scholarly journals Role of CX3CR1 Signaling in Malignant Transformation of Gliomas

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Sungho Lee ◽  
Khatri Latha ◽  
Ganesh Rao
Keyword(s):  
Overall Survival ◽  
Malignant Transformation ◽  
Microvessel Density ◽  
Median Overall Survival ◽  
M2 Macrophage ◽  
Low Grade ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Altered Expression

Abstract INTRODUCTION High-grade gliomas (HGGs), including the most common primary brain tumor, glioblastoma (GBM), may arise from malignant transformation of low-grade gliomas (LGGs). While LGGs are often clinically indolent, GBMs have dismal outcomes despite maximal therapy. Accumulating evidence suggests that chemokine signaling directly contributes to malignant progression of LGGs by altering tumor behavior or impacting the immune microenvironment. Here, we examined the role of CX3CR1 signaling in malignant transformation of LGGs. METHODS First, patients with malignantly transformed LGGs were genotyped for the presence of the common loss-of-function CX3CR1 V249I polymorphism, and median overall survival was compared between the genotypes. Second, RNA sequencing data was analyzed for differential gene expression based on genotype. Third, surgical samples were examined for altered expression of M2 macrophage markers and microvessel density between the genotypes. Finally, genetically engineered murine model was leveraged to generate endogenous intracranial gliomas with targeted expression of CX3CL1 and CX3CR1, individually or in combination. RESULTS Heterozygosity (V/I) or homozygosity (I/I) for the loss-of-function CX3CR1 polymorphism is associated with significantly better median overall survival in patients with malignantly transformed LGGs, compared to the wild type genotype (V/V). In addition, HGGs from V/I and I/I genotypes exhibit significantly decreased levels of CCL2, important for the recruitment of M2 macrophages, as well as decreased levels of ANGPT1 and MMP9, which mediate angiogenesis. This correlates with reduced intratumoral accumulation of CD204-positive macrophages and microvessel density in tumors from V/I and I/I patients. Finally, in the RCAS-PDGFB driven model of LGG, co-expression of CX3CL1 and CX3CR1 promotes more malignant tumor phenotype and shorter tumor-free survival in association with increased intratumoral microglia and macrophage infiltration and microvessel density. CONCLUSION Taken together, our results show that CX3CL1-CX3CR1 signaling promotes malignant transformation of LGGs via accumulation of glioma associated macrophages and microglia and increased angiogenesis.

scholarly journals TMIC-61. ROLE OF CX3CR1 SIGNALING IN MALIGNANT TRANSFORMATION OF GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi261-vi261
Author(s):  
Sungho Lee ◽  
Khatri Latha ◽  
Ganesh Rao
Keyword(s):  
Overall Survival ◽  
Malignant Transformation ◽  
Microvessel Density ◽  
Median Overall Survival ◽  
M2 Macrophage ◽  
Low Grade ◽  
M2 Macrophages ◽  
Loss Of Function ◽  
Altered Expression

Abstract High-grade gliomas (HGGs), including the most common primary brain tumor, glioblastoma (GBM), may arise from malignant transformation of low-grade gliomas (LGGs). While LGGs are often clinically indolent, GBMs have dismal outcomes despite maximal therapy. Accumulating data suggest that chemokine signaling directly contributes to malignant transformation of LGGs by altering tumor behavior or impacting the immune microenvironment. Here, we examined the role of CX3CR1 signaling in the malignant transformation of LGGs. First, patients with malignantly transformed LGGs were genotyped for the presence of the common loss-of-function CX3CR1 V249I polymorphism, and median overall survival was compared between the genotypes. Second, RNA sequencing data was analyzed for differential gene expression based on genotype. Third, surgical samples were examined for altered expression of M2 macrophage markers and microvessel density between the genotypes. Finally, a genetically-engineered murine model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3CL1 and CX3CR1, individually or in combination. Our data demonstrate that heterozygosity (V/I) or homozygosity (I/I) for the loss-of-function CX3CR1 polymorphism was associated with significantly better median overall survival in patients with LGGs that have transformed to HGGs, compared to the wild type genotype (V/V). In addition, HGGs from V/I and I/I genotypes exhibit significantly decreased levels of CCL2, important for the recruitment of M2 macrophages, as well as decreased levels of ANGPT1 and MMP9, which mediate angiogenesis. This correlates with reduced intratumoral accumulation of CD204 positive macrophages and microvessel density in tumors from V/I and I/I patients. Finally, in the RCAS-PDGFB driven model of LGG, co-expression of CX3CL1 and CX3CR1 promotes more malignant tumor phenotype and shorter tumor-free survival. Taken together, our results show that CX3CR1 signaling promotes malignant transformation of LGGs via accumulation of glioma associated M2 macrophages and microglia and increased angiogenesis.

