Peripheral Nerve Tumors: Management Strategies and Molecular Insights

Because of its relative rarity and a wide variety of clinical manifestations, peripheral nerve tumors (PNTs) often present to specialists from widely different disciplines, thus often resulting in delayed diagnosis and a non-cohesive pattern of management. Critical appraisal of the history and physical examination followed by radiological investigations, by experienced medical personnel, ultimately suggests that the extremity mass is perhaps a PNT, rather than the wide variety and more common soft tissue tumors. Included in this appraisal is a search for a pre-disposition syndrome, the most common of which are neurofibromatosis-1 and -2 (NF1, NF2) and schwannomatosis, which may require life-long careful follow up. Intra-operative and post-operative management decisions in a multidisciplinary manner with knowledge of the biological, pathological and clinical behavior of the PNT, is of utmost importance. In the context of pre-disposition syndromes, where multiple tumors may exist along with other nervous system lesions, molecular biological insights and hopefully the biological therapies that stem from this knowledge are of interest. In this article the spectrum of PNTs and their management protocols, including the algorithm for treatment of malignant PNTs advocated by our institute, are presented and currently available genetic insights and probable role of experimental therapies are briefly reviewed.     

Role of Ang1 and its interaction with VEGF-A in astrocytomas

Angiopoietins (Ang1 and Ang2) modulate the activity of the endothelial cell (EC)-specific receptor tyrosine kinase Tie2, which together with vascular endothelial growth factor (VEGF-A) and its EC-specific receptors, VEGFR1 and VEGFR2, regulate normal physiological vessel development. The functional role of angiopoietins in tumor angiogenesis, in particular astrocytoma angiogenesis, remains unclear. In this study, we focus on the specific contribution of Ang1 to the vascular growth of glioblastoma multiforme (GBM) and its interactive role with VEGF-A. Subcutaneous and intracranial GBM xenografts were generated using 3 established astrocytoma cell lines (U87, U373, and U343) that were transfected to stably over-express Ang1. GBM xenografts were also generated to express low levels of VEGF-A and high Angl. We found that Ang1 increases the vascular growth of both subcutaneous and intracranial xenografts of GBM by approximately 3-fold. However, the increased vascular growth was only seen in xenografts with concurrent VEGF-A elevation, since decreasing VEGF-A expression resulted in a loss of the pro-angiogenic growth advantage seen with Ang1. Collectively, our data suggest that Ang1 regulates GBM vascularity in a VEGF-A dependent manner, synergizing the initial pro-angiogenic response that is triggered by VEGF-A and promoting the vascular growth of GBM.     

First report in India of HIV transmission through artificial insemination

A case of HIV-1 transmission through artificial inseminations from infertility clinics in Kolkata, is reported.     

Oligodendrogliomas result from the expression of an activated mutant epidermal growth factor receptor in a RAS transgenic mouse astrocytoma model

A significant proportion of human malignant gliomas exhibit amplification, overexpression, or mutations of the epidermal growth factor receptor (EGFR). To define the functional role(s) of the EGFR in the pathogenesis of gliomas, we established transgenic mice that express both wild-type (wt) and mutant (EGFRvIII) EGFR molecules using the human glial fibrillary acidic protein (GFAP) promoter. Both GFAP-EGFR(wt) and GFAP-EGFRvIII transgenic mice demonstrated increased numbers of astrocytes compared with control littermates, however, developed normally without formation of gliomas. To determine whether EGFR overexpression could modify the tumor phenotype in our previously reported GFAP-V(12)Ha-ras transgenic mouse astrocytoma model, mice expressing both activated RAS and EGFR were developed. GFAP-V(12)Ha-ras;GFAP-EGFRvIII, but not GFAP-V(12)Ha-ras;GFAP-EGFR(wt) double transgenic mice, had decreased survival with fifty percent of the mice dead at 2-4 weeks from gliomas, compared with 12-16 weeks for the GFAP-V(12)Ha-ras mice. Furthermore, GFAP-V(12)Ha-ras;GFAP-EGFRvIII mice developed oligodendrogliomas and mixed oligoastrocytoma tumors, instead of the fibrillary astrocytomas observed in GFAP-V(12)Ha-ras mice. In addition to yielding a spontaneous model of infiltrating oligodendroglioma, this study demonstrates that astrocyte-specific expression of EGFRvIII alone is insufficient for gliomagenesis but rather contributes to glioma progression in the context of existing predisposing genetic changes.     

