoplasms/drug therapy , Skin Neoplasms/metabolism , src-Family Kinases/metabolismABSTRACT
Melanoma is known to show considerable variation in its histopathological presentation. In exceptional cases, heterologous or divergent differentiation (metaplastic melanoma) can be observed. We report a case of a 69-year-old man who was diagnosed with nodular melanoma on the right upper leg. One year later, the patient presented with an inguinal lymph node metastasis and a lymph node dissection was carried out. In two out of five positive lymph nodes, an angiosarcomatous component was found next to a conventional melanoma component. Shortly after, the patient developed two in-transit metastases in which again an angiosarcomatous component was seen. The vascular component stained positive for ERG and CD31 and negative for melanocytic markers (Mart-1, S100, SOX-10), while the conventional melanoma had an opposite staining pattern. Molecular analysis on both components showed an identical mutation in the NRAS gene, which in our opinion proves the divergent differentiation. To the best of our knowledge, this is the first case report describing angiosarcomatous transdifferentiation of melanoma.
Subject(s)
Hemangiosarcoma/drug therapy , Hemangiosarcoma/pathology , Inguinal Canal/pathology , Lymphatic Metastasis/diagnosis , Melanoma/secondary , Skin Neoplasms/secondary , Aged , Cell Transdifferentiation/genetics , GTP Phosphohydrolases/genetics , Hemangiosarcoma/blood supply , Hemangiosarcoma/metabolism , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immunohistochemistry , Lymph Node Excision/methods , Male , Membrane Proteins/genetics , Mutation , Nivolumab/therapeutic use , Palliative Care , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Transcriptional Regulator ERG/metabolism , Treatment Outcome , Melanoma, Cutaneous MalignantABSTRACT
BACKGROUND: Previous studies have indicated that MFG-E8 enhances tumor cell survival, invasion and angiogenesis. However, the role of MFG-E8 in angiosarcoma (AS) has not been clarified. OBJECTIVE: Objective was to elucidate the mechanism of the regulation by MFG-E8 in AS and the association between MFG-E8 and clinicopathological features of AS. METHODS: The effects of the depletion of MFG-E8 by siRNA on tube formation, migration and proliferation in murine AS cells were examined. The effect of administration of anti-MFG-E8 antibody (Ab) on tumor growth of AS in mice was examined. The associations of MFG-E8 expression and clinicopathological features of human AS were assessed. RESULTS: The expressions of MFG-E8 in murine and human AS cells were significantly higher than those in melanoma cells, macrophages and endothelial cells. Depletion of MFG-E8 in murine AS cells by siRNA significantly inhibited the formation of capillary-like structures and migration, but not proliferation. Administration of anti-MFG-E8 Ab significantly inhibited tumor growth and decreased the number of tumor-associated macrophages (TAMs) in AS tumors. Tumor size and the number of TAMs in human AS with high expression of MFG-E8 were significantly increased compared to those of AS with low expression of MFG-E8. Progression-free survival and overall survival time of the patients of AS with high expression of MFG-E8 were significantly shorter than those of AS with low expression of MFG-E8. CONCLUSIONS: AS-derived MFG-E8 might enhance tumor growth via angiogenesis and the induction of TAMs in autocrine/paracrine manner, and administration of anti-MFG-E8 Ab could be a therapeutic potential for AS.
Subject(s)
Antigens, Surface/metabolism , Hemangiosarcoma/pathology , Milk Proteins/metabolism , Neovascularization, Pathologic/pathology , Skin Neoplasms/pathology , Aged , Animals , Antibodies/administration & dosage , Antigens, Surface/genetics , Biopsy , Cell Line, Tumor/transplantation , Disease Models, Animal , Female , Gene Knockdown Techniques , Hemangiosarcoma/blood supply , Hemangiosarcoma/drug therapy , Human Umbilical Vein Endothelial Cells , Humans , Male , Mice , Milk Proteins/antagonists & inhibitors , Milk Proteins/genetics , Neovascularization, Pathologic/drug therapy , Pericytes , RAW 264.7 Cells , RNA, Small Interfering/metabolism , Skin/blood supply , Skin/pathology , Skin Neoplasms/blood supply , Skin Neoplasms/drug therapyABSTRACT
BACKGROUND: Mesenteric angiography is a sensitive method for visualizing portal perfusion in the dog. OBJECTIVES: To evaluate hepatic portal perfusion in dogs with incompletely resectable hepatic tumors using mesenteric angiography. ANIMALS: Five client-owned dogs with incompletely resectable hepatic tumors evaluated with mesenteric angiography. METHODS: Retrospective case series. Electronic medical records at the Animal Medical Center were analyzed to identify dogs that underwent mesenteric portography to determine blood flow to nonresectable hepatic tumors and subsequently determine ideal routes for transarterial embolization, vascular stent placement, or both. The images obtained from mesenteric angiography were analyzed and compared to those obtained from computed tomography angiography. RESULTS: Portography was accomplished using direct mesenteric venography in 3 dogs with hepatocellular carcinoma (HCC), cranial mesenteric arteriography in 1 dog with hepatic adenoma or well-differentiated HCC, and via splenic arteriovenous fistula in 1 dog with diffuse hepatic hemangiosarcoma metastases. Mean pixel densities in areas of hepatic tumor growth identified statistically significant decreases in portal blood flow (P = .02) compared to normal hepatic parenchyma. CONCLUSIONS AND CLINICAL IMPORTANCE: Initial findings indicate that the blood supply to large and metastatic hepatic tumors in dogs may correlate with that in humans, such that the majority of the tumor blood supply arises from the hepatic artery and not the portal vein. Differences in blood supply between normal hepatic parenchyma and hepatic tumors might be exploited by developing selective tumor therapies such as arterial embolization or chemoembolization that largely spare normal liver tissue. Further investigation is warranted.
Subject(s)
Liver Circulation , Liver Neoplasms/veterinary , Portography/veterinary , Adenoma, Liver Cell/blood supply , Adenoma, Liver Cell/veterinary , Animals , Carcinoma, Hepatocellular/blood supply , Carcinoma, Hepatocellular/veterinary , Computed Tomography Angiography/veterinary , Dogs , Female , Hemangiosarcoma/blood supply , Hemangiosarcoma/veterinary , Liver Neoplasms/blood supply , Male , Pilot Projects , Portography/methods , Retrospective StudiesABSTRACT
Angiosarcoma, epithelioid hemangioendothelioma, and Kaposi sarcoma are classified according to the line of differentiation that these neoplastic cells most closely resemble: the endothelial cell. Although these malignant vascular sarcomas demonstrate immunohistochemical and ultrastructural features typical of this lineage, they vary dramatically in presentation and behavior, reflecting oncologic mechanisms unique to each. Antineoplastic therapies offer significant benefit, but because of the rarity of these cancers, novel therapies are slow to develop, and treatment options for these cancers remain limited. Antiangiogenic approaches that have shown benefit in other malignancies have not fully realized their promise in vascular tumors, suggesting that these tumors do not depend entirely on either angiogenic growth factors or on neighboring endothelia that are affected by these agents. Nonetheless, translational studies have begun to unravel these distinct pathologies, identifying novel translocation products, targets of oncogenic virulence factors, and genomic mutations that hijack angiogenic signaling and drive malignant growth. Concurrently, an elaborate and highly regulated model of angiogenesis and lymphangiogenesis involving vascular endothelial growth factor-receptor tyrosine kinase and TGF-ß and Notch pathways has emerged that informs treatment of these tumors as well as cancer in general. This review summarizes the literature on malignant vascular sarcomas in the context of current models of angiogenesis and, in light of recent clinical trial data, could help clinician-scientists generate novel therapeutic approaches.
Subject(s)
Hemangioendothelioma, Epithelioid/drug therapy , Hemangiosarcoma/drug therapy , Neovascularization, Pathologic/drug therapy , Sarcoma, Kaposi/drug therapy , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Hemangioendothelioma, Epithelioid/blood supply , Hemangioendothelioma, Epithelioid/pathology , Hemangiosarcoma/blood supply , Hemangiosarcoma/pathology , Humans , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Sarcoma, Kaposi/blood supply , Sarcoma, Kaposi/pathology , Signal Transduction/drug effects , Vascular Endothelial Growth Factor A/metabolismABSTRACT
BACKGROUND: Angiosarcomas are rare and aggressive soft-tissue sarcomas. The only potential curative treatment is complete surgical excision. This study reports the outcome of isolated limb perfusion (ILP) with high-dose melphalan and tumour necrosis factor α for locally advanced angiosarcoma. MATERIAL AND METHODS: All patients who underwent an ILP for angiosarcomas between 1991 and 2016 in three tertiary referral centres were identified from prospectively maintained databases. RESULTS: A total of 39 patients were included, with a median follow-up of 18 months (interquartile range 6.1-60.8). Of these patients, 23 (58.9%) patients had a complete response (CR) after ILP, 10 (25.6%) had a partial response, 4 (10.3%) had stable disease and 2 (5.1%) patients had progressive disease immediately after ILP. A total of 22 patients developed local progression (56.4%), whereas nine (23.1%) developed distant metastases. The patients with CR had a significantly prolonged median local progression-free survival (PFS) (15.4 versus 7.3 months, p = 0.015) when compared with non-CR patients, and a trend towards better median overall survival (81.2 versus 14.5 months, p = 0.054). Six patients underwent multiple ILPs, whereby the CR rate of the first, second and third ILPs were 60%, 80% and 67%, respectively. Thirteen (33.3%) patients needed further surgical intervention, consisting of resection in eight patients (20.5%) and amputation in five patients (12.8%). CONCLUSION: ILP is an effective treatment option for patients with locally advanced angiosarcoma in the extremities, resulting in a high number of CRs, a high limb salvage rate and prolonged local PFS.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Cancer, Regional Perfusion/methods , Extremities/blood supply , Hemangiosarcoma/blood supply , Hemangiosarcoma/therapy , Melphalan/administration & dosage , Soft Tissue Neoplasms/blood supply , Soft Tissue Neoplasms/therapy , Tumor Necrosis Factor-alpha/administration & dosage , Adult , Aged , Aged, 80 and over , Amputation, Surgical , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemotherapy, Cancer, Regional Perfusion/adverse effects , Chemotherapy, Cancer, Regional Perfusion/mortality , Databases, Factual , Disease Progression , Disease-Free Survival , Extremities/pathology , Female , Hemangiosarcoma/mortality , Hemangiosarcoma/secondary , Humans , Kaplan-Meier Estimate , Limb Salvage , London , Male , Melphalan/adverse effects , Middle Aged , Netherlands , Proportional Hazards Models , Regional Blood Flow , Retreatment , Retrospective Studies , Risk Factors , Soft Tissue Neoplasms/mortality , Soft Tissue Neoplasms/pathology , Time Factors , Treatment Outcome , Tumor Necrosis Factor-alpha/adverse effects , Young AdultSubject(s)
Head and Neck Neoplasms/diagnostic imaging , Hemangiosarcoma/diagnostic imaging , Skin Neoplasms/diagnostic imaging , Ultrasonography, Doppler, Color , Aged, 80 and over , Antineoplastic Agents, Phytogenic/therapeutic use , Biopsy , Dermatitis, Allergic Contact/diagnosis , Diagnosis, Differential , Female , Head and Neck Neoplasms/blood supply , Head and Neck Neoplasms/diagnosis , Hemangiosarcoma/blood supply , Hemangiosarcoma/diagnosis , Hemangiosarcoma/drug therapy , Humans , Paclitaxel/therapeutic use , Skin Neoplasms/blood supply , Skin Neoplasms/diagnosis , Skin Neoplasms/drug therapyABSTRACT
BACKGROUND: Pazopanib is a multitargeted tyrosine kinase inhibitor approved for the treatment of patients with selective subtypes of advanced soft tissue sarcoma (STS) who have previously received standard chemotherapy including anthracyclines. Data on the efficacy in vascular sarcomas are limited. The main objective of this study was to investigate the activity of pazopanib in vascular sarcomas. PATIENTS AND METHODS: A retrospective study of patients with advanced vascular sarcomas, including angiosarcoma (AS), epithelioid hemangioendothelioma (HE) and intimal sarcoma (IS) treated with pazopanib in real life practice at EORTC centers as well as patients treated within the EORTC phase II and III clinical trials (62043/62072) was performed. Patient and tumor characteristics were collected. Response was assessed according to RECIST 1.1. and survival analysis was performed. RESULTS: Fifty-two patients were identified, 40 (76.9%), 10 (19.2%) and two (3.8%) with AS, HE and IS, respectively. The response rate was eight (20%), two (20%) and two (100%) in the AS, HE and IS subtypes, respectively. There was no significant difference in response rate between cutaneous and non-cutaneous AS and similarly between radiation-associated and non-radiation-associated AS. Median progression-free survival (PFS) and median overall survival (OS; from commencing pazopanib) were three months (95% CI 2.1-4.4) and 9.9 months (95% CI 6.5-11.3) in AS, respectively. CONCLUSION: The activity of pazopanib in AS is comparable to its reported activity in other STS subtypes. In this study, the activity of pazopanib was similar in cutaneous/non-cutaneous and in radiation/non-radiation-associated AS. In addition, pazopanib showed promising activity in HE and IS, worthy of further evaluation.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Hemangioendothelioma, Epithelioid/drug therapy , Hemangiosarcoma/drug therapy , Neoplasms/drug therapy , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Tunica Intima/drug effects , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Hemangioendothelioma, Epithelioid/blood supply , Hemangioendothelioma, Epithelioid/secondary , Hemangiosarcoma/blood supply , Hemangiosarcoma/secondary , Humans , Indazoles , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Staging , Neoplasms/pathology , Prognosis , Retrospective Studies , Survival Rate , Tunica Intima/pathologyABSTRACT
Due to optimization of surgical techniques in surgical oncology and vascular surgery, the most modern approaches of anesthesia and intensive care medicine and effective multimodal therapeutic strategies, locally advanced malignant tumors are resected more frequently with a potentially curative intent. In the case of extensive tumors with infiltration of vital vascular structures or of structures which are crucial for extremity preservation, the necessary surgical procedure for complete tumor removal poses a major challenge for the surgeon and incorporates a high risk of perioperative morbidity for the patient. The decision to attempt tumor resection should therefore always be based on a concept considering all aspects of the malignant disease. The treating team should be highly experienced in this complex field of surgery, not only with respect to the surgical approach but also regarding the management of postoperative complications. In this article relevant aspects of decision making, surgical technique and postoperative outcome for malignant tumors involving vascular structures of the retroperitoneum and pelvis are presented.
Subject(s)
Pelvic Neoplasms/blood supply , Pelvic Neoplasms/surgery , Sarcoma/blood supply , Sarcoma/surgery , Vascular Neoplasms/blood supply , Vascular Neoplasms/surgery , Vascular Surgical Procedures/methods , Aorta, Abdominal/pathology , Aorta, Abdominal/surgery , Combined Modality Therapy , Decision Support Techniques , Hemangiosarcoma/blood supply , Hemangiosarcoma/pathology , Hemangiosarcoma/secondary , Hemangiosarcoma/surgery , Humans , Leiomyosarcoma/blood supply , Leiomyosarcoma/pathology , Leiomyosarcoma/secondary , Leiomyosarcoma/surgery , Neoplasm Invasiveness , Pelvic Neoplasms/pathology , Retroperitoneal Neoplasms/blood supply , Retroperitoneal Neoplasms/pathology , Retroperitoneal Neoplasms/secondary , Retroperitoneal Neoplasms/surgery , Sarcoma/pathology , Sarcoma/secondary , Vascular Neoplasms/pathology , Vascular Neoplasms/secondaryABSTRACT
An A10 aptamer (Apt)-functionalized, sub-100 nm doxorubicin-polylactide (Doxo-PLA) nanoconjugate (NC) with controlled release profile was developed as an intravenous therapeutic strategy to effectively target and cytoreduce canine hemangiosarcoma (cHSA), a naturally occurring solid tumor malignancy composed solely of tumor-associated endothelium. cHSA consists of a pure population of malignant endothelial cells expressing prostate-specific membrane antigen (PSMA) and is an ideal comparative tumor model system for evaluating the specificity and feasibility of tumor-associated endothelial cell targeting by A10 Apt-functionalized NC (A10 NC). In vitro, A10 NCs were selectively internalized across a panel of PSMA-expressing cancer cell lines, and when incorporating Doxo, A10 Doxo-PLA NCs exerted greater cytotoxic effects compared to nonfunctionalized Doxo-PLA NCs and free Doxo. Importantly, intravenously delivered A10 NCs selectively targeted PSMA-expressing tumor-associated endothelial cells at a cellular level in tumor-bearing mice and dramatically increased the uptake of NCs by endothelial cells within the local tumor microenvironment. By virtue of controlled drug release kinetics and selective tumor-associated endothelial cell targeting, A10 Doxo-PLA NCs possess a desirable safety profile in vivo, being well-tolerated following high-dose intravenous infusion in mice, as supported by the absence of any histologic organ toxicity. In cHSA-implanted mice, two consecutive intravenous infusions of A10 Doxo-PLA NCs exerted rapid and substantial cytoreductive activities within a period of 7 days, resulting in greater than 70% reduction in macroscopic tumor-associated endothelial cell burden as a consequence of enhanced cell death and necrosis.
Subject(s)
Aptamers, Nucleotide/chemistry , Doxorubicin/pharmacology , Nanoconjugates/therapeutic use , Nanomedicine/methods , Neovascularization, Pathologic/drug therapy , Polyesters/chemistry , Animals , Antigens, Surface/metabolism , Aptamers, Nucleotide/genetics , Base Sequence , Cell Line, Tumor , Delayed-Action Preparations , Dogs , Doxorubicin/chemistry , Doxorubicin/therapeutic use , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Gene Expression Regulation, Neoplastic/drug effects , Glutamate Carboxypeptidase II/metabolism , Hemangiosarcoma/blood supply , Hemangiosarcoma/drug therapy , Hemangiosarcoma/pathology , Humans , Male , Mice , Models, Molecular , Molecular Conformation , Nanoconjugates/chemistry , Nanoconjugates/toxicity , Tissue DistributionABSTRACT
Aortic sarcomas are predominantly endoluminal tumours that are believed derived from the intima. Because of their rarity, relatively little is known about their pathological features. We report a series of 26 aortic and iliofemoral tumours with histopathological and clinical data.Of the 26 cases, there were 16 men (63.6â±â13 years) and 10 women (58.6â±â18 years). Tumours occurred in the abdominal aorta (13), descending thoracic aorta (8), iliac or femoral arteries (4) and ascending aorta (1). Presenting tumour manifestations included claudication or peripheral vascular disease (6), pain (5), pulsatile aneurysm (2) abdominal aortic aneurysm (AAA; 2), occluded graft (2), renal artery stenosis (1), pain from bone metastasis (1), aortic rupture (1), fever (1), weight loss (1), vasculitis (1) impotence (1), incidental finding (1) and bowel ischaemia (1). The diagnosis was not suspected clinically in any case. The tumours were sampled by endarterectomy (9), aortic resection (8), repair of aneurysm (5), and in four the diagnosis was made at autopsy. Histologically and immunohistochemically, 13 were categorised as poorly differentiated angiosarcomas, seven as undifferentiated sarcomas, three as osteosarcomas, two as myxofibrosarcomas, and one as myxoid sarcoma, not otherwise specified. The undifferentiated sarcomas and angiosarcomas were histologically similar to one another and were characterised by tumour cells within and overlying thrombus. The angiosarcomas were defined by diffuse CD31 expression with co-expression of pancytokeratin in 10 (77%). Undifferentiated sarcomas were composed of spindled and/or epithelioid cells and 71% expressed smooth muscle actin. Histological material from metastatic tumours was available in two osteosarcomas and two undifferentiated sarcomas, and showed undifferentiated pleomorphic sarcoma in all cases.In this series, half of aortic intimal sarcomas are histologically undifferentiated and express endothelial and epithelial markers (epithelioid angiosarcoma). The second largest group is undifferentiated sarcoma without immunohistochemical evidence of endothelial differentiation and frequent actin positivity. Rare types include myxofibrosarcoma and osteosarcoma.
Subject(s)
Aorta/pathology , Femoral Artery/pathology , Hemangiosarcoma/blood supply , Adult , Aged , Aged, 80 and over , Aortic Aneurysm, Abdominal/etiology , Aortic Aneurysm, Abdominal/pathology , Female , Hemangiosarcoma/complications , Humans , Male , Middle Aged , Tunica Intima/pathology , Vascular Neoplasms/complications , Vascular Neoplasms/pathologyABSTRACT
Angiosarcoma is a biologically aggressive vascular malignancy with a high metastatic potential. In the era of targeted medicine, knowledge of specific molecular tumor characteristics has become more important. Molecular imaging using targeted ultrasound contrast agents can monitor tumor progression non-invasively. Secreted frizzled related protein 2 (SFRP2) is a tumor endothelial marker expressed in angiosarcoma. We hypothesize that SFRP2-directed imaging could be a novel approach to imaging the tumor vasculature. To develop an SFRP2 contrast agent, SFRP2 polyclonal antibody was biotinylated and incubated with streptavidin-coated microbubbles. SVR angiosarcoma cells were injected into nude mice, and when tumors were established the mice were injected intravenously with the SFRP2 -targeted contrast agent, or a control streptavidin-coated contrast agent. SFRP2 -targeted contrast agent detected tumor vasculature with significantly more signal intensity than control contrast agent: the normalized fold-change was 1.6 ± 0.27 (n = 13, p = 0.0032). The kidney was largely devoid of echogenicity with no significant difference between the control contrast agent and the SFRP2-targeted contrast agent demonstrating that the SFRP2-targeted contrast agent was specific to tumor vessels. Plotting average pixel intensity obtained from SFRP2-targeted contrast agent against tumor volume showed that the average pixel intensity increased as tumor volume increased. In conclusion, molecularly-targeted imaging of SFRP2 visualizes angiosarcoma vessels, but not normal vessels, and intensity increases with tumor size. Molecular imaging of SFRP2 expression may provide a rapid, non-invasive method to monitor tumor regression during therapy for angiosarcoma and other SFRP2 expressing cancers, and contribute to our understanding of the biology of SFRP2 during tumor development and progression.
