In JoVE (1)
Other Publications (13)
- Cardiovascular Pathology : the Official Journal of the Society for Cardiovascular Pathology
- Proceedings of the National Academy of Sciences of the United States of America
- Nature Methods
- Stem Cells (Dayton, Ohio)
- Diagnostic Pathology
- Pathology, Research and Practice
- Virchows Archiv : an International Journal of Pathology
- Diagnostic Cytopathology
- The Journal of Pathology
- Annals of Maxillofacial Surgery
- Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
- Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
- Frontiers in Oncology
Articles by Sophia George in JoVE
In Vivo and Ex Vivo Approaches to Study Ovarian Cancer Metastatic Colonization of Milky Spot Structures in Peritoneal Adipose Venkatesh Krishnan1, Robert Clark1, Marina Chekmareva2, Amy Johnson1, Sophia George3, Patricia Shaw4, Victoria Seewaldt4,5, Carrie Rinker-Schaeffer1 1Section of Urology, Department of Surgery, The University of Chicago, 2Department of Pathology, Robert Wood Johnson Medical School, 3Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, 4Department of Laboratory Medicine and Pathobiology, Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University of Toronto, University Health Network, 5Departments of Medicine, Pharmacology, and Cancer Biology, Duke University Medical Center We outline a protocol that implements both in vivo and ex vivo approaches to study ovarian cancer colonization of peritoneal adipose tissues, particularly the omentum. Furthermore, we present a protocol to quantitate and analyze immune cell-structures in the omentum known as milky spots, which promote metastases of peritoneal adipose.
Other articles by Sophia George on PubMed
Malignant Small Round Cell Tumor of the Heart: a Diagnostic Dilemma Cardiovascular Pathology : the Official Journal of the Society for Cardiovascular Pathology. Jan-Feb, 2007 | Pubmed ID: 17218216 We report a rare malignant small round cell tumor of the heart in a 26-year-old woman. She had been symptomatic 15 days after vaginal delivery. Immunohistochemistry revealed divergent differentiation; hence, the tumor was designated as desmoplastic small round cell tumor. This is the first report of such a tumor in the heart.
Developmental and Adult Phenotyping Directly from Mutant Embryonic Stem Cells Proceedings of the National Academy of Sciences of the United States of America. Mar, 2007 | Pubmed ID: 17360545 Tetraploid embryo complementation assay has shown that mouse ES cells alone are capable of supporting embryonic development and adult life of mice. Newly established F(1) hybrid ES cells allow the production of ES cell-derived animals at a high enough efficiency to directly make ES cell-based genetics feasible. Here we report the establishment and characterization of 12 new F(1) hybrid ES cell lines and the use of one of the best (G4) in a gain- and loss-of-function genetic study, where the in vivo phenotypes were assessed directly from ES cell-derived embryos. We found the generation of G4 ES cell-derived animals to be very efficient. Furthermore, even after two consecutive rounds of genetic modifications, the majority of transgenic lines retained the original potential of the parental lines; with 10-40% of chimeras producing ES cell-derived animals/embryos. Using these genetically altered ES cells, this success rate, in most cases, permitted the derivation of a sufficient number of mutants for initial phenotypic analyses only a few weeks after the establishment of the cell lines. Although the experimental design has to take into account a moderate level of uncontrolled damage on ES cell lines, our proof-of-principle experiment provides useful data to assist future designs harnessing the power of this technology to accelerate our understanding of gene function.
Functional Immobilization of Signaling Proteins Enables Control of Stem Cell Fate Nature Methods. Jul, 2008 | Pubmed ID: 18552855 The mode of ligand presentation has a fundamental role in organizing cell fate throughout development. We report a rapid and simple approach for immobilizing signaling ligands to maleic anhydride copolymer thin-film coatings, enabling stable signaling ligand presentation at interfaces at defined concentrations. We demonstrate the utility of this platform technology using leukemia inhibitory factor (LIF) and stem cell factor (SCF). Immobilized LIF supported mouse embryonic stem cell (mESC) pluripotency for at least 2 weeks in the absence of added diffusible LIF. Immobilized LIF activated signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling in a dose-dependent manner. The introduced method allows for the robust investigation of cell fate responses from interface-immobilized ligands.
Soluble Flt-1 Regulates Flk-1 Activation to Control Hematopoietic and Endothelial Development in an Oxygen-responsive Manner Stem Cells (Dayton, Ohio). Nov, 2008 | Pubmed ID: 18772315 Vascular endothelial growth factor (VEGF) and the vascular endothelial growth factor receptors (VEGFRs) regulate the development of hemogenic mesoderm. Oxygen concentration-mediated activation of hypoxia-inducible factor targets such as VEGF may serve as the molecular link between the microenvironment and mesoderm-derived blood and endothelial cell specification. We used controlled-oxygen microenvironments to manipulate the generation of hemogenic mesoderm and its derivatives from embryonic stem cells. Our studies revealed a novel role for soluble VEGFR1 (sFlt-1) in modulating hemogenic mesoderm fate between hematopoietic and endothelial cells. Parallel measurements of VEGF and VEGFRs demonstrated that sFlt-1 regulates VEGFR2 (Flk-1) activation in both a developmental-stage-dependent and oxygen-dependent manner. Early transient Flk-1 signaling occurred in hypoxia because of low levels of sFlt-1 and high levels of VEGF, yielding VEGF-dependent generation of hemogenic mesoderm. Sustained (or delayed) Flk-1 activation preferentially yielded hemogenic mesoderm-derived endothelial cells. In contrast, delayed (sFlt-1-mediated) inhibition of Flk-1 signaling resulted in hemogenic mesoderm-derived blood progenitor cells. Ex vivo analyses of primary mouse embryo-derived cells and analysis of transgenic mice secreting a Flt-1-Fc fusion protein (Fc, the region of an antibody which is constant and binds to receptors) support a hypothesis whereby microenvironmentally regulated blood and endothelial tissue specification is enabled by the temporally variant control of the levels of Flk-1 activation. Disclosure of potential conflicts of interest is found at the end of this article.
Clinicopathological Features and the Value of Differential Cytokeratin 7 and 20 Expression in Resolving Diagnostic Dilemmas of Ovarian Involvement by Colorectal Adenocarcinoma and Vice-versa Diagnostic Pathology. 2008 | Pubmed ID: 18801162 The distinction between metastasis from a colorectal adenocarcinoma into the ovary and an ovarian adenocarcinoma is vital, but challenging at times, due to overlapping morphological features. Similarly, a distinction between an ovarian metastasis into the colorectum and a colorectal adenocarcinoma, although rare; is important and can be daunting. We report an analysis of 20 cases of ovarian involvement by metastatic colorectal adenocarcinomas and colorectal involvement by metastatic ovarian adenocarcinomas, including the value of differential expression of cytokeratins 7 & 20 by immunohistochemistry (IHC), in these cases. Nine cases (45%) were identified as colorectal adenocarcinomas metastatic to the ovary. On biopsy, all these cases showed a 'garland-like' tumor necrosis, with desmoplasia and predominantly exhibited a tubuloalveolar pattern (67% cases). On IHC, all 8 of 9 such cases, where staining for cytokeratin 20 was performed, displayed strong positivity and 7 cases, where staining for carcinoembryogenic antigen (CEA) was performed, revealed positivity for this marker (100%). Other 11 cases (55%) were ovarian adenocarcinomas, metastatic to the colorectum. These showed metachronous presentations, with the ovarian tumor preceding the colorectal tumor deposits. Morphologically, psammomatous calcification was noted in 73% of these cases, whereas 'garland-like' necrosis was absent in all. The chief morphological subtype was serous papillary cystadenocarcinoma (55% cases). On IHC, CK7 and CA 125 were positive in all 6 of 11 such cases, whereas CK 20 was negative in all these cases.In cases of complex presentations like an ovarian involvement by a metastatic colorectal adenocarcinoma and vice-versa, certain clinicopathological features are useful. Differential expression of CK 7 and CK20 is vital in resolving these dilemmas. CK20 positivity and CK7 negativity is associated with a colorectal adenocarcinoma. Markers like CEA and CA-125 have an added value.
Extranodal Follicular Dendritic Cell Sarcoma of the Tonsil - Case Report of an Epithelioid Cell Variant with Osteoclastic Giant Cells Pathology, Research and Practice. 2009 | Pubmed ID: 18774654 Follicular dendritic cell sarcomas are rare neoplasms arising from the accessory cells of the lymph nodes, the follicular dendritic cells. They commonly occur in the lymph nodes, but have also been reported at extranodal sites (especially the tonsil). At both sites, there is usually a proliferation of spindled to ovoid cells, mimicking a mesenchymal tumor. Herein, we report a tonsillar tumor in a 50-year-old man, which was composed exclusively of large polygonal cells and numerous osteoclastic giant cells that resembled a giant cell carcinoma. The true nature of the tumor was revealed after an array of immunohistochemical stains. The patient is well 4 years after tonsillectomy.
