Publications by authors named "Jennie C Holmberg"

14 Publications

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The amino acid transporter Slc7a5 regulates the mTOR pathway and is required for granule cell development.

Hum Mol Genet 2020 11;29(18):3003-3013

Department of Biological Sciences, Clemson University, Clemson, SC 29634-0314, USA.

Pathogenic mutations in the solute carrier family 7 member 5 (SLC7A5) gene, which encodes an amino acid transporter cause microcephaly and seizures, yet the mechanisms responsible for these phenotypes are unclear. Models have demonstrated that Slc7a5 deletion is embryonic lethal and that these embryos lack a fully formed telencephalon. This phenotype is similar to that of mammalian target of rapamycin (mTOR) protein kinase deletion or mTOR inhibition. Notably, in many cells, Slc7a5 import of amino acids is required to maintain mTOR activity. Slc7a5 is present within neurogenic regions during embryogenesis, is found in cultured neurons and can modulate neuronal electrophysiological properties. However, Slc7a5 is also highly expressed within endothelial cells of the blood-brain barrier where removal in conditional mice leads to severe behavioral defects and non-cell autonomous changes in neurons. Therefore, the extent that neural Slc7a5 is required for development is unclear. Here, subventricular zone neural stem cells that generate olfactory bulb granule cell neurons were electroporated with SLC7A5 or Slc7a5 short hairpin RNA encoding plasmids. Although early phases of neural development were unaltered, Slc7a5 knockdown effected late phases of GC dendrite maturation and survival. Slc7a5 knockdown also decreased mTOR pathway activity. Ras homolog enriched in brain, an mTOR activator, rescued the effect of Slc7a5 knockdown on mTOR pathway activity and dendrite arbors. The data presented here demonstrate that Slc7a5 is required for GC mTOR pathway activity, maturation and survival, which may help explain why Slc7a5 mutations prevent normal brain development and function.
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http://dx.doi.org/10.1093/hmg/ddaa186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645712PMC
November 2020

A transgenic inducible GFP extracellular-vesicle reporter (TIGER) mouse illuminates neonatal cortical astrocytes as a source of immunomodulatory extracellular vesicles.

Sci Rep 2019 02 28;9(1):3094. Epub 2019 Feb 28.

Department of Biological Sciences, Clemson University, Clemson, SC, 29634-0314, USA.

Extracellular vesicles (EVs) are cellular derived particles found throughout the body in nearly all tissues and bodily fluids. EVs contain biological molecules including small RNAs and protein. EVs are proposed to be transferred between cells, notably, cells of the immune system. Tools that allow for in vivo EV labeling while retaining the ability to resolve cellular sources and timing of release are required for a full understanding of EV functions. Fluorescent EV fusion proteins are useful for the study of EV biogenesis, release, and identification of EV cellular recipients. Among the most plentiful and frequently identified EV proteins is CD9, a tetraspanin protein. A transgenic mouse containing a CRE-recombinase inducible CAG promoter driven CD9 protein fused to Turbo-GFP derived from the copepod Pontellina plumata was generated as an EV reporter. The transgenic inducible GFP EV reporter (TIGER) mouse was electroporated with CAG-CRE plasmids or crossed with tamoxifen inducible CAG-CRE-ER or nestin-CRE-ER mice. CD9-GFP labeled cells included glutamine synthetase and glial fibrillary acidic protein positive astrocytes. Cortical astrocytes released ~136 nm EVs that contained CD9. Intraventricular injected EVs were taken up by CD11b/IBA1 positive microglia surrounding the lateral ventricles. Neonatal electroporation and shRNA mediated knockdown of Rab27a in dorsal subventricular zone NSCs and astrocytes increased the number of CD11b/IBA1 positive rounded microglia. Neonatal astrocyte EVs had a unique small RNA signature comprised of morphogenic miRNAs that induce microglia cytokine release. The results from this study demonstrate that inducible CD9-GFP mice will provide the EV community with a tool that allows for EV labeling in a cell-type specific manner while simultaneously allowing in vivo experimentation and provides evidence that EVs are required immunomodulators of the developing nervous system.
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http://dx.doi.org/10.1038/s41598-019-39679-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395689PMC
February 2019

Neonatal Subventricular Zone Neural Stem Cells Release Extracellular Vesicles that Act as a Microglial Morphogen.

