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An expanded myeloid derived suppressor cell population does not play a role in gammaherpesvirus-exacerbated breast cancer metastases  [cached]
Nelson Daniel A,Chauhan Vinita S,Tolbert Melanie D,Bost Kenneth L
Infectious Agents and Cancer , 2012, DOI: 10.1186/1750-9378-7-22
Abstract: Background Mice latently infected with murine gammaherpesvirus 68 (HV-68) and transplanted with 4 T1 breast cancer cells developed exacerbated metastatic lesions when compared to controls. The mechanisms responsible for this viral-exacerbated disease were not clear. The ability of HV-68 infection to induce S100A8 and S100A9 production and to expand a population of CD11b+Gr-1+ cells suggested that increased numbers, or activity, of viral-expanded myeloid derived suppressor cells (MDSCs) might contribute to HV-68-associated metastatic breast cancer in this model. We questioned whether mock or HV-68 infected mice with significant breast cancer might have differences in the number and/or activity of MDSCs. Methods Myeloid-derived macrophages and dendritic cells were isolated from normