Perioperative management of pediatric patients undergoing juvenile angiofibroma resection. A case series and educational review highlighting patient blood management.

BACKGROUND: Juvenile nasopharyngeal angiofibromas are one of the most enigmatic, bloody tumors encountered by otorhinolarygnologists, head and neck surgeons, neurosurgeons, and anesthesiologists. Juvenile nasopharyngeal angiofibromas are rare, benign, highly vascular tumors with a propensity towards aggressive local invasion. Surgery, open or endoscopic, to remove the growth is the primary treatment of choice for Juvenile nasopharyngeal angiofibromas. Historically, surgical resection was associated with massive, rapid blood loss, traditionally managed by blood product transfusion and deliberate hypotension. Preventative management employing multimodal blood conservation strategies should be an essential standard of perioperative care for patients with Juvenile nasopharyngeal angiofibromas. METHODS: We describe a contemporary and comprehensive approach in the management of patients with high grade Juvenile nasopharyngeal angiofibromas. This includes surgical strategies such as preemptive external carotid artery embolization, endoscopic surgical approach, and staged operations, as well as anesthetic strategies including antifibrinolytic therapy and acute normovolemic hemodilution. These surgeries, once synonymous with massive transfusion, may potentially be performed without allogeneic blood transfusion, or deliberate hypotension. AIMS: Using a case series, the authors introduce a contemporary approach to multimodal, multidisciplinary blood conservation strategies for Juvenile nasopharyngeal angiofibromas surgery. RESULTS: Here in the authors report on an updated contemporary perioperative clinical approach to patients with Juvenile nasopharyngeal angiofibromas. From an anesthetic perspective, we describe the successful use of normal hemodynamic goals, restrictive transfusion strategy, antifibrinolytic therapy, autologous normovolemic hemodilution, and early extubation in the care of three adolescent males with highly invasive tumors. We demonstrate that new surgical and anesthetic strategies have yielded a significant decrease in intraoperative blood loss and eliminated the need for transfusion of autologous red blood cells, which enable improved outcomes. CONCLUSIONS: The perioperative approach to elective surgery for Juvenile nasopharyngeal angiofibromas management is presented from a multidisciplinary patient blood management perspective.

Efficacy and safety of preoperative internal maxillary arterial embolization with gelfoam for nasopharyngeal angiofibroma.

PURPOSE: To investigate the efficacy and safety of preoperative internal maxillary arterial embolization with gelfoam particles in patients with nasopharyngeal angiofibroma. MATERIALS AND METHODS: We retrospectively reviewed a total of 27 consecutive patients with pathologically confirmed nasopharyngeal angiofibroma from August 2006 to September 2018. Of the 27 enrolled patients, 10 patients received surgical excision alone; 17 patients received preoperative internal maxillary arterial embolization followed by surgical excision. Embolic agents were gelfoam particles. RESULTS: The mean volume of intro-operative blood loss was 385.3 ml in patients with preoperative arterial embolization, which was significantly lower than 1215.0 ml in the patients without preoperative arterial embolization (P < 0.001). The mean surgical time was shorter in patients with preoperative arterial embolization than in the patient without preoperative arterial embolization, but the difference had no statistical significance (205.0 vs 264.5 min, P = 0.064). Neurological complications such as facial palsy or vision loss or hemiplegia were not observed in patients with preoperative arterial embolization. CONCLUSION: Internal maxillary artery embolization with gelfoam particles suffices to provide an effective and safe adjuvant procedure for surgical excision of nasopharyngeal angiofibroma.