Extraconal Orbital Tumors in Children--a Spectrum Virchows Archiv : an International Journal of Pathology. Jun, 2009 | Pubmed ID: 19421774 Orbital masses in children are uncommon but extremely challenging problems for clinicians and pathologists due to their critical location and availability of limited diagnostic material. We analyzed 47 specimens comprising biopsies, excision specimens, and FNAC of extraconal pediatric orbital masses (excluding retinoblastoma) accessioned in the pathology department over 5 years in a tertiary referral cancer center. Immunohistochemistry (IHC-74%) and molecular methods (one case) were done where necessary. The chief presenting symptom was proptosis in 55.3% patients and radiologically 53.8% malignant tumors showed extraorbital extension. A diagnostic algorithm was formulated to assess which cases needed pathology evaluation. Malignant round cell tumors (76.6%), chiefly embryonal rhabdomyosarcoma (51%), benign spindle cell neoplasms, and infectious lesions (tuberculosis, fungal infections), were seen. Of the malignant tumors, those confined to the orbit achieved good treatment response and had an event-free follow-up while those with extraorbital spread had poor outcome. Pediatric orbital masses range from completely treatable infectious lesions, surgically resectable benign neoplasms to aggressive malignancies requiring chemotherapy and radiotherapy. Pathologists play a key role in distinguishing these on small biopsy material and expediating accurate treatment thus saving the vision or life of a patient.
Evaluation of Pediatric Abdominal Masses by Fine-needle Aspiration Cytology: a Clinicoradiologic Approach Diagnostic Cytopathology. Jan, 2010 | Pubmed ID: 19688767 The pathologist forms a very important part of the clinical team in the management of pediatric intra-abdominal masses in giving a rapid, accurate diagnosis for these potentially curable tumors. Fine-needle aspiration cytology (FNAC) is an invaluable tool in this regard when interpreted with clinicoradiologic parameters. With this in mind, we decided to evaluate the role of FNAC in pediatric abdominal masses in our institution. A total of 83 of 105 FNAC accessioned in the pathology department over 5 years (2003-2007) were studied. These included only cases where a diagnosis could be offered on cytology. Detailed clinicoradiological features were obtained from hospital records. Cytomorphological features examined included cellularity, architectural pattern, background, key cellular details. Immunocytochemistry were done where necessary. Lesions diagnosed on FNAC included Wilms' tumor (19), lymphoma (10), neuroblastoma (6), hepatoblastoma (5), PNET (5), rhabdomyosarcoma (2), DSRCT (2), germ cell tumor (6), and miscellaneous tumors (7). Definite diagnosis could be offered on cytomorphology in 74.7% (62) cases, while in 25.3% (21) cases only a diagnosis of round cell tumor could be offered. Concordance with final histopathology and biochemical parameters was subsequently obtained in 79/83 (95.5%) of cases. A clinically relevant classification is possible on FNAC in pediatric abdominal tumors when interpreted with clinicoradiologic parameters. This obviates the need for a more time-consuming biopsy procedure in critical situations and in stage II nephroblastoma where it is contraindicated.
Identification of Abrogated Pathways in Fallopian Tube Epithelium from BRCA1 Mutation Carriers The Journal of Pathology. Sep, 2011 | Pubmed ID: 21744340 The discovery of occult invasive and intra-epithelial tubal carcinomas in BRCA1 mutation carriers undergoing prophylactic surgery has implicated the fallopian tube epithelium as the source of serous cancer. However, little is known of the early molecular events of serous oncogenesis, or why cancers in BRCA1 mutation carriers are found preferentially in tissues which are responsive to reproductive hormones. We hypothesize that molecular alterations present in morphologically normal tubal epithelium from BRCA1 heterozygotes reflect the earliest events in serous carcinogenesis and may be markers of increased cancer risk as well as targets for risk reduction. Genetic profiling of microdissected tubal epithelium from histologically normal BRCA1 mutation carriers and controls was performed. We sought to define a signature which differentiated BRCA1 mutant tubal epithelium from women with low risk of developing ovarian cancer. Molecular differences between the follicular and luteal phases were prominent and, by using filtering techniques and a two-way ANOVA without a False Discovery Rate correction, we identified 440 probe sets with a more than two-fold change in gene expression related to BRCA1 mutation status. Using gene ontology and known associations to cancer pathways, we selected five genes for further analysis by qPCR and immunohistochemistry, and were able to demonstrate statistically significant differentiation of BRCA1 and control cases in an independent set of cases. The altered expression profiles in histologically normal tubal epithelium from BRCA1 heterozygotes suggest that these cells may respond differently to microenvironmental stresses.
