Pieter Wesseling

The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells.

Myeloid‐derived suppressor cells (MDSC) and regulatory T (Treg) cells are major components of the immune suppressive tumour microenvironment (TME). Both cell types expand systematically in preclinical tumour models and promote T‐cell dysfunction that in turn favours tumour progression. Clinical reports show a positive correlation between elevated levels of both suppressors and tumour burden. Recent studies further revealed that MDSCs can modulate the de novo development and induction of Treg cells. The overlapping target cell population of Treg cells and MDSCs is indicative for the importance and flexibility of immune suppression under pathological conditions. It also suggests the existence of common pathways that can be used for clinical interventions aiming to manipulate the TME. Elimination or reprogramming of the immune suppressive TME is one of the major current challenges in immunotherapy of cancer. Interestingly, recent findings suggest that natural killer T (NKT) cells can acquire the ability to convert immunosuppressive MDSCs into immunity‐promoting antigen‐presenting cells. Here we will review the cross‐talk between MDSCs and other immune cells, focusing on Treg cells and NKT cells. We will consider its impact on basic and applied cancer research and discuss how targeting MDSCs may pave the way for future immunocombination therapies.

Myc-associated zinc finger protein (MAZ) is regulated by miR-125b and mediates VEGF-induced angiogenesis in glioblastoma.

In patients with glioblastomas, vascular endothelial growth factor (VEGF) is a key mediator of tumor‐associated angiogenesis. Glioblastomas are notorious for their capacity to induce neovascularization, driving continued tumor growth. Here we report that miR‐125b is down‐regulated in glioblastoma‐associated endothelial cells, resulting in increased expression of its target, myc‐associated zinc finger protein (MAZ), a transcription factor that regulates VEGF. The down‐regulation of miR‐125b was also observed on exposure of endothelial cells to glioblastoma‐conditioned medium or VEGF, resulting in increased MAZ expression. Further analysis revealed that inhibition of MAZ accumulation by miR‐125b, or by MAZ‐specific shRNAs, attenuated primary human brain endothelial cell migration and tubule formation in vitro, phenomena considered to mimick angiogenic processes in vitro. Moreover, MAZ expression was elevated in brain blood vessels of glioblastoma patients. Altogether these results demonstrate a functional feed‐forward loop in glioblastoma‐related angiogenesis, in which VEGF inhibits the expression of miR‐125b, resulting in increased expression of MAZ, which in its turn causes transcriptional activation of VEGF. This loop is functionally impeded by the VEGF receptor inhibitor vandetanib, and our results may contribute to the further development of inhibitors of tumor‐angiogenesis.—Smits, M., Wurdinger, T., van het Hof, B., Drexhage, J. A. R., Geerts, D., Wesseling, P., Noske, D. P., Vandertop, W. P., de Vries, H. E., Reijerkerk, A. Myc‐associated zinc finger protein (MAZ) is regulated by miR‐125b and mediates VEGF‐induced angiogenesis in glioblastoma. FASEB J. 26, 2639‐2647 (2012). www.fasebj.org

Effects of Dual Targeting of Tumor Cells and Stroma in Human Glioblastoma Xenografts with a Tyrosine Kinase Inhibitor against c-MET and VEGFR2