Cell Rep 2018 04;23(1):78-89

Department of Biological Sciences, Clemson University, Clemson, SC 29634-0314, USA. Electronic address:

Subventricular zone (SVZ) neural stem cells (NSCs) are the cornerstone of the perinatal neurogenic niche. Microglia are immune cells of the nervous system that are enriched in the neonatal SVZ. Although microglia regulate NSCs, the extent to which this interaction is bi-directional is unclear. Extracellular vesicles (EVs) are cell-derived particles that encase miRNA and proteins. Here, we demonstrate that SVZ NSCs generate and release EVs. Neonatal electroporated fluorescent EV fusion proteins were released by NSCs and subsequently cleared from the SVZ. EVs were preferentially targeted to microglia. Small RNA sequencing identified miRNAs within the EVs that regulate microglia physiology and morphology. EVs induced a transition to a CD11b/Iba1 non-stellate microglial morphology. The transition accompanied a microglial transcriptional state characterized by Let-7-regulated cytokine release and a negative feedback loop that controlled NSC proliferation. These findings implicate an NSC-EV-microglia axis and provide insight to normal and pathophysiological brain development.
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http://dx.doi.org/10.1016/j.celrep.2018.03.037DOI Listing
April 2018

Murine model for non-invasive imaging to detect and monitor ovarian cancer recurrence.

J Vis Exp 2014 Nov 2(93):e51815. Epub 2014 Nov 2.

Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine.

Epithelial ovarian cancer is the most lethal gynecologic malignancy in the United States. Although patients initially respond to the current standard of care consisting of surgical debulking and combination chemotherapy consisting of platinum and taxane compounds, almost 90% of patients recur within a few years. In these patients the development of chemoresistant disease limits the efficacy of currently available chemotherapy agents and therefore contributes to the high mortality. To discover novel therapy options that can target recurrent disease, appropriate animal models that closely mimic the clinical profile of patients with recurrent ovarian cancer are required. The challenge in monitoring intra-peritoneal (i.p.) disease limits the use of i.p. models and thus most xenografts are established subcutaneously. We have developed a sensitive optical imaging platform that allows the detection and anatomical location of i.p. tumor mass. The platform includes the use of optical reporters that extend from the visible light range to near infrared, which in combination with 2-dimensional X-ray co-registration can provide anatomical location of molecular signals. Detection is significantly improved by the use of a rotation system that drives the animal to multiple angular positions for 360 degree imaging, allowing the identification of tumors that are not visible in single orientation. This platform provides a unique model to non-invasively monitor tumor growth and evaluate the efficacy of new therapies for the prevention or treatment of recurrent ovarian cancer.
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http://dx.doi.org/10.3791/51815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353409PMC
November 2014

Ovulation and extra-ovarian origin of ovarian cancer.

Sci Rep 2014 Aug 19;4:6116. Epub 2014 Aug 19.

Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT 06520, USA.