Subject(s)
Biomarkers, Tumor/genetics , Hemangiosarcoma/blood supply , Membrane Proteins/genetics , Molecular Imaging/methods , Skin Neoplasms/blood supply , Animals , Antibodies/chemistry , Biomarkers, Tumor/chemistry , Biotinylation , Cell Line, Tumor , Contrast Media/pharmacokinetics , Gene Expression , Hemangiosarcoma/diagnosis , Hemangiosarcoma/diagnostic imaging , Hemangiosarcoma/pathology , Male , Membrane Proteins/chemistry , Mice , Mice, Nude , Microbubbles , Neoplasm Transplantation , Skin Neoplasms/diagnosis , Skin Neoplasms/diagnostic imaging , Skin Neoplasms/pathology , Streptavidin/chemistry , UltrasonographyABSTRACT
PURPOSE: Angiosarcomas are rare, aggressive vascular tumours known to express vascular endothelial growth factor (VEGF), a key pro-angiogenic growth factor. The aim of this study was to determine the potential effects of vascular-targeted agents for the treatment of angiosarcoma, using two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS), and human dermal microvascular endothelial cells (HuDMECs) for comparison. METHODS: Protein arrays were used to assess the expression of angiogenesis-related proteins, and potential drug targets were assessed by ELISA and Western blotting. Response to vascular-targeted agents, including bevacizumab an anti-VEGF antibody, axitinib a VEGF-receptor tyrosine kinase inhibitor, everolimus an mTOR inhibitor, selumetinib a MEK inhibitor and vadimezan a vascular-disrupting agent were compared in functional in vitro cellular assays, including viability, differentiation and migration assays. RESULTS: ASM and ISO-HAS cells expressed a broad range of pro-angiogenic growth factors. ASM and ISO-HAS VEGF expression was significantly increased (p = 0.029) compared with HuDMECs. Striking responses were seen to vadimezan with an IC50 of 90 and 150 µg/ml for ASM and ISO-HAS cells, respectively. Selumetinib inhibited ASM with an IC50 of 1,750 ng/ml, but was not effective in ISO-HAS. Everolimus reduced both ASM and ISO-HAS viable cell counts by 20 % (p < 0.001). Minimal responses were observed to bevacizumab and axitinib in assays with ASM and ISO-HAS cells. CONCLUSIONS: Further studies are warranted to investigate mTOR inhibitors, MEK inhibitors and vascular-disrupting agents for the treatment of angiosarcoma.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Hemangiosarcoma/blood supply , Hemangiosarcoma/drug therapy , Antibodies, Monoclonal, Humanized/pharmacology , Axitinib , Bevacizumab , Cell Death/drug effects , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Doxorubicin/pharmacology , Everolimus , Hemangiosarcoma/metabolism , Hemangiosarcoma/pathology , Humans , Imidazoles/pharmacology , Indazoles/pharmacology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Paclitaxel/pharmacology , Protein Array Analysis , Sirolimus/analogs & derivatives , Sirolimus/pharmacology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolismABSTRACT
The breast angiosarcoma is an endothelial malign tumor. Its prevalence is about 0.04% of all breast malignant tumors. The characteristics of angiosarcoma are its malignancy and its clinical and radiologic polymorphism. The breast angiocarcinoma has a bad prognostic because of the frequency of metastases and recurrence. The purpose of this paper is to report the clinical, imaging and pathological features of breast angiosarcoma, a rare but aggressive tumor, based on a review of one case.