scholarly journals Role of CX3CR1 signaling in malignant transformation of gliomas

2020 ◽  
Vol 22 (10) ◽  
pp. 1463-1473 ◽  
Author(s):  
Sungho Lee ◽  
Khatri Latha ◽  
Ganiraju Manyam ◽  
Yuhui Yang ◽  
Arvind Rao ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Mouse Model ◽  
Malignant Transformation ◽  
Microvessel Density ◽  
Progression Free Survival ◽  
Macrophage Infiltration ◽  
M2 Macrophage ◽  
Low Grade ◽  
Free Survival

Abstract Background Chemokine signaling may contribute to progression of low-grade gliomas (LGGs) by altering tumor behavior or impacting the tumor microenvironment. In this study, we investigated the role of CX3C chemokine receptor 1 (CX3CR1) signaling in malignant transformation of LGGs. Methods Ninety patients with LGGs were genotyped for the presence of common CX3CR1 V249I polymorphism and examined for genotype-dependent alterations in survival, gene expression, and tumor microenvironment. A genetically engineered mouse model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3C ligand 1 (CX3CL1) and CX3CR1, individually or in combination. Results LGG patients who were heterozygous (V/I; n = 43) or homozygous (I/I; n = 2) for the CX3CR1 V249I polymorphism had significantly improved median overall (14.8 vs 9.8 y, P < 0.05) and progression-free survival (8.6 vs 6.5 y, P < 0.05) compared with those with the wild type genotype (V/V; n = 45). Tumors from the V/I + I/I group exhibited significantly decreased levels of CCL2 and MMP9 transcripts, correlating with reduced intratumoral M2 macrophage infiltration and microvessel density. In an immunocompetent mouse model of LGGs, coexpression of CX3CL1 and CX3CR1 promoted a more malignant tumor phenotype characterized by increased microglia/macrophage infiltration and microvessel density, resulting in shorter survival. Conclusions CX3CR1 V249I polymorphism is associated with improved overall and progression-free survival in LGGs. CX3CR1 signaling enhances accumulation of tumor associated microglia/macrophages and angiogenesis during malignant transformation.

scholarly journals Inflammatory Mediators and Insulin Resistance in Obesity: Role of Nuclear Receptor Signaling in Macrophages

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Lucía Fuentes ◽  
Tamás Rőszer ◽  
Mercedes Ricote
Keyword(s):  
Insulin Resistance ◽  
Nuclear Receptor ◽  
Cytokine Production ◽  
Current Knowledge ◽  
Liver Steatosis ◽  
Visceral Obesity ◽  
M2 Macrophage ◽  
Low Grade ◽  
The Impact

Visceral obesity is coupled to a general low-grade chronic inflammatory state characterized by macrophage activation and inflammatory cytokine production, leading to insulin resistance (IR). The balance between proinflammatory M1 and antiinflammatory M2 macrophage phenotypes within visceral adipose tissue appears to be crucially involved in the development of obesity-associated IR and consequent metabolic abnormalities. The ligand-dependent transcription factors peroxisome proliferator activated receptors (PPARs) have recently been implicated in the determination of the M1/M2 phenotype. Liver X receptors (LXRs), which form another subgroup of the nuclear receptor superfamily, are also important regulators of proinflammatory cytokine production in macrophages. Disregulation of macrophage-mediated inflammation by PPARs and LXRs therefore underlies the development of IR. This review summarizes the role of PPAR and LXR signaling in macrophages and current knowledge about the impact of these actions in the manifestation of IR and obesity comorbidities such as liver steatosis and diabetic osteopenia.

scholarly journals Spatial distribution of malignant transformation in patients with low-grade glioma

2020 ◽  
Vol 146 (2) ◽  
pp. 373-380 ◽  
Author(s):  
Asgeir S. Jakola ◽  
David Bouget ◽  
Ingerid Reinertsen ◽  
Anne J. Skjulsvik ◽  
Lisa Millgård Sagberg ◽  
...  
Keyword(s):  
Spatial Distribution ◽  
Malignant Transformation ◽  
Visual Inspection ◽  
Premature Death ◽  
Low Grade ◽  
Local Transformation ◽  
Natural Evolution ◽  
Catastrophic Event ◽  
Common Space

Abstract Background Malignant transformation represents the natural evolution of diffuse low-grade gliomas (LGG). This is a catastrophic event, causing neurocognitive symptoms, intensified treatment and premature death. However, little is known concerning the spatial distribution of malignant transformation in patients with LGG. Materials and methods Patients histopathological diagnosed with LGG and subsequent radiological malignant transformation were identified from two different institutions. We evaluated the spatial distribution of malignant transformation with (1) visual inspection and (2) segmentations of longitudinal tumor volumes. In (1) a radiological transformation site < 2 cm from the tumor on preceding MRI was defined local transformation. In (2) overlap with pretreatment volume after importation into a common space was defined as local transformation. With a centroid model we explored if there were particular patterns of transformations within relevant subgroups. Results We included 43 patients in the clinical evaluation, and 36 patients had MRIs scans available for longitudinal segmentations. Prior to malignant transformation, residual radiological tumor volumes were > 10 ml in 93% of patients. The transformation site was considered local in 91% of patients by clinical assessment. Patients treated with radiotherapy prior to transformation had somewhat lower rate of local transformations (83%). Based upon the segmentations, the transformation was local in 92%. We did not observe any particular pattern of transformations in examined molecular subgroups. Conclusion Malignant transformation occurs locally and within the T2w hyperintensities in most patients. Although LGG is an infiltrating disease, this data conceptually strengthens the role of loco-regional treatments in patients with LGG.

Exploring the role of inflammation in the malignant transformation of low-grade gliomas

2016 ◽  
Vol 297 ◽  
pp. 132-140 ◽  
Author(s):  
Nicole Michelson ◽  
Jordina Rincon-Torroella ◽  
Alfredo Quiñones-Hinojosa ◽  
Jeffrey P. Greenfield
Keyword(s):  
Malignant Transformation ◽  
Low Grade ◽  
Low Grade Gliomas

Association of neoadjuvant chemotherapy on survival in locally advanced gallbladder cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16716-e16716
Author(s):  
Syed Mohammad Ali Kazmi ◽  
Suleyman Yasin Goksu ◽  
Muhammet Ozer ◽  
Nina Niu Sanford ◽  
Matthew R. Porembka ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lymph Node ◽  
Neoadjuvant Chemotherapy ◽  
Propensity Score ◽  
Gallbladder Cancer ◽  
Propensity Score Matching ◽  
Median Overall Survival ◽  
Locally Advanced ◽  
Node Positive

e16716 Background: Gallbladder cancer (GBC) is an uncommon but highly fatal malignancy. Surgery remains the only potentially curative treatment for GBC. The role of neoadjuvant chemotherapy in patients with locally advanced GBC undergoing surgery is unknown. We studied the association of neoadjuvant chemotherapy on survival in locally advanced GBC patients who underwent resection. Methods: We identified adult patients with locally advanced (stage III-IV) GBC who underwent definitive surgery between 2004 and 2016 using the National Cancer Database. Treatment was categorized as neoadjuvant chemotherapy plus surgery (NAT), surgery plus adjuvant therapy (AT), and surgery alone (SA). Categorical variables were compared using the chi-square test with Bonferroni correction. Kaplan-Meier and Cox regression were used for survival analyses. We used 1:3 nearest neighbor propensity score matching based on NAT for each group. Results: Out of a total of 5,962 patients, 122 (2.2%) received NAT, 2934 (53.6%) AT, and 2421 (44.2%) SA. NAT was associated with private insurance and treatment at an academic/research facility (all p < .001) while SA patients were older, Hispanic, had government insurance, and higher comorbidities (all p < .001). Although all groups had similar lymph node assessment (NAT: 45%, AT: 46%, SA: 37%, p < .001), NAT was associated with lymph node negative disease (NAT 23%, AT 13.2%, SA 13.2%, p < .001). Median overall survival was higher in NAT compared to AT or SA (21 vs. 14 vs. 6 months, p < .001) which persisted after propensity score matching (21 vs. 15 vs. 9 months, p < .001) and multivariable regression analysis (Table). In node positive GBC, NAT was associated with improved median overall survival (NAT 24, AT 18, SA 8 months, p < .001). Conclusions: NAT is infrequently used in patients with locally advanced GBC. NAT is associated with improved median overall survival compared to AT and SA, and appears to be most beneficial in node positive disease. Prospective studies are needed to evaluate the role of neoadjuvant chemotherapy in locally advanced GB. [Table: see text]

Long-term outcomes for low-grade intracranial ganglioglioma: 30-year experience from the Mayo Clinic

2012 ◽  
Vol 117 (5) ◽  
pp. 825-830 ◽  
Author(s):  
Julia J. Compton ◽  
Nadia N. Issa Laack ◽  
Laurence J. Eckel ◽  
David A. Schomas ◽  
Caterina Giannini ◽  
...  
Keyword(s):  
Overall Survival ◽  
Radiation Therapy ◽  
Mayo Clinic ◽  
Progression Free Survival ◽  
Low Grade ◽  
Term Survival ◽  
Free Survival

Object Gangliogliomas comprise less than 1% of all brain tumors and occur most often in children. Therefore, there are a limited number of patients and data involving the use or role of adjuvant therapy after subtotal resections (STRs) of gangliogliomas. The objective of this study was to examine and review the Mayo Clinic experience of 88 patients with gangliogliomas, their follow-up, risk of recurrence, and the role of radiation therapy after STR or only biopsy. Methods Eighty-eight patients with gangliogliomas diagnosed between 1970 and 2007 were reviewed. Data on clinical outcomes and therapy received were analyzed. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival. Results The median age at diagnosis was 19 years. The median potential follow-up as of June 2008 was 142 months (range 9–416 months). Fifteen-year overall survival was 94%, median PFS was 5.6 years, with a 10-year PFS rate of 37%. Progression-free survival was dramatically affected by extent of initial resection (p < 0.0001). Conclusions This single-institution retrospective series of patients with gangliogliomas is unique given its large cohort size with a long follow-up duration, and confirms the excellent long-term survival rate in this group. The study also shows the importance of resection extent on likelihood of recurrence. Patients with gangliogliomas who undergo STR or biopsy alone have poor PFS. Radiation therapy may delay time to progression in patients with unresectable disease.

scholarly journals LOXL1-AS1 predicts poor prognosis and promotes cell proliferation, migration, and invasion in osteosarcoma

2019 ◽  
Vol 39 (4) ◽  
Author(s):  
Si Chen ◽  
Weiguo Li ◽  
Ai Guo
Keyword(s):  
Cell Proliferation ◽  
Overall Survival ◽  
Poor Prognosis ◽  
Histological Grade ◽  
Migration And Invasion ◽  
Osteosarcoma Cell ◽  
Loss Of Function ◽  
Osteoblast Cell Line ◽  
Enneking Stage

Abstract lncRNA LOXL1 antisense RNA 1 (lncRNA LOXL1-AS1) was recently found to function as oncogenic lncRNA in glioblastoma, prostate cancer, and medulloblastoma. The role of LOXL1-AS1 in osteosarcoma was still unknown. In our study, we found LOXL1-AS1 expression levels were higher in osteosarcoma tissues and cell lines than normal bone tissues and normal osteoblast cell line, respectively. Moreover, high-expression of LOXL1-AS1 was correlated with Enneking stage, tumor size, distant metastasis, histological grade, and overall survival time in osteosarcoma patients. Furthermore, LOXL1-AS1 overexpression acted as an independent poor predictor for overall survival in osteosarcoma patients. The loss-of-function studies showed knockdown of LOXL1-AS1 dramatically inhibited osteosarcoma cell proliferation, migration, and invasion through suppressing PI3K-AKT pathway. In conclusion, LOXL1-AS1 predicts clinical progression and poor prognosis in osteosarcoma patients and functions as oncogenic lncRNA to regulate cell proliferation, cell cycle, migration, and invasion.

scholarly journals Ovarian insufficiency and CTNNB1 mutations drive malignant transformation of endometrial hyperplasia with altered PTEN/PI3K activities

2019 ◽  
Vol 116 (10) ◽  
pp. 4528-4537 ◽  
Author(s):  
Jumpei Terakawa ◽  
Vanida Ann Serna ◽  
Makoto Mark Taketo ◽  
Takiko Daikoku ◽  
Adrian A. Suarez ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Biological Significance ◽  
Myometrial Invasion ◽  
Premenopausal Women ◽  
Driver Mutations ◽  
Low Grade ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Normal Endometrium

Endometrioid endometrial carcinomas (EECs) carry multiple driver mutations even when they are low grade. However, the biological significance of these concurrent mutations is unknown. We explored the interactions among three signature EEC mutations: loss-of-function (LOF) mutations inPTEN, gain-of-function (GOF) mutations of phosphoinositide 3-kinase (PI3K), andCTNNB1exon 3 mutations, utilizing in vivo mutagenesis of the mouse uterine epithelium. While epithelial cells with a monoallelic mutation in any one of three genes failed to propagate in the endometrium, any combination of two or more mutant alleles promoted the growth of epithelium, causing simple hyperplasia, in a dose-dependent manner. Notably,Ctnnb1exon 3 deletion significantly increased the size of hyperplastic lesions by promoting the growth of PTEN LOF and/or PI3K GOF mutant cells through the activation of neoadenogenesis pathways. Although these three mutations were insufficient to cause EEC in intact female mice, castration triggered malignant transformation, leading to myometrial invasion and serosal metastasis. Treatment of castrated mice with progesterone or estradiol attenuated the neoplastic transformation. This study demonstrates that multiple driver mutations are required for premalignant cells to break the growth-repressing field effect of normal endometrium maintained by ovarian steroids and thatCTNNB1exon 3 mutations play critical roles in the growth of preneoplastic cells within the endometrium of premenopausal women and in the myometrial invasion of EECs in menopausal women.

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