Neutrophil Elastase and GPNMB as Novel Potential Therapeutic Targets in a Tsc2-null Mouse Model for Lymphangioleiomyomatosis (LAM) Tumor Growth PDF Download
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Author: Manisha Taya
Publisher:
ISBN:
Category :
Languages : en
Pages : 118
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Book Description
Lymphangioleiomyomatosis (LAM) is a devastating rare lung disease that is primarily seen in women during their reproductive years, whereby metastatic smooth-muscle cell-like adenomas grow within the lungs, resulting in loss of pulmonary function.Although the origin of LAM remains unknown, our previous work demonstrated the presence of myometrial tumors in mice after inactivation of Tsc2 in the uterus, which resembled all features of LAM. Half of animals show metastatic spread of myometrial tumors to the lungs, suggesting that LAM cells might originate from the myometrium and possibly explaining its overwhelming female prevalence. Since this deadly cancer is regulated by estrogen, we further explored estrogen-dependent genes using RNASeq analysis of Tsc2-null myometrial tumors, which demonstrated overexpression of neutrophil elastase (NE) and melanocytic markers such as GPNMB. Thus, the work in this thesis focuses on characterizing NE and GPNMB as promising therapeutic targets to treat LAM. NE is a proteolytic enzyme known to regulate migration, invasion and metastasis in various tumors. Increased levels of NE and their potential source, circulating myeloidderived suppressor cells (MDSC), correlate with poor prognosis in many cancers. In this study, we examine the impact of MDSCs on lymphangioleiomyomatosis (LAM) and report that MDSCs were significantly increased in the periphery and in tumors of uterinespecific Tsc2-null mice. Importantly, MDSC depletion or inhibition of their recruitment impaired myometrial tumor growth. Consistent with the enhanced expression and activity of the serine protease neutrophil elastase (NE) in Tsc2-null myometrial tumors, we found that NE inhibition caused a significant reduction in tumor growth, which was comparable to that seen after MDSC depletion. Furthermore, in vitro evidence shows that NE promotes growth, invasion and migration of TSC2-null tumor cells. Finally, MDSCs were detected in lungs of LAM patients. These data suggest that MDSC-derived NE might facilitate LAM tumor cell progression and should be considered as a novel therapeutic target in LAM. Through RNAseq analysis of genes that are regulated by both estrogen and TSC2, we also identified a novel melanocytic marker called glycoprotein NMB (GPNMB) that was highly expressed in Tsc2-null uterine tumors, and, more importantly, upregulated in human LAM lung tissue. GPNMB is a transmembrane protein enriched on the cell surface of numerous cancer cells, including melanoma and triple-negative breast cancer. There is growing evidence identifying GPNMB as a tumor-promoter; however, despite its biological and clinical significance, the molecular mechanisms engaged by GPNMB to promote tumorigenesis are not well understood. We are interested in studying the role of GPNMB in LAM tumor progression. Herein, we find that GPNMB promotes aggressive behaviors such as tumor cell migration and invasion by transwell assay, and stimulates proliferation demonstrated by increased BrdU incorporation in Tsc2-null cells in vitro. Moreover, as seen in other tumors, we find that the extracellular domain (ECD) of GPNMB is shed from the cell surface of Tsc2-null cells, and we discuss the mechanism and importance of ECD shedding in mediating biological functions. Most importantly, this shedding is thought to promote recruitment of angiogenic factors such as matrix metalloproteinases (MMPs) to the tumor microenvironment that then enhance tumor migration and invasion. Accordingly, this might explain the observed over-expression of MMP-2 and -9 in Tsc2-null myometrial tumors in vivo. We hypothesize that GPNMB exerts its pro-tumorigenic role both intracellularly and in a paracrine fashion through shedding its ECD. Thus, our data highlights the importance of GPNMB in LAM progression and identifies novel molecular mediators of GPNMB-induced tumor growth and invasion.
Author: Manisha Taya
Publisher:
ISBN:
Category :
Languages : en
Pages : 118
Get Book Here
Book Description
Lymphangioleiomyomatosis (LAM) is a devastating rare lung disease that is primarily seen in women during their reproductive years, whereby metastatic smooth-muscle cell-like adenomas grow within the lungs, resulting in loss of pulmonary function.Although the origin of LAM remains unknown, our previous work demonstrated the presence of myometrial tumors in mice after inactivation of Tsc2 in the uterus, which resembled all features of LAM. Half of animals show metastatic spread of myometrial tumors to the lungs, suggesting that LAM cells might originate from the myometrium and possibly explaining its overwhelming female prevalence. Since this deadly cancer is regulated by estrogen, we further explored estrogen-dependent genes using RNASeq analysis of Tsc2-null myometrial tumors, which demonstrated overexpression of neutrophil elastase (NE) and melanocytic markers such as GPNMB. Thus, the work in this thesis focuses on characterizing NE and GPNMB as promising therapeutic targets to treat LAM. NE is a proteolytic enzyme known to regulate migration, invasion and metastasis in various tumors. Increased levels of NE and their potential source, circulating myeloidderived suppressor cells (MDSC), correlate with poor prognosis in many cancers. In this study, we examine the impact of MDSCs on lymphangioleiomyomatosis (LAM) and report that MDSCs were significantly increased in the periphery and in tumors of uterinespecific Tsc2-null mice. Importantly, MDSC depletion or inhibition of their recruitment impaired myometrial tumor growth. Consistent with the enhanced expression and activity of the serine protease neutrophil elastase (NE) in Tsc2-null myometrial tumors, we found that NE inhibition caused a significant reduction in tumor growth, which was comparable to that seen after MDSC depletion. Furthermore, in vitro evidence shows that NE promotes growth, invasion and migration of TSC2-null tumor cells. Finally, MDSCs were detected in lungs of LAM patients. These data suggest that MDSC-derived NE might facilitate LAM tumor cell progression and should be considered as a novel therapeutic target in LAM. Through RNAseq analysis of genes that are regulated by both estrogen and TSC2, we also identified a novel melanocytic marker called glycoprotein NMB (GPNMB) that was highly expressed in Tsc2-null uterine tumors, and, more importantly, upregulated in human LAM lung tissue. GPNMB is a transmembrane protein enriched on the cell surface of numerous cancer cells, including melanoma and triple-negative breast cancer. There is growing evidence identifying GPNMB as a tumor-promoter; however, despite its biological and clinical significance, the molecular mechanisms engaged by GPNMB to promote tumorigenesis are not well understood. We are interested in studying the role of GPNMB in LAM tumor progression. Herein, we find that GPNMB promotes aggressive behaviors such as tumor cell migration and invasion by transwell assay, and stimulates proliferation demonstrated by increased BrdU incorporation in Tsc2-null cells in vitro. Moreover, as seen in other tumors, we find that the extracellular domain (ECD) of GPNMB is shed from the cell surface of Tsc2-null cells, and we discuss the mechanism and importance of ECD shedding in mediating biological functions. Most importantly, this shedding is thought to promote recruitment of angiogenic factors such as matrix metalloproteinases (MMPs) to the tumor microenvironment that then enhance tumor migration and invasion. Accordingly, this might explain the observed over-expression of MMP-2 and -9 in Tsc2-null myometrial tumors in vivo. We hypothesize that GPNMB exerts its pro-tumorigenic role both intracellularly and in a paracrine fashion through shedding its ECD. Thus, our data highlights the importance of GPNMB in LAM progression and identifies novel molecular mediators of GPNMB-induced tumor growth and invasion.