Subject(s)
Breast Neoplasms/pathology , Hemangiosarcoma/pathology , Adult , Age Factors , Biomarkers, Tumor , Biopsy , Breast Neoplasms/blood supply , Breast Neoplasms/diagnosis , Breast Neoplasms/diagnostic imaging , Cell Differentiation , Diagnosis, Differential , Fatal Outcome , Female , Hemangioma/diagnosis , Hemangiosarcoma/blood supply , Hemangiosarcoma/diagnosis , Hemangiosarcoma/diagnostic imaging , Humans , Mammography , Mastectomy, Simple , Neoplasm Grading , Neoplasm Invasiveness , Neoplasms, Radiation-Induced/etiology , PrognosisABSTRACT
Angiogenesis, the emergence of vessels from an existing vascular network, is pathologically associated with tumor progression and is of great interest for therapeutic intervention. PTEN is a frequently mutated tumor suppressor and has been linked to the progression of many types of tumors, including hemangiosarcomas in zebrafish. Here, we report that mutant zebrafish embryos lacking functional Pten exhibit enhanced angiogenesis, accompanied by elevated levels of phosphorylated Akt (pAkt). Inhibition of phosphoinositide 3-kinase (PI3K) by LY294002 treatment and application of sunitinib, a widely used anti-angiogenic compound, suppressed enhanced angiogenesis in Pten mutants. Vegfaa has a crucial role in angiogenesis and vegfaa expression was upregulated in embryos lacking functional Pten. Interestingly, vegfaa expression was also upregulated in hemangiosarcomas from haploinsufficient adult zebrafish Pten mutants. Elevated vegfaa expression in mutant embryos lacking functional Pten was suppressed by LY294002. Surprisingly, sunitinib treatment dramatically enhanced vegfaa expression in Pten mutant embryos, which might account for tumor relapse in human patients who are treated with sunitinib. Combined treatment with suboptimal concentrations of sunitinib and LY294002 rescued enhanced angiogenesis in pten mutant embryos without the dramatic increase in vegfaa expression, suggesting a new approach for therapeutic intervention in VEGFR-signaling-dependent tumors.
Subject(s)
Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Phosphoprotein Phosphatases/deficiency , Vascular Endothelial Growth Factor A/metabolism , Zebrafish Proteins/deficiency , Zebrafish Proteins/metabolism , Zebrafish/metabolism , Animals , Chromones/pharmacology , Chromones/therapeutic use , Drug Therapy, Combination , Endothelial Cells/metabolism , Endothelial Cells/pathology , Haploinsufficiency/drug effects , Haploinsufficiency/genetics , Hemangiosarcoma/blood supply , Hemangiosarcoma/drug therapy , Hemangiosarcoma/pathology , Humans , Indoles/pharmacology , Indoles/therapeutic use , Morpholines/pharmacology , Morpholines/therapeutic use , Mutation/genetics , Neovascularization, Pathologic/drug therapy , Phosphoprotein Phosphatases/genetics , Phosphoprotein Phosphatases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Pseudopodia/drug effects , Pseudopodia/metabolism , Pyrroles/pharmacology , Pyrroles/therapeutic use , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sunitinib , Up-Regulation/drug effects , Zebrafish/embryology , Zebrafish Proteins/geneticsABSTRACT
Gankyrin (also called p28 or PSMD10) is an oncoprotein commonly overexpressed in hepatocellular carcinomas. It consists of 7 ankyrin repeats and interacts with multiple proteins including Rb, Cdk4, MDM2 and NF-κB. To assess the oncogenic activity in vivo, we produced transgenic mice that overexpress gankyrin specifically in the hepatocytes. Unexpectedly, 5 of 7 F2 transgenic mice overexpressing hepatitis B virus X protein (HBX) promoter-driven gankyrin, and one of 3 founder mice overexpressing serum amyloid P component (SAP) promoter-driven gankyrin developed hepatic vascular neoplasms (hemangioma/hemangiosarcomas) whereas none of the wild-type mice did. Endothelial overgrowth was more frequent in the livers of diethylnitrosamine-treated transgenic mice than wild-type mice. Mouse hepatoma Hepa1-6 cells overexpressing gankyrin formed tumors with more vascularity than parental Hepa1-6 cells in the transplanted mouse skin. We found that gankyrin binds to and sequester factor inhibiting hypoxia-inducible factor-1 (FIH-1), which results in decreased interaction between FIH-1 and hypoxia-inducible factor-1α (HIF-1α) and increased activity of HIF-1 to promote VEGF production. The effects of gankyrin were more prominent under 3% O2 than 1% or 20% O2 conditions. Thus, the present study clarified, at least partly, mechanisms of vascular tumorigenesis, and suggests that gankyrin might play a physiological role in hypoxic responses besides its roles as an oncoprotein.