The mortality rate of ovarian cancer remains high due to late diagnosis and recurrence. A fundamental step toward improving detection and treatment of this lethal disease is to understand its origin. A growing number of studies have revealed that ovarian cancer can develop from multiple extra-ovarian origins, including fallopian tube, gastrointestinal tract, cervix and endometriosis. However, the mechanism leading to their ovarian localization is not understood. We utilized in vitro, ex vivo, and in vivo models to recapitulate the process of extra-ovarian malignant cells migrating to the ovaries and forming tumors. We provided experimental evidence to support that ovulation, by disrupting the ovarian surface epithelium and releasing chemokines/cytokines, promotes the migration and adhesion of malignant cells to the ovary. We identified the granulosa cell-secreted SDF-1 as a main chemoattractant that recruits malignant cells towards the ovary. Our findings revealed a potential molecular mechanism of how the extra-ovarian cells can be attracted by the ovary, migrate to and form tumors in the ovary. Our data also supports the association between increased ovulation and the risk of ovarian cancer. Understanding this association will lead us to the development of more specific markers for early detection and better prevention strategies.
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http://dx.doi.org/10.1038/srep06116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137344PMC
August 2014

Phenotypic modifications in ovarian cancer stem cells following Paclitaxel treatment.

Cancer Med 2013 Dec 27;2(6):751-62. Epub 2013 Aug 27.

Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, New Haven, Connecticut.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite initial responsiveness, 80% of EOC patients recur and present with chemoresistant and a more aggressive disease. This suggests an underlying biology that results in a modified recurrent disease, which is distinct from the primary tumor. Unfortunately, the management of recurrent EOC is similar to primary disease and does not parallel the molecular changes that may have occurred during the process of rebuilding the tumor. We describe the characterization of unique in vitro and in vivo ovarian cancer models to study the process of recurrence. The in vitro model consists of GFP+/CD44+/MyD88+ EOC stem cells and mCherry+/CD44-/MyD88- EOC cells. The in vivo model consists of mCherry+/CD44+/MyD88+ EOC cells injected intraperitoneally. Animals received four doses of Paclitaxel and response to treatment was monitored by in vivo imaging. Phenotype of primary and recurrent disease was characterized by quantitative polymerase chain reaction (qPCR) and Western blot analysis. Using the in vivo and in vitro models, we confirmed that chemotherapy enriched for CD44+/MyD88+ EOC stem cells. However, we observed that the surviving CD44+/MyD88+ EOC stem cells acquire a more aggressive phenotype characterized by chemoresistance and migratory potential. Our results highlight the mechanisms that may explain the phenotypic heterogeneity of recurrent EOC and emphasize the significant plasticity of ovarian cancer stem cells. The significance of our findings is the possibility of developing new venues to target the surviving CD44+/MyD88+ EOC stem cells as part of maintenance therapy and therefore preventing recurrence and metastasis, which are the main causes of mortality in patients with ovarian cancer.
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http://dx.doi.org/10.1002/cam4.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892380PMC
December 2013

TLR2 enhances ovarian cancer stem cell self-renewal and promotes tumor repair and recurrence.

Cell Cycle 2013 Feb 16;12(3):511-21. Epub 2013 Jan 16.

Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, New Haven, CT, USA.

Primary ovarian cancer is responsive to treatment, but chemoresistant recurrent disease ensues in majority of patients. Recent compelling evidence demonstrates that a specific population of cancer cells, the cancer stem cells, initiates and sustains tumors. It is therefore possible that this cell population is also responsible for recurrence. We have shown previously that CD44+/MyD88+ epithelial ovarian cancer stem cells (CD44+/MyD88+ EOC stem cells) are responsible for tumor initiation. In this study, we demonstrate that this population drives tumor repair following surgery- and chemotherapy-induced tumor injury. Using in vivo and in vitro models, we also demonstrate that during the process of tumor repair, CD44+/MyD88+ EOC stem cells undergo self-renewal as evidenced by upregulation of stemness-associated genes. More importantly, we show that a pro-inflammatory microenvironment created by the TLR2-MyD88-NFκB pathway supports EOC stem cell-driven repair and self-renewal. Overall, our findings point to a specific cancer cell population, the CD44+/MyD88+ EOC stem cells and a specific pro-inflammatory pathway, the TLR2-MyD88-NFκB pathway, as two of the required players promoting tumor repair, which is associated with enhanced cancer stem cell load. Identification of these key players is the first step in elucidating the steps necessary to prevent recurrence in EOC patients.
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http://dx.doi.org/10.4161/cc.23406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587452PMC
February 2013

An in vitro model for the study of human implantation.