Induction of chemokine (C-C motif) ligand 5 by Epstein-Barr virus infection enhances tumor angiogenesis in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is etiologically associated with Epstein-Barr virus (EBV) infection and is known to be highly vascularized. Previous studies have suggested that EBV oncoproteins contribute to NPC angiogenesis. However, the regulatory network of EBV in angiogenesis still remains elusive. Herein, we reveal a novel mechanism of EBV-induced angiogenesis in NPC. First, we showed that EBV-infected NPC cell lines generated larger tumors with more microvessels in mouse xenograft models. Subsequent proteomic analysis revealed that EBV infection increased the expression of a series of angiogenic factors, including chemokine (C-C motif) ligand 5 (CCL5). We then proved that CCL5 was a target of EBV in inducing tumor angiogenesis and growth. Further investigation through transcriptome analysis indicated that the pro-angiogenic function of CCL5 might be mediated by the PI3K/AKT pathway. Furthermore, we confirmed that activation of the PI3K/AKT and hypoxia-inducible factor-1α pathways was essential for CCL5-promoted angiogenesis. Finally, the immunohistochemical analysis of human NPC specimens also showed that CCL5 was correlated with angiogenesis. Taken together, our study identifies CCL5 as a key EBV-regulated molecular driver that promotes NPC angiogenesis, suggesting it as a potential therapeutic target.

Ophthalmic artery occlusion following neuro-embolization of the external carotid artery, a case report.

BACKGROUND: Embozene® is a new neuroembolizing microsphere used to reduce intraoperative bleeding for head and neck tumours. We report a case of iatrogenic ophthalmic artery occlusion after Embozene® embolization of the external carotid artery (ECA). CASE PRESENTATION: A 22-year-old African gentleman presented with left nasal obstruction and epistaxis for 2 years and was diagnosed with nasopharyngeal carcinoma. He subsequently underwent embolization of the maxillary branch of the left ECA using Embozene® Microspheres - 250 µm in size before endoscopic tumour excision to reduce intra-operative bleeding. He complained of sudden painless profound visual loss in the left eye (LE) two hours after embolization. Visual acuity in LE was no light perception. Fundus examination showed pale retina with no cherry red spot. Arterial narrowing and segmentation were seen in all quadrants. A diagnosis of left ophthalmic artery occlusion was made. Despite immediate management including ocular massage and lowering of intraocular pressure, the visual loss remained. Retrospective review of digital subtraction angiogram showed an anastomosis between the left ophthalmic artery and anterior deep temporal artery as a potential route for microspheres migration. CONCLUSION: Pre-operative angio-architecture understanding and diligent selection of embolic material are helpful in preventing this adverse event. The use of newer agents for embolotherapy may cause migration of embolic material from the external to the internal carotid system leading to ophthalmic artery occlusion and blindness.

Elevated expression of CD93 promotes angiogenesis and tumor growth in nasopharyngeal carcinoma.

CD93, also known as the complement component C1q receptor (C1qRp), has been reported to promote the progression of some cancer types. However, the expression and physiological significance of CD93 in nasopharyngeal carcinoma (NPC) remain largely elusive. In this study, we first examined the expression of CD93 in NPC and experimentally manipulated its expression. We observed that vascular CD93 expression is elevated in NPC and is correlated with T classification, N classification, distant metastasis, clinical stage and poor prognosis (all P < 0.05). In addition, overexpression of CD93 promoted angiogenesis in vitro. What's more, we found that CD93 was highly expressed in NPC tissues and cells, and the regulation of CD93 on cell proliferation was determined by cell counting kit (CCK)-8 assay and cell cycle analyses. Our findings provide unique insight into the pathogenesis of NPC and underscore the need to explore novel therapeutic targets such as CD93 to improve NPC treatment.

Association between vascular supply, stage and tumour size of juvenile nasopharyngeal angiofibroma.

Juvenile nasopharyngeal angiofibroma (JNA) is a highly vascular tumour seen in adolescent males. To study the vascular pattern of these tumours, we retrospectively reviewed the records of patients with JNA who underwent preoperative angiography. Most (82.2 %) of the 45 patients assessed were Radkowski stage III with a mean size of 5.29 cm. There was a significant association between tumour stage and size (p = 0.029). Ten different vessels were seen to supply these tumours. All tumours had primary supply from the distal third of the ipsilateral internal maxillary artery (IMA). Accessory vessel supply was chiefly from the Vidian branch of internal carotid artery (ICA) (55.6 %). Stage III tumours were supplied by a greater number of feeding vessels than earlier stage tumours (p < 0.01). Larger tumours were more likely to have ICA supply (p = 0.04). Bilateral supply was seen in 48.7 %. However, there was no predominance of bilateral over ipsilateral IMA supply even in advanced stage tumours. One patient in our series was found to have a caroticocavernous fistula. Residual or recurrent tumours were characterized by new vasculature (100 %) and greater accessory supply from the ipsilateral ICA (85.7 %). Our study highlights the fact that surgical planning cannot be dependent on staging alone and should include preoperative assessment of tumour vasculature by angiography.

