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      NanoFlares for the detection, isolation, and culture of live tumor cells from human blood.

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          Abstract

          Metastasis portends a poor prognosis for cancer patients. Primary tumor cells disseminate through the bloodstream before the appearance of detectable metastatic lesions. The analysis of cancer cells in blood—so-called circulating tumor cells (CTCs)—may provide unprecedented opportunities for metastatic risk assessment and investigation. NanoFlares are nanoconstructs that enable live-cell detection of intracellular mRNA. NanoFlares, when coupled with flow cytometry, can be used to fluorescently detect genetic markers of CTCs in the context of whole blood. They allow one to detect as few as 100 live cancer cells per mL of blood and subsequently culture those cells. This technique can also be used to detect CTCs in a murine model of metastatic breast cancer. As such, NanoFlares provide, to our knowledge, the first genetic-based approach for detecting, isolating, and characterizing live cancer cells from blood and may provide new opportunities for cancer diagnosis, prognosis, and personalized therapy.

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          Most cited references 17

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          Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases.

          The purpose of this study was to determine the accuracy, precision, and linearity of the CellSearch system and evaluate the number of circulating tumor cells (CTCs) per 7.5 mL of blood in healthy subjects, patients with nonmalignant diseases, and patients with a variety of metastatic carcinomas. The CellSearch system was used to enumerate CTCs in 7.5 mL of blood. Blood samples spiked with cells from tumor cell lines were used to establish analytical accuracy, reproducibility, and linearity. Prevalence of CTCs was determined in blood from 199 patients with nonmalignant diseases, 964 patients with metastatic carcinomas, and 145 healthy donors. Enumeration of spiked tumor cells was linear over the range of 5 to 1,142 cells, with an average recovery of >/=85% at each spike level. Only 1 of the 344 (0.3%) healthy and nonmalignant disease subjects had >/=2 CTCs per 7.5 mL of blood. In 2,183 blood samples from 964 metastatic carcinoma patients, CTCs ranged from 0 to 23,618 CTCs per 7.5 mL (mean, 60 +/- 693 CTCs per 7.5 mL), and 36% (781 of 2,183) of the specimens had >/=2 CTCs. Detection of >/=2 CTCs occurred at the following rates: 57% (107 of 188) of prostate cancers, 37% (489 of 1,316) of breast cancers, 37% (20 of 53) of ovarian cancers, 30% (99 of 333) of colorectal cancers, 20% (34 of 168) of lung cancers, and 26% (32 of 125) of other cancers. The CellSearch system can be standardized across multiple laboratories and may be used to determine the clinical utility of CTCs. CTCs are extremely rare in healthy subjects and patients with nonmalignant diseases but present in various metastatic carcinomas with a wide range of frequencies.
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            Gold nanoparticles for biology and medicine.

            Gold colloids have fascinated scientists for over a century and are now heavily utilized in chemistry, biology, engineering, and medicine. Today these materials can be synthesized reproducibly, modified with seemingly limitless chemical functional groups, and, in certain cases, characterized with atomic-level precision. This Review highlights recent advances in the synthesis, bioconjugation, and cellular uses of gold nanoconjugates. There are now many examples of highly sensitive and selective assays based upon gold nanoconjugates. In recent years, focus has turned to therapeutic possibilities for such materials. Structures which behave as gene-regulating agents, drug carriers, imaging agents, and photoresponsive therapeutics have been developed and studied in the context of cells and many debilitating diseases. These structures are not simply chosen as alternatives to molecule-based systems, but rather for their new physical and chemical properties, which confer substantive advantages in cellular and medical applications.
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              Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype.

              Epithelial-mesenchymal transition (EMT) is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. In carcinoma cells, EMT can be associated with increased aggressiveness, and invasive and metastatic potential. To assess the occurrence of EMT in human breast tumors, we conducted a tissue microarray-based immunohistochemical study in 479 invasive breast carcinomas and 12 carcinosarcomas using 28 different markers. Unsupervised hierarchical clustering of the tumors and statistical analysis showed that up-regulation of EMT markers (vimentin, smooth-muscle-actin, N-cadherin, and cadherin-11) and overexpression of proteins involved in extracellular matrix remodeling and invasion (SPARC, laminin, and fascin), together with reduction of characteristic epithelial markers (E-cadherin and cytokeratins), preferentially occur in breast tumors with the "basal-like phenotype." Moreover, most breast carcinosarcomas also had a basal-like phenotype and showed expression of mesenchymal markers in their sarcomatous and epithelial components. To assess whether basal-like cells have intrinsic phenotypic plasticity for mesenchymal transition, we performed in vitro studies with the MCF10A cell line. In response to low cell density, MCF10A cells suffer spontaneous morphologic and phenotypic EMT-like changes, including cytoskeleton reorganization, vimentin and Slug up-regulation, cadherin switching, and diffuse cytosolic relocalization of the catenins. Moreover, these phenotypic changes are associated with modifications in the global genetic differentiation program characteristic of the EMT process. In summary, our data indicate that in breast tumors, EMT likely occurs within a specific genetic context, the basal phenotype, and suggests that this proclivity to mesenchymal transition may be related to the high aggressiveness and the characteristic metastatic spread of these tumors.
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                Author and article information

                Journal
                Proc. Natl. Acad. Sci. U.S.A.
                Proceedings of the National Academy of Sciences of the United States of America
                1091-6490
                0027-8424
                Dec 2 2014
                : 111
                : 48
                Affiliations
                [1 ] Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208-3113;
                [2 ] Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611; Simpson Querrey Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL, 60611; Walter S. and Lucienne Driskill Graduate Training Program in Life Sciences, Northwestern University, Chicago, IL 60611;
                [3 ] Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611; Simpson Querrey Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL, 60611; Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
                [4 ] Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611; Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
                [5 ] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705; and.
                [6 ] Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611; Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 cthaxton003@md.northwestern.edu chadnano@northwestern.edu chengc@northwestern.edu.
                [7 ] Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208-3113; Department of Materials Science and Engineering, and cthaxton003@md.northwestern.edu chadnano@northwestern.edu chengc@northwestern.edu.
                [8 ] International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208-3113; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611; Simpson Querrey Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL, 60611; Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; cthaxton003@md.northwestern.edu chadnano@northwestern.edu chengc@northwestern.edu.
                Article
                1418637111
                10.1073/pnas.1418637111
                25404304

                nanotechnology, NanoFlares, cancer metastasis, diagnostic, mRNA

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