Am J Reprod Immunol 2012 Feb 12;67(2):169-78. Epub 2011 Dec 12.

Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.

Problem: Implantation remains the rate-limiting step for the success of in vitro fertilization. Appropriate models to study the molecular aspects of human implantation are necessary in order to improve fertility.

Methods: First trimester trophoblast cells are differentiated into blastocyst-like spheroids (BLS) by culturing them in low attachment plates. Immortalized human endometrial stromal cells and epithelial cells (ECC-1) were stably transfected with GFP or tdTomato. Co-culture experiments were monitored using Volocity imaging analysis system.

Results: This method demonstrates attachment and invasion of BLS, formed by trophoblast cells, into stromal cells, but not to uterine epithelial cells.

Conclusion: We have developed an in vitro model of uterine implantation. The manipulation of this system allows for dual color monitoring of the cells over time. Additionally, specific compounds can be added to the culture media to test how this may affect implantation and invasion. This model is a helpful tool in understanding the complexity of human implantation.
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http://dx.doi.org/10.1111/j.1600-0897.2011.01095.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703643PMC
February 2012

Prevalence of epithelial ovarian cancer stem cells correlates with recurrence in early-stage ovarian cancer.

J Oncol 2011 29;2011:620523. Epub 2011 Aug 29.

Department of Oncology, Vejle Hospital, Kabbeltoft 25, 7100 Vejle, Denmark.

Epithelial ovarian cancer stem cells (EOC stem cells) have been associated with recurrence and chemoresistance. CD44 and CK18 are highly expressed in cancer stem cells and function as tools for their identification and characterization. We investigated the association between the number of CD44+ EOC stem cells in ovarian cancer tumors and progression-free survival. EOC stem cells exist as clusters located close to the stroma forming the cancer stem cell "niche". 17.1% of the samples reveled high number of CD44+ EOC stem cells (>20% positive cells). In addition, the number of CD44+ EOC stem cells was significantly higher in patients with early-stage ovarian cancer (FIGO I/II), and it was associated with shorter progression-free survival (P = 0.026). This study suggests that quantification of the number of EOC stem cells in the tumor can be used as a predictor of disease and could be applied for treatment selection in early-stage ovarian cancer.
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http://dx.doi.org/10.1155/2011/620523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166719PMC
November 2011

Targeting the mitochondria activates two independent cell death pathways in ovarian cancer stem cells.

Mol Cancer Ther 2011 Aug 15;10(8):1385-93. Epub 2011 Jun 15.

Department of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine, Yale University, New Haven, CT 06520, USA.

Cancer stem cells are responsible for tumor initiation and chemoresistance. In ovarian cancer, the CD44+/MyD88+ ovarian cancer stem cells are also able to repair the tumor and serve as tumor vascular progenitors. Targeting these cells is therefore necessary to improve treatment outcome and patient survival. The previous demonstration that the ovarian cancer stem cells are resistant to apoptotic cell death induced by conventional chemotherapy agents suggests that other forms of targeted therapy should be explored. We show in this study that targeting mitochondrial bioenergetics is a potent stimulus to induce caspase-independent cell death in a panel of ovarian cancer stem cells. Treatment of these cells with the novel isoflavone derivative, NV-128, significantly depressed mitochondrial function exhibited by decrease in ATP, Cox-I, and Cox-IV levels, and by increase in mitochondrial superoxide and hydrogen peroxide. This promotes a state of cellular starvation that activates two independent pathways: (i) AMPKα1 pathway leading to mTOR inhibition; and (ii) mitochondrial MAP/ERK kinase/extracellular signal-regulated kinase pathway leading to loss of mitochondrial membrane potential. The demonstration that a compound can specifically target the mitochondria to induce cell death in this otherwise chemoresistant cell population opens a new venue for treating ovarian cancer patients.
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http://dx.doi.org/10.1158/1535-7163.MCT-11-0023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703662PMC
August 2011

Inhibition of Aurora-A kinase induces cell cycle arrest in epithelial ovarian cancer stem cells by affecting NFĸB pathway.

