Abstract A11: An alveolar soft part sarcoma model to explore the mechanisms of tumorigenesis and metastasis

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Abstract

Alveolar soft part sarcoma (ASPS) is a highly malignant soft tissue tumor affecting predominantly children and adolescents in their buttocks or lower extremities. ASPS is characterized by its distinct histological features and t(X;17) translocation generating the ASPL-TFE3 gene fusion. However, the exact mechanisms of tumorigenesis and metastasis of ASPS remain largely unknown.

A genetically engineered ASPS mouse model that showed histopothological and transriptome features similar to human ASPS has recently been established by M L Goodwin and L B Jones et al. (Cancer Cell 2014). An important role of lactate metabolism in the tumor microenvironment for sarcomagenesis was reported, though tumor localization was different from that of human ASPS. Using a different ex vivo approach, we have developed a model of ASPS. ASPL-TFE3 was retrovirally introduced into embryonic mesenchymal cells followed by allogenic transplantation. The histopathological examination of our ASPS model showed typical alveolar structures composed of tumor cells having round nuclei and abundant cytoplasms separated with delicate blood vessels. PAS-positive rod-shaped crystal structures, which are detected in human ASPS cells, were also observed in cytoplasm of the mouse ASPS cells. Electron micrograph showed that the mouse ASPS cells were rich in mitochondria and contains crystalline structures.

Extensive and integral vasculogenesis followed by frequent hematogenous metastases are important biological properties of human ASPS. Our ASPS model also showed prominent angiogenesis and vascular involvement of tumor cells. Moreover, spontaneous multiple pulmonary metastases was frequently observed. However, tail vein injection of ASPS tumor cell suspensions failed to show pulmonary metastasis. Careful examination of tumor blood vessels as well as heart showed tumor emboli covered with non-neoplastic stromal cells. These cells were positive for α-smooth muscle actin and PDGFRβ and negative for CD31 and CD34, suggesting that they are originated from pericytes. In support of the idea, culture supernatants of mouse ASPS cells induced migration of the pericytes significantly. Collectively, these results suggest that cellular interaction between ASPS cells and pericytes plays an important role in hematogenous metastasis.

Gene expression profiling of our mouse model and human ASPS identified genes involved in vaculogenesis including Angptl2, Ctsk, Mdk and Pdgfrd as upregulated genes. In addition, Gpnmb, a known target of TFE/MITF family transcription factors, was upregulated in mouse ASPS as well as embryonic mesenchymal cells introduced with ASPL-TFE3. Gpnmb encodes glycoprotein non-metastatic B that plays an important role in tumor invasion and cell-cell interaction. Immunostaining of Gpnmb showed its strong localization at the front of invasion and vascular involvement of ASPS tumor cells. Thus, metastatic processes of ASPS such as vasculogenesis, intra-vascular tumor invasion and protection of tumor cells in blood stream are orchestrated by the ASPL-TFE3 fusion protein in an appropriate cellular context.

Citation Format: Miwa Tanaka, Yukari Yamazaki, Mizuki Homme, Takuro Nakamura. An alveolar soft part sarcoma model to explore the mechanisms of tumorigenesis and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A11.

©2016 American Association for Cancer Research.

https://cancerres.aacrjournals.org/cont ... lement/A11

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The Role of GPNMB in Inflammation

Inflammation is a response to a lesion in the tissue or infection. This process occurs in a specific manner in the central nervous system and is called neuroinflammation, which is involved in neurodegenerative diseases. GPNMB, an endogenous glycoprotein, has been recently related to inflammation and neuroinflammation. GPNMB is highly expressed in macrophages and microglia, which are cells involved with innate immune response in the periphery and the brain, respectively. Some studies have shown increased levels of GPNMB in pro-inflammatory conditions, such as LPS treatment, and in pathological conditions, such as neurodegenerative diseases and cancer. However, the role of GPNMB in inflammation is still not clear. Even though most studies suggest that GPNMB might have an anti-inflammatory role by promoting inflammation resolution, there is evidence that GPNMB could be pro-inflammatory. In this review, we gather and discuss the published evidence regarding this interaction.


https://www.frontiersin.org/articles/10 ... 74739/full

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Immunoglobulin G glycosylation in aging and diseases

Highlights

Abstract

The Immunoglobulin G (IgG) glycome is well known for its heterogeneity and shows a significant degree of variation within populations. IgG glycome composition is influenced both by genes and by environment, making it an excellent biomarker of a person's general health state, i.e. biological age. IgG glycosylation appears to be highly regulated, both during homeostasis and in cases of its disturbance. Changes in IgG glycosylation patterns have been observed in aging and in various diseases. Differential IgG glycosylation is known to modulate IgG effector functions and is involved in disease development and progression, representing both a predisposition and a functional mechanism involved in disease pathology. This makes IgG glycosylation analysis a promising add-on to improve existing disease biomarkers.

https://www.sciencedirect.com/science/a ... 4918303253



“Immunoglobulins, also known as antibodies, are glycoprotein molecules produced by plasma cells (white blood cells). They act as a critical part of the immune response by specifically recognizing and binding to particular antigens, such as bacteria or viruses, and aiding in their destruction.”