Matrix metalloproteinase 13-containing exosomes promote nasopharyngeal carcinoma metastasis.

Nasopharyngeal cancer (NPC) is an endemic type of head and neck cancer with a high rate of cervical lymph node metastasis. Metastasis is the major cause of death in NPC patients. Increasing evidence indicates that exosomes play a pivotal role in promoting cancer metastasis by enhancing angiogenesis and ECM degradation. Matrix metalloproteinase 13 is an important kind of matrix proteinase that is often overexpressed in various tumors and increases the risk of metastasis. However, little is known about the potential role of MMP13-containing exosomes in NPC. In this study, we found that MMP13 was overexpressed in NPC cells and exosomes purified from conditioned medium (CM) as well as NPC patients' plasma. Transwell analysis revealed that MMP13-containing exosomes facilitated the metastasis of NPC cells. Furthermore, siRNA inhibited the effect of MMP13-containing exosomes on tumor cells metastasis as well as angiogenesis. The current findings provided novel insight into the vital role of MMP13-containing exosomes in NPC progression which might offer unique insights for potential therapeutic strategies for NPC progressions.

EMP1 inhibits nasopharyngeal cancer cell growth and metastasis through induction apoptosis and angiogenesis.

This study aimed to analyze the expression, clinical significance of epithelial membrane protein-1 (EMP1) in nasopharyngeal carcinoma, and the biological effect in its cell line by EMP1 overexpression. Immunohistochemistry and Western blot were used to analyze the EMP1 protein expression in 75 cases of nasopharyngeal cancer and 31 cases of normal tissues to study the relationship between EMP1 expression and clinical factors. Recombinant lentiviral vector was constructed to overexpress EMP1 and then infect nasopharyngeal cancer CNE2 cell line. Quantitative real-time RT-PCR and Western blot were used to detect the mRNA level and protein of EMP1. MTT assay, cell apoptosis, migration, and invasion assays were also conducted to determine the influence of the upregulated expression of EMP1 that might be found on CNE2 cells' biological effect. Immunohistochemistry and Western blot: The level of EMP1 protein expression was found to be significantly lower in nasopharyngeal cancer tissue than in the normal tissues (P < 0.05). Decreased expression of EMP1 was significantly correlated with T stages, lymph node metastasis, clinic stage, and histological grade of patients with nasopharyngeal cancer (P < 0.05). Meanwhile, the loss of EMP1 expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). The result of biological function has shown that CNE2 cell-transfected EMP1 had a lower survival fraction, higher cell apoptosis, significant decrease in migration and invasion, higher caspase-9, and lower vascular endothelial growth factor C protein expression compared with CNE2 cell-untransfected EMP1 (P < 0.05). EMP1 expression decreased in nasopharyngeal cancer and correlated significantly T stages, lymph node metastasis, clinic stage, histological grade, and poor overall survival, suggesting that EMP1 may play important roles as a negative regulator to nasopharyngeal cancer cell.

An oncolytic adenovirus enhances antiangiogenic and antitumoral effects of a replication-deficient adenovirus encoding endostatin by rescuing its selective replication in nasopharyngeal carcinoma cells.

A replication-deficient adenovirus (Ad) encoding secreted human endostatin (Ad-Endo) has been demonstrated to have promising antiangiogenic and antitumoral effects. The E1B55k-deleted Ad H101 can selectively lyse cancer cells. In this study, we explored the antitumor effects and cross-interactions of Ad-Endo and H101 on nasopharyngeal carcinoma (NPC). The results showed that H101 dramatically promoted endostatin expression by Ad-Endo via rescuing Ad-Endo replication in NPC cells, and the expressed endostatin proteins significantly inhibited the proliferation of human umbilical vein endothelial cells. E1A and E1B19k products are required for the rescuing of H101 to Ad-Endo replication in CNE-1 and CNE-2 cells, but not in C666-1 cells. On the other hand, Ad-Endo enhanced the cytotoxicity of H101 by enhancing Ad replication in NPC cells. The combination of H101 and Ad-Endo significantly inhibited CNE-2 xenografts growth through the increased endostatin expression and Ad replication. These findings indicate that the combination of Ad-Endo gene therapy and oncolytic Ad therapeutics could be promising in comprehensive treatment of NPC.

Preoperative angiography and external carotid artery embolization of juvenile nasopharyngeal angiofibromas in a tertiary referral paediatric centre.

AIM: To evaluate the relationship between intraoperative blood loss and juvenile nasopharyngeal angiofibroma (JNA) vascular supply and tumour stage in patients who underwent superselective external carotid artery (ECA) embolization. This series is unique in that all embolizations were performed by dedicated paediatric interventional radiologists at a tertiary referral paediatric centre. MATERIALS AND METHODS: Seventeen male patients treated from January 2002 to August 2009 underwent preoperative angiography and embolization using polyvinyl alcohol (PVA) particles. Tumours were graded using three different staging systems based on preoperative imaging and correlated to surgical blood loss. All patients underwent bilateral internal and external carotid angiography, with embolization of ECA tumour supply via microcatheter delivery of PVA particles. Particle size ranged from 150-500 µm with a mean size of 250-355 µm. Surgical resection was performed with either endoscopic or open techniques within 24 h and intraoperative blood loss was reported. RESULTS: Seven lesions were supplied strictly by the ECA circulation and had mean surgical blood loss of 336 ml. Twelve lesions had both ECA and internal carotid artery (ICA) supply and had mean surgical blood loss of 842 ml. The difference in blood loss in these two groups was statistically significant (p = 0.03). There was no case of inadvertent intracranial or ophthalmic embolization. There were statistically significant correlations between estimated surgical blood loss and the Andrews (p = 0.008), Radkowski (p = 0.015), and University of Pittsburgh Medical Center (UPMC; p = 0.015) preoperative tumour staging systems, respectively. CONCLUSION: Preoperative embolization of JNA tumours can be safely performed without neurological complications. The present study identified a statistically significant difference in intraoperative blood loss between those lesions with a purely ECA vascular supply and a combination of ECA and ICA vascular supply. Angiography is helpful in delineating ICA supply and can help guide surgical planning.

Comparison of narrow-band imaging and conventional nasopharyngoscopy for the screening of unaffected members of families with nasopharyngeal carcinoma.

Familial aggregation of nasopharyngeal carcinoma (NPC) has been widely reported. The excess risk is about 4-8-fold among first-degree relatives of NPC patients compared with those without a family history of the disease. We used nasopharyngoscopy and a narrow-band image system (NBI) to screen NPC high-risk patients and identify a good tool for the early detection of NPC in these high-risk groups. We recruited all available, affected blood relations of the patients. When NPC patients were more distant relatives, such as cousins, we recruited their shared second-degree relatives, such as unaffected aunts and uncles, to genetically connect the NPC cases. We performed transnasal endoscopy, first in white-light mode, then under the NBI system. There were two NBI patterns in NPC: microvascular proliferation and engorged blood vessels. The NBI pattern in normal nasopharyngeal mucosa was a regular cobblestone pattern. A prospective study included 211 asymptomatic members from 154 NPC families. We found four cases of NPC, all with a tumor stage of T1. In one patient (1/4), MRI revealed a 2-cm-diameter neck lymphadenopathy (N1). The correlation between conventional nasopharyngoscopy and NBI was very high (κ = 0.798, P = 0.000). In conclusions, NBI is not superior to conventional nasopharyngoscopy for the early detection of NPC in unaffected members of families with NPC history. The long-term follow-up is necessary in high-risk NPC patients. Further studies will be needed to determine which screening tool-conventional nasopharyngoscopy, NBI, or EB virus titer-is most effective.

Combination of pigment epithelium-derived factor with radiotherapy enhances the antitumor effects on nasopharyngeal carcinoma by downregulating vascular endothelial growth factor expression and angiogenesis.

Nasopharyngeal carcinoma (NPC), which has the highest incidence in South China, is mainly treated by radiotherapy. However, the survival rate remains low. Angiogenesis is closely correlated with progress of NPC. Thus, the combination of anti-angiogenesis with radiation is an attractive strategy for NPC treatment. A heterogenic xenografted human NPC nude mice model was established to investigate the effect of pigment epithelium-derived factor (PEDF), a potent anti-angiogenic factor, and the combined effect of PEDF and radiotherapy on nasopharyngeal carcinoma. Pigment epithelium- derived factor remarkably suppressed the growth of NPC by 43.52% and decreased the tumor microvessel density (MVD). Pigment epithelium-derived factor had no effects on the proliferation and apoptosis of NPC cell lines by MTT and flow cytometry assay. However, PEDF decreased vascular endothelial growth factor (VEGF) in NPC cell lines by downregulation of hypoxia-inducible factor 1a, a crucial transcriptional factor for VEGF expression, as demonstrated by western blotting and immunofluorescent staining assay. Interestingly, irradiation alone could also effectively downregulate VEGF and MVD of xenografted tumor, which indicates that irradiation suppresses NPC not only by killing tumor cells but also through anti-angiogenesis. Furthermore, combined treatment of PEDF with irradiation enhanced the antitumor efficacy. The MVD and VEGF in the combined therapy were much less than in the treatment with PEDF or radiotherapy alone. Our observation demonstrated that the combination of PEDF with radiotherapy enhances the efficacy of the antitumor effect on NPC by the coordinated inhibition on angiogenesis, which implies the potential role of PEDF as an adjuvant agent for NPC treatment.

The accuracy of computed tomographic perfusion in detecting recurrent nasopharyngeal carcinoma after radiation therapy.

OBJECTIVES: To assess the diagnostic accuracy of computed tomographic (CT) perfusion technique in discriminating recurrent nasopharyngeal carcinoma (NPC) after radiation therapy. METHODS: Forty-eight patients with a pathologic finding as reference standards were divided into 2 groups, recurrent and nonrecurrent NPCs. Perfusion parameters blood flow (BF), blood volume (BV), permeability surface (PS), and mean transit time were statistically analyzed. A receiver operating characteristic curve was used to study whether CT perfusion parameters could aid in detecting recurrent NPC. RESULTS: Blood flow, BV, and PS values between recurrent NPC (n = 27) and nonrecurrent NPC (n = 21) were 526.8 (168.1) versus 312.1 (214.4) mL/100 g per minute, 35.1 (23.6) versus 9.2 (8.0) (ml/100 g), and 53.4 (34.3) versus 17.6 (14.7) mL/100 g per minute, respectively. There was a significant difference between these 2 groups (P < 0.01). Mean transit time values in these 2 groups were 3.5 (2.0) versus 4.3 (2.7) seconds; there was no statistical difference. To optimize sensitivity and specificity, BF, BV, and PS threshold values for differentiating between recurrent and nonrecurrent NPCs were 537.20 mL/100 g per minute, 37.18 (ml/100 g), and 57.34 mL/100 g per minute, respectively. According to threshold values of BF, BV, and PS, sensitivity and specificity for distinguishing recurrent and nonrecurrent NPCs were 92.6% and 76.2%, 96.3% and 81%, and 81.5% and 61.9%, respectively. CONCLUSIONS: The CT perfusion technique may be helpful to find patients with recurrent NPC after radiation therapy.

Advanced craniofacial juvenile nasopharyngeal angiofibroma. Description of surgical series, case report, and review of literature.

BACKGROUND: Juvenile nasopharyngeal angiofibroma (JNA) is a rare benign tumor occurring almost exclusively in adolescent and young adult males. The tumor is characterized by slow progression, aggressive growth, high vascularization, and increased rate of persistence and recurrence. The aim of this study was to describe a case of giant JNA from our practice and discuss the controversies of surgical treatment of advanced JNA. MATERIAL AND METHODS: A series of 29 consecutive male patients with JNA Fisch grade III and IV was surgically treated in Burdenko Neurosurgical Institute from 2000 until 2008. In the vast majority of cases, endovascular embolization and surgical removal via orbitozygomatic approach were applied. RESULTS: Gross total resection was achieved in 24 cases (83%). Complications were encountered in eight cases. No mortality was observed. In three patients, the diseases recurred. An illustrative case is described. CONCLUSION: Surgical treatment is the basic tactics in management of extensive JNA including endovascular embolization and resection of the tumor. We recommend using orbitozygomatic approach or its modifications in JNA. Radiation therapy may be recommended for patients with small residual tumor.

CircRNA ZNF609 promotes angiogenesis in nasopharyngeal carcinoma by regulating miR-145/STMN1 axis.

Nasopharyngeal carcinoma (NPC) is the most common type of human malignant tumor in the head and neck, and tumor angiogenesis is essential for its development. Here, we showed that the circRNA ZNF609/microRNA (miR)-145/Stathmin 1 (STMN1) axis regulated angiogenesis in NPC.Circ-ZNF609, miR-145, and STMN1 expression in NPC cells and NPC samples were examined using qRT-PCR. The protein levels of STMN1, VEGFR1, and VEGFR2 were evaluated using western blotting. VEGF level was determined by ELISA. The proliferation of NPC cells and HUVECs was examined using a CCK-8 assay. Transwell assays and wound-healing assays were applied to assess the migration of NPC cells and HUVECs, respectively. Angiogenesis of HUVECs was evaluated by an angiogenesis assay. In addition, a dual-luciferase reporter assay and RNA pull-down assays were employed to verify the binding relationship between circ-ZNF609 and miR-145 as well as between miR-145 and STMN1. Here, we showed that circ-ZNF609 and STMN1 expression was increased, while miR-145 expression was decreased in NPC cells and NPC samples. Circ-ZNF609 may negatively regulate miR-145 expression by acting as a ceRNA. Silencing circ-ZNF609 suppressed cell proliferation, migration, and angiogenesis in NPC, while knockdown of miR-145 reversed these effects. In addition, we found that STMN1 was the downstream target of miR-145. MiR-145 overexpression suppressed cell proliferation, migration, and angiogenesis in NPC, which was abolished by STMN1 overexpression. Our data suggested that circ-ZNF609 promotes cell proliferation, migration, and angiogenesis in NPC by upregulating the expression of STMN1 by sponging miR-145 in NPC.

Direct Tumoral Puncture Onyx Embolization for a Juvenile Nasopharyngeal Angiofibroma in a Hybrid Neurointerventional Suite.

This case video demonstrates a multidisciplinary approach to resection of a juvenile nasopharyngeal angiofibroma highlighting direct intratumoral onyx embolization. The patient is a 14-year-old boy who presented with a 1-month history of worsening epistaxis and nasal congestion. Preoperative magnetic resonance imaging demonstrated a 4.5 x 3 x 3 cm lobulated mass in the right pterygomaxillary space, sphenoid, and the nasopharynx adjacent to the cavernous carotid. Given the high vascularity of the lesion, intratumoral onyx embolization was undertaken, which significantly reduced intraoperative blood loss in this case. The present video demonstrates the technique for safe direct intratumoral onyx embolization and its role in significantly reducing intraoperative blood loss (Video 1). Postoperatively, the patient made an uncomplicated recovery. The patient consented to the procedure.

Foxq1 promotes metastasis of nasopharyngeal carcinoma by inducing vasculogenic mimicry via the EGFR signaling pathway.