Cell Cycle 2011 Jul 1;10(13):2206-14. Epub 2011 Jul 1.

Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, New Haven, CT, USA.

Recurrent ovarian cancer is resistant to conventional chemotherapy. A sub-population of ovarian cancer cells, the epithelial ovarian cancer stem cells (EOC stem cells) have stemness properties, constitutive NFκB activity, and represent the chemoresistant population. Currently, there is no effective treatment that targets these cells. Aurora-A kinase (Aurora-A) is associated with tumor initiation and progression and is overexpressed in numerous malignancies. The aim of this study is to determine the effect of Aurora-A inhibition in EOC stem cells. EOC stem cells were treated with the Aurora-A inhibitor, MK-5108. Cell growth was monitored by Incucyte real-time imaging system, cell viability was measured using the Celltiter 96 assay and cytokine levels were quantified using xMAP technology. The intracellular changes associated with MK-5108 treatment are: (1) polyploidy and cell cycle arrest; (2) inhibition of NFκB activity; (3) decreased cytokine production; and (4) nuclear accumulation of IκBα. Thus, inhibition of Aurora-A decreases cell proliferation in the EOC stem cells by inducing cell cycle arrest and affecting the NFκB pathway. As EOC stem cells represent a source of recurrence and chemoresistance, these results suggest that Aurora-A inhibition may effectively target the cancer stem cell population in ovarian cancer.
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http://dx.doi.org/10.4161/cc.10.13.16348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154367PMC
July 2011

Environmental symbiont acquisition may not be the solution to warming seas for reef-building corals.

PLoS One 2010 Oct 7;5(10):e13258. Epub 2010 Oct 7.

Graduate Program in Evolution, Ecology and Behavior, Department of Geology, University at Buffalo, Buffalo, New York, United States of America.

Background: Coral reefs worldwide are in decline. Much of the mortality can be attributed to coral bleaching (loss of the coral's intracellular photosynthetic algal symbiont) associated with global warming. How corals will respond to increasing oceanic temperatures has been an area of extensive study and debate. Recovery after a bleaching event is dependent on regaining symbionts, but the source of repopulating symbionts is poorly understood. Possibilities include recovery from the proliferation of endogenous symbionts or recovery by uptake of exogenous stress-tolerant symbionts.

Methodology/principal Findings: To test one of these possibilities, the ability of corals to acquire exogenous symbionts, bleached colonies of Porites divaricata were exposed to symbiont types not normally found within this coral and symbiont acquisition was monitored. After three weeks exposure to exogenous symbionts, these novel symbionts were detected in some of the recovering corals, providing the first experimental evidence that scleractinian corals are capable of temporarily acquiring symbionts from the water column after bleaching. However, the acquisition was transient, indicating that the new symbioses were unstable. Only those symbiont types present before bleaching were stable upon recovery, demonstrating that recovery was from the resident in situ symbiont populations.

Conclusions/significance: These findings suggest that some corals do not have the ability to adjust to climate warming by acquiring and maintaining exogenous, more stress-tolerant symbionts. This has serious ramifications for the success of coral reefs and surrounding ecosystems and suggests that unless actions are taken to reverse it, climate change will lead to decreases in biodiversity and a loss of coral reefs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013258PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951366PMC
October 2010

Regulation of inflammation by the NF-κB pathway in ovarian cancer stem cells.

Am J Reprod Immunol 2011 Apr 6;65(4):438-47. Epub 2010 Sep 6.