Anti-angiogenic treatment of glioblastoma with Vascular Endothelial Growth Factor (VEGF)- or VEGF Receptor 2 (VEGFR2) inhibitors normalizes tumor vessels, resulting in a profound radiologic response and improved quality of life. This approach however does not halt tumor progression by diffuse infiltration, as this phenotype is less angiogenesis dependent. Combined inhibition of angiogenesis and diffuse infiltrative growth would therefore be a more effective treatment approach in these tumors. The HGF/c-MET axis is important in both angiogenesis and cell migration in several tumor types including glioma. We therefore analyzed the effects of the c-MET- and VEGFR2 tyrosine kinase inhibitor cabozantinib (XL184, Exelixis) on c-MET positive orthotopic E98 glioblastoma xenografts, which routinely present with angiogenesis-dependent areas of tumor growth, as well as diffuse infiltrative growth. In in vitro cultures of E98 cells, cabozantinib effectively inhibited c-MET phosphorylation, concomitant with inhibitory effects on AKT and ERK1/2 phosphorylation, and cell proliferation and migration. VEGFR2 activation in endothelial cells was also effectively inhibited in vitro. Treatment of BALB/c nu/nu mice carrying orthotopic E98 xenografts resulted in a significant increase in overall survival. Cabozantinib effectively inhibited angiogenesis, resulting in increased hypoxia in angiogenesis-dependent tumor areas, and induced vessel normalization. Yet, tumors ultimately escaped cabozantinib therapy by diffuse infiltrative outgrowth via vessel co-option. Of importance, in contrast to the results from in vitro experiments, in vivo blockade of c-MET activation was incomplete, possibly due to multiple factors including restoration of the blood-brain barrier resulting from cabozantinib-induced VEGFR2 inhibition. In conclusion, cabozantinib is a promising therapy for c-MET positive glioma, but improving delivery of the drug to the tumor and/or the surrounding tissue may be needed for full activity.

Transalar Sphenoidal Encephalocele and Respiratory Distress in a Neonate: A Case Report

We present a full-term newborn infant who suffered from immediate postpartum severe respiratory distress. The infant had an inspiratory stridor as a result of a swelling of the soft palate, extending from the roof of the nasopharynx. Transoral endotracheal intubation resulted in normal saturation levels. Histologic examination after an open biopsy showed mature neuroglial tissue. Radiology demonstrated the presence of a right parapharyngeal process obstructing the nasopharynx and oropharynx and extending to the right middle and posterior fossa, via the foramen ovale. After transoral debulking, the infant was extubated successfully. After an uneventful period of 5 months, the patient was readmitted at our hospital for treatment of meningitis. Subsequently, the inspiratory stridor recurred, and staged surgery was performed. First, a transcranial approach was used to remove a large intradural part of the process and close the defect at Meckels cave. Two weeks later the retro- and parapharyngeal part of the process were removed transorally. Given the site of the defect of the skull base and the intradural location of the process, the diagnosis is a transalar sphenoidal encephalocele. This is a rare type of basal encephalocele, and has never been reported in an infant nor known to present with respiratory distress. The pathogenesis, clinical presentation, pathology, and therapeutic implications of basal encephaloceles are discussed.

Pituitary apoplexy after mild head injury misinterpreted as bacterial meningitis.