Subject(s)
Cell Transformation, Neoplastic/metabolism , Hemangioma/blood supply , Hemangiosarcoma/blood supply , Hypoxia-Inducible Factor 1, alpha Subunit/agonists , Liver Neoplasms/blood supply , Mixed Function Oxygenases/antagonists & inhibitors , Neovascularization, Pathologic/metabolism , Transcription Factors/biosynthesis , Animals , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Hemangioma/genetics , Hemangioma/metabolism , Hemangiosarcoma/genetics , Hemangiosarcoma/metabolism , Hepatocytes/metabolism , Hepatocytes/pathology , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Mice , Mice, Transgenic , Neovascularization, Pathologic/genetics , Transcription Factors/genetics , Vascular Endothelial Growth Factor A/metabolismABSTRACT
BACKGROUND: The development of angiosarcoma in oedematous tissue is referred to as Stewart-Treves syndrome (STS). This rare and fatal complication is associated with chronic post mastectomy lymphoedema and radiotherapy for breast cancer. Angiosarcoma spread is facilitated by the formation of blood vessels (angiogenesis) and lymph vessels (lymphangiogenesis). In the future antiangiogenic therapy may improve the poor outcome of current treatments. There was evidence that blocking the angiogenenesis would inhibit progression of angiosarcoma. It seems reasonable to hypothesize that blocking the lymphangiogenesis may yield similar results. Although angiosarcomas commonly derive from blood vessels, in case of STS angiosarcomas chronic lymphoedema may suggest its lymphatic origin. The goal of this study was to visualize interstitial space and lymphatics in the central and peripheral regions of STS angiosarcoma. METHODS: On tissue samples obtained from STS angiosarcoma we have performed: first colour stereoscopic lymphography to visualise the morphology of lymphatic vessels and extracellular spaces, second immunohistochemical staining specific for lymphatic vessels endothelium (LYVE-1) and blood endothelial cells (CD31, factor VIII) and prolymphangiogenic vascular endothelial growth factor (VEGF-C) for precise identification of lymphatic endothelia. STS angiosarcoma morphology was assessed by comparison of pictures obtained on lymphography, microscopy and confocal microscopy. RESULTS: STS angiosarcomas present heterogenous morphology with areas dominated by hemangiosarcoma and lymphangiosarcoma structures. STS angiosarcoma expressed phenotypes of both blood and lymphatic endothelia. LYVE-1 and VEGF-C is expressed by STS angiosarcoma and may be used to discriminate tumour differentiation. Morphology of lymphatic vessels and spaces in the tumour suggest absence of their normal lymphatic function. CONCLUSIONS: Our results confirmed both hemangio- and lymphangiogenic origin of STS angiosarcoma. Expression of VEGF-C makes STS angiosarcoma a good candidate for targeted antilymphangiogenic therapy. However, morphology of intratumoral lymphatics on colour lymphography suggested their impaired function, which can hamper drug distribution.
Subject(s)
Hemangiosarcoma/blood supply , Lymphangiosarcoma/blood supply , Lymphatic Vessels/pathology , Aged , Female , Hemangiosarcoma/drug therapy , Hemangiosarcoma/pathology , Humans , Immunohistochemistry , Lymphangiogenesis , Lymphangiosarcoma/drug therapy , Lymphangiosarcoma/pathology , Lymphography , Microscopy, Confocal , PhenotypeABSTRACT
Splenic haemangiosarcomas (HSAs) from 122 dogs were characterized and classified according to their patterns of growth, survival time post splenectomy, metastases and chemotherapy. The most common pattern of growth was a mixture of cavernous, capillary and solid tumour tissue. Survival time post splenectomy was independent of the growth pattern; however, it was influenced by chemotherapy and metastases. Immunohistochemical assessment of the expression of angiogenic factors (fetal liver kinase-1, angiopoietin-2, angiopoietin receptor-2 and vascular endothelial growth factor A) and conventional endothelial markers (CD31, factor VIII-related antigen) revealed variable expression, particularly in undifferentiated HSAs. Therefore, a combination of endothelial markers should be used to confirm the endothelial origin of splenic tumours.