In nasopharyngeal carcinoma (NPC), the treatment of tumor metastasis and recurrence is challenging and is associated with poor clinical efficacy. Vasculogenic mimicry (VM) is a new blood-supply model of malignant tumor that is closely related to tumors' distant metastasis. Our previous study demonstrated that miR-124 could target Foxq1 to inhibit NPC metastasis. Whether Foxq1 affects metastasis through vasculogenic mimicry is worth consideration. In this study, we show that VM formation positively correlates with the expression of Foxq1, and EGFR, and the TNM stage in 114 NPC patient samples. Meanwhile, we show that VM-positive NPC patients have a poor prognosis. Furthermore, using in vitro and vivo approaches, we confirm that Foxq1 has a significant effect on NPC metastasis through promoting VM formation, which could be effectively inhibited by EGFR inhibitors (Nimotuzumab or Erlotinib). Also a synergistic efficacy of anti-EGFR and anti-VEGF drugs has been found in NPC inhibition. Mechanistically, the luciferase reporter gene and CHIP assays show that Foxq1 directly binds to the EGFR promoter region and regulates EGFR transcription. In conclusion, our results show that Foxq1 is regulated by miR-124 and that it promotes NPC metastasis by inducing VM via the EGFR signaling pathway. Overall, these results provide a new theoretical support and a novel target selection for anti-VM therapy in the treatment of nasopharyngeal carcinoma.

Nuclear exosome HMGB3 secreted by nasopharyngeal carcinoma cells promotes tumour metastasis by inducing angiogenesis.

Distant metastasis accompanied by angiogenesis is the main cause of nasopharyngeal carcinoma (NPC)-related death. Nuclear exosomes (nEXOs) are potential tumour biomarkers. High mobility group box 3 (HMGB3), a nuclear protein, is known to be overexpressed in cancers. However, its role in NPC has not been elucidated. Here, we explore for the first time the function of nEXO HMGB3 in tumour angiogenesis involved in NPC metastasis using a series of in vitro experiments with NPC cell lines and clinical specimens and in vivo experiments with tumour xenograft zebrafish angiogenesis model. We found a high expression of HMGB3 in NPC, accompanied by the formation of micronuclei, to be associated with metastasis. Furthermore, the NPC-secreted HMGB3 expression was associated with tumour angiogenesis. Moreover, HMGB3-containing nEXOs, derived from the micronuclei of NPC cells, were ingested by the human umbilical vein endothelial cells (HUVECs), and accelerated angiogenesis in vitro and in vivo. Importantly, western blotting and flow cytometry analysis showed that circulating nEXO HMGB3 positively correlated with NPC metastasis. In summary, nEXO HMGB3 can be a significant biomarker of NPC metastasis and provide a novel basis for anti-angiogenesis therapy in clinical metastasis.

Macrophage migration inhibitory factor contributes angiogenesis by up-regulating IL-8 and correlates with poor prognosis of patients with primary nasopharyngeal carcinoma.

BACKGROUND AND OBJECTIVES: We aim at the association of macrophage migration inhibitory factor (MIF) with neovascularization and survival of nasopharyngeal carcinoma (NPC), and determine whether MIF is a valuable prognostic predictor for NPC patients. METHODS: One hundred and forty one cases of NPC and 25 normal tissues of nasopharynx were collected. The expression of MIF and interleukin 8 (IL-8) was evaluated in tissues microarray by immunostaining. Intratumoral microvessel density (IMD) in relation to immunostainings and clinicopathological factors were analyzed statistically as well as the follow-up data of patients. RESULTS: High-expression of both MIF (69.5%) and IL-8 (56.0%) were significantly associated with increased microvessels and lymph node metastasis. High-expression of MIF, IL-8 and higher level of IMD were correlated with either patients' overall survival or disease-specific survival in univariate analysis, but only angiogenesis and lymph node status exhibited in relation to survival of patients as independent prognostic factor of NPC by multivariate analysis. In addition, high-expression of MIF and higher level of IMD were closely associated with locoregional failure of NPC patients. CONCLUSIONS: MIF may contribute to lymph node metastasis in NPC by inducing angiogenesis through the way of upregulation of IL-8 expression in an autocrine EBV-independent pathway.