Sirs, Pituitary apoplexy usually results from sudden hemorrhage or infarction-induced swelling in a pituitary adenoma [1]. Acute pituitary dysfunction may also be a consequence of head injury. We describe a patient who developed pituitary apoplexy after mild head injury. A 30-year-old man presented with vomiting, frontal headache, and pain behind his left eye. His medical history was unremarkable. Three weeks before, he had sustained amild head injury when he fell of a truck. No loss of consciousness but a short period of confusion was present. Hereafter, he noticed a marked fatigue and lost 10 kg of body weight. Neurologic examination, brain computed tomography (CT) and cerebrospinal fluid (CSF) were normal. One day later, the headache increased suddenly and he became febrile (39.2 C) and neck stiff. Bacterialmeningitis was suspected. Intravenous antibiotics were started. Repeat lumbar puncture showed CSF clouding and increased leukocyte counts (426/ll) predominantly neutrophilic granulocytes, and increased protein (900 mg/l) level. CSFgram staining and cultures of CSF, blood and urine were normal. Sodium (129 mmol/l) serum level was decreased, potassium (4.5 mmol/l) and creatinine (80 lmol/l) were normal, Creactive protein (226 mg/l) was increased. Five days after start of the treatment, no improvement occurred. He was transferred to our hospital. His blood pressure was 90/50 mmHg, heart rate 56 b.p.m., body temperature 38.6 C. Neurologic examination revealed a Glasgow Coma Scale score (GCS) of 13: eyes opening to speech, obeying commands and disorientation in time. Neck stiffness, left-sided ptosis, and abducens palsy with horizontal diplopia were present. Pupillary reactions, ocular fundi, and confrontation visual fields were normal. Visual acuity was 0.50 (OD) and 0.80 (OS). Repeat CT and magnetic resonance imaging demonstrated a suprasellar mass (Fig. 1a–c). A complete analysis showed defective secretion of all anterior pituitary hormones (Table 1), with secondary hypocortisolism. Corticosteroid substitution was immediately started (prednisone 12.5 mg o.d.). Thereafter, consciousness, blood pressure, and body temperature normalized within hours. Transsphenoidal removal of the tumor was performed. Histopathologic examination showed extensive necrosis within a pituitary adenoma. Five months later, vision and eye movements were normal. This case portrays apoplexy in an adenoma with anterior pituitary dysfunction and secondary hypocortisolism initially misinterpreted as bacterial meningitis. The estimated apoplexy rate is low (2.9%). Several explanations account for diagnostic delays and misclassifications as subarachnoid hemorrhage, (viral) meningo-encephalitis or migraine[2,3]. The high temperature pointed in the direction of infection, but is in fact a typical finding in patients with acute pituitary apoplexy. Diagnosis of the tumor with CT (isodense to brain tissue) is difficult even when hemorrhage is present [3]. Eye muscle paresis, a frequent and classical finding in pituitary apoplexy, due to the effects of pressure on cranial nerves secondary to swelling of the pituitary lesion was misinterpreted as ocular motility disturbances associated with meningitis [4]. Minor or mild head injury may cause damage to the pituitary and provoke defects in the separate hormonal axes but is a rare predisposing factor for apoplexy [5]. In our patient, mild head injury was the initial event after which clinical manifestations started.

Computer-assisted analysis of the microvasculature in untreated glioblastomas

ConclusionsElucidation of the pathogenesis and biological significance of MVP in GBMs is essential for developing a rational treatment directed at the abrogation of neovascularization in these neoplasms. The present quantitative study illustrates the striking heterogeneity of the microvasculature in GBMs such that the number of vessels in many tumor areas does not exceed that of normal white matter. Thus, many regions of GBMs may not be overtly angiogenesis dependent and may be difficult to treat by anti-angiogenic therapy alone. Even in areas with florid MVP the efficacy of anti-angiogenic therapy is questionable since the contribution of these aberrant blood vessels to the functional circulation and thus to the viability and growth of GBMs is unclear.

Benign and malignant tumors in Rubinstein-Taybi syndrome

Rubinstein–Taybi syndrome (RSTS) is a multiple congenital anomalies syndrome associated with mutations in CREBBP (70%) and EP300 (5–10%). Previous reports have suggested an increased incidence of specific benign and possibly also malignant tumors. We identified all known individuals diagnosed with RSTS in the Netherlands until 2015 (nu2009=u200987) and studied the incidence and character of neoplastic tumors in relation to their CREBBP/EP300 alterations. The population–based Dutch RSTS data are compared to similar data of the Dutch general population and to an overview of case reports and series of all RSTS individuals with tumors reported in the literature to date. Using the Nationwide Network and Registry of Histopathology and Cytopathology in the Netherlands (PALGA Foundation), 35 benign and malignant tumors were observed in 26/87 individuals. Meningiomas and pilomatricomas were the most frequent benign tumors and their incidence was significantly elevated in comparison to the general Dutch population. Five malignant tumors were observed in four persons with RSTS (medulloblastoma; diffuse large‐cell B‐cell lymphoma; breast cancer; non‐small cell lung carcinoma; colon carcinoma). No clear genotype–phenotype correlation became evident. The Dutch population‐based data and reported case studies underscore the increased incidence of meningiomas and pilomatricomas in individuals with RSTS. There is no supporting evidence for an increased risk for malignant tumors in individuals with RSTS, however, due to the small numbers this risk may not be fully dismissed.

Additional file 4: of Comprehensive protein tyrosine phosphatase mRNA profiling identifies new regulators in the progression of glioma

Immunohistochemical staining for PTPRT on formalin-fixed paraffin-embedded materials. (PDF 303Âxa0kb)