Department of Obstetrics Gynecology and Reproductive Sciences, Yale University, New Haven, CT 06520, USA.

Problem: The NFκB pathway is a major source of pro-inflammatory cytokines, which may contribute to cancer chemoresistance. We showed that constitutive NFκB activity is characteristic of the ovarian cancer stem cells (OCSCs). The aim of this study is to determine whether the inhibition of NFκB by Eriocalyxin B (EriB) in the OCSCs may induce cell death in otherwise chemoresistant cells.

Methods: OCSCs and mature ovarian cancer cells (mOCCs) were treated with increasing concentrations of EriB. Cell viability was measured using the Celltiter 96 assay, and caspase activity was quantified using Caspase-Glo™ assay. Cytokine levels were quantified using xMAP technology.

Results: EriB decreased the percent of viable cells in all cultures tested with GI(50) of 0.5-1 μm after 48 hrs of treatment. The intracellular changes associated with EriB-induced cell death are: (i) inhibition of NF-κB activity; (ii) decreased cytokine production; (iii) activation of caspases; and (iv) down-regulation of XIAP. In addition, EriB is able to sensitize OCSCs to TNFα and FasL-mediated cell death.

Conclusion: Inhibition of the NFκB pathway induces cell death in the OCSCs. Because the OCSCs may represent the source of recurrence and chemoresistance, the use of NFκB inhibitors like EriB may prevent recurrence in patients with ovarian cancer.
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http://dx.doi.org/10.1111/j.1600-0897.2010.00914.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006007PMC
April 2011

Clostridium perfringens enterotoxin carboxy-terminal fragment is a novel tumor-homing peptide for human ovarian cancer.

BMC Cancer 2010 Jul 2;10:349. Epub 2010 Jul 2.

Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.

Background: Development of innovative, effective therapies against recurrent/chemotherapy-resistant ovarian cancer remains a high priority. Using high-throughput technologies to analyze genetic fingerprints of ovarian cancer, we have discovered extremely high expression of the genes encoding the proteins claudin-3 and claudin-4.

Methods: Because claudin-3 and -4 are the epithelial receptors for Clostridium perfringens enterotoxin (CPE), and are sufficient to mediate CPE binding, in this study we evaluated the in vitro and in vivo bioactivity of the carboxy-terminal fragment of CPE (i.e., CPE290-319 binding peptide) as a carrier for tumor imaging agents and intracellular delivery of therapeutic drugs. Claudin-3 and -4 expression was examined with rt-PCR and flow cytometry in multiple primary ovarian carcinoma cell lines. Cell binding assays were used to assess the accuracy and specificity of the CPE peptide in vitro against primary chemotherapy-resistant ovarian carcinoma cell lines. Confocal microscopy and biodistribution assays were performed to evaluate the localization and uptake of the FITC-conjugated CPE peptide in established tumor tissue.

Results: Using a FITC-conjugated CPE peptide we show specific in vitro and in vivo binding to multiple primary chemotherapy resistant ovarian cancer cell lines. Bio-distribution studies in SCID mice harboring clinically relevant animal models of chemotherapy resistant ovarian carcinoma showed higher uptake of the peptide in tumor cells than in normal organs. Imunofluorescence was detectable within discrete accumulations (i.e., tumor spheroids) or even single chemotherapy resistant ovarian cancer cells floating in the ascites of xenografted animals while a time-dependent internalization of the FITC-conjugated CPE peptide was consistently noted in chemotherapy-resistant ovarian tumor cells by confocal microscopy.

Conclusions: Based on the high levels of claudin-3 and -4 expression in chemotherapy-resistant ovarian cancer and other highly aggressive human epithelial tumors including breast, prostate and pancreatic cancers, CPE peptide holds promise as a lead peptide for the development of new diagnostic tracers or alternative anticancer agents.
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http://dx.doi.org/10.1186/1471-2407-10-349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908101PMC
July 2010
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