Molecular regulators of angiogenesis in the developing nervous system and adult brain tumors (review)

Angiogenesis involves a highly regulated and coordinated interaction of multiple angiogenic factors and is critical for both embryonal development and physiological vessel formation in adults. Angiogenesis is also proven to significantly contribute to the progression of various disease processes. Pathological angiogenesis is thought to recapitulate physiological angiogenesis, however the precise molecular mechanisms are not understood. Various angiogenic genes and gene products have been isolated, purified, and cloned from both neoplastic and normal tissues that contribute to the angiogenic process. In this review we summarize the role of the main angiogenic factors in both normal embryonal vascularization of the embryonal nervous system together with the main brain tumors seen in adults.     

Arsenic in drinking water and skin lesions: dose-response data from West Bengal,India

BACKGROUND: Over 6 million people live in areas of West Bengal, India, where groundwater sources are contaminated with naturally occurring arsenic. The key objective of this nested case-control study was to characterize the dose-response relation between low arsenic concentrations in drinking water and arsenic-induced skin keratoses and hyperpigmentation. METHODS: We selected cases (persons with arsenic-induced skin lesions) and age- and sex-matched controls from participants in a 1995-1996 cross-sectional survey in West Bengal. We used a detailed assessment of arsenic exposure that covered at least 20 years. Participants were reexamined between 1998 and 2000. Consensus agreement by four physicians reviewing the skin lesion photographs confirmed the diagnosis in 87% of cases clinically diagnosed in the field. RESULTS: The average peak arsenic concentration in drinking water was 325 microg/liter for cases and 180 microg/liter for controls. The average latency for skin lesions was 23 years from first exposure. We found strong dose-response gradients with both peak and average arsenic water concentrations. CONCLUSIONS: The lowest peak arsenic ingested by a confirmed case was 115 microg/liter. Confirmation of case diagnosis and intensive longitudinal exposure assessment provide the basis for a detailed dose-response evaluation of arsenic-caused skin lesions.     

Role of the Rap1 GTPase in astrocyte growth regulation

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome in which affected individuals develop nervous system abnormalities that might reflect astrocyte dysfunction. The TSC2 gene product, tuberin, encodes a GTPase-activating protein (GAP) domain, which regulates the activity of Rap1 in vitro. To determine whether dysregulated Rap1, resulting from TSC2 inactivation, leads to increased astrocyte proliferation in vivo, we generated transgenic mice expressing activated Rap1(G12V) specifically in astrocytes. We observed no statistically significant difference in the number of astrocytes between wild-type and GFAP-Rap1(G12V) littermates in vivo; however, during log-phase growth, we observed a 25% increase in GFAP-Rap1(G12V) astrocyte doubling times compared to wild-type controls. This decreased proliferation was associated with delayed MAP kinase, but not AKT, activation. Lastly, to determine whether constitutive Rap1 activation could reverse the increased astrocyte proliferation observed in transgenic mice expressing oncogenic Ras(G12V), we generated transgenic mice expressing both Ras(G12V) and Rap1(G12V) in astrocytes. These double transgenic mice showed a striking reversion of the Ras(G12V) astrocyte growth phenotype. Collectively, these results argue that the tumor suppressor properties of tuberin are unlikely to be related to Rap1 inactivation and that Rap1 inhibits mitogenic Ras pathway signaling in astrocytes.     

Role of leptin in the regulation of body fluid volume and pressures

Leptin is a circulating polypeptide hormone produced by an adipocyte-specific gene. It regulates energy balance by binding to receptors in the hypothalamus, leading to alterations in food intake, temperature, and energy expenditure. More recent pharmacologic information suggests that this circulating hormone may play an important role in the regulation of body fluid volume and pressures through direct and indirect actions. Although the relevance of the endogenous leptin on cardiovascular and renal function is yet to be clearly determined, it seems to be a potential salt-regulating factor and may function pathophysiologically as a common link to obesity and hypertension.