Chondroid Syringoma with Extensive Ossification Annals of Maxillofacial Surgery. Jan, 2011 | Pubmed ID: 23483813 Chondroid syringoma is a rare appendagel skin tumor. Due to its uncharacteristic presentation, it is rarely diagnosed clinically. Here we present one such case in a 50-year-old lady. She presented with a hard mobile lesion over her nose which was excised. The histologic picture is characterized by a combination of epithelial and myoepithelial structures within a chondromyxoid and fibrous stroma. For these tumors, excision is the treatment of choice.
Proliferation in the Normal FTE is a Hallmark of the Follicular Phase, Not BRCA Mutation Status Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Nov, 2012 | Pubmed ID: 22967960 Women who have inherited germline mutations of BRCA1/BRCA2 are at increased risk of developing high-grade serous carcinoma, and many of these cancers arise in the distal fimbriated end of the fallopian tube. We have previously shown that the fallopian tube epithelia of BRCA1 mutation carriers (FTE-BRCA) have altered signaling pathways compared to nonmutation carriers. In this study, we sought to determine whether these differences result in a proliferative advantage to the epithelia in this high-risk patient population and to investigate whether the postovulation environment of the FTE-BRCA compared to FTE from nonmutation carriers experiences a differential abundance of immune cells.
Retinoblastoma Pathway Deregulatory Mechanisms Determine Clinical Outcome in High-grade Serous Ovarian Carcinoma Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. Jul, 2014 | Pubmed ID: 24336157 Alterations in the retinoblastoma pathway are frequent in ovarian/tubal high-grade serous cancers, but the mechanism of deregulation and the impact on patient outcome are poorly understood. A cohort of 334 high-grade serous carcinomas was studied by immunohistochemical analysis of RB1, p16, cyclin D1, cyclin E1, and Ki67. Additional detailed analyses including RB1 allelic deletion (n=42), mutation (n=75), methylation (n=31), and SNP array analyses (n=75) were performed on cases with clinical parameters, including age, debulking status, treatment, and clinical outcome. p16/RB1 expression results yielded three distinct clinically relevant subgroups upon multivariable analysis controlling for stage, debulking status, and treatment types: p16 homogeneous/RB1+ with the shortest progression-free survival (median 15 months (95% CI: 13-18); P=0.016) compared with the p16 heterogeneous/RB1+ subgroup (median 22 months (95% CI: 16-32)) and the p16 homogeneous/RB1- subgroup (median 20 months (95% CI: 15-24)). Patients in the p16 homo/RB1- subgroup showed a significant increase in overall survival (>60 months; P=0.013), which suggests an increase in sensitivity to cytotoxic agents. Analyses of Rb pathway mechanistic differences among these groups revealed frequent RB1 genomic alterations such as RB1 allelic loss and/or large spanning deletions (83%) in the p16 homo/RB1- subgroups, also indicating that RB1 deletions are frequent in high-grade serous carcinoma. CCNE1 gene gains/amplifications were frequent in the p16 homogeneous/RB1+ subgroup (68%) and cyclin D1 protein overexpression was predominantly characteristic of the p16 heterogeneous/RB1+ subgroup. These subcategories occur early in tumor progression and are seen with similar frequency in the cancer precursor lesion, serous tubal intra-epithelial carcinoma. Overall, this study uniquely identifies multiple non-synonymous mechanisms of retinoblastoma pathway deregulation that correlate with significantly different clinical outcomes. Furthermore, deregulations identified in precursor lesions suggest a key role of this pathway in serous tumor development. Recognition of these categories may identify patients with increased sensitivity to chemotherapy and new opportunities for novel therapeutics.
BRCA and Early Events in the Development of Serous Ovarian Cancer Frontiers in Oncology. 2014 | Pubmed ID: 24478985 Women who have an inherited mutation in the BRCA1 or BRCA2 genes have a substantial increased lifetime risk of developing epithelial ovarian cancer (EOC), and epidemiological factors related to parity, ovulation, and hormone regulation have a dramatic effect on the risk in both BRCA mutation carriers and non-carriers. The most common and most aggressive histotype of EOC, high-grade serous carcinoma (HGSC), is also the histotype associated with germline BRCA mutations. In recent years, evidence has emerged indicating that the likely tissue of origin of HGSC is the fallopian tube. We have reviewed, what is known about the fallopian tube in BRCA mutation carriers at both the transcriptional and translational aspect of their biology. We propose that changes of the transcriptome in BRCA heterozygotes reflect an altered response to the ovulatory stresses from the microenvironment, which may include the post-ovulation inflammatory response and altered reproductive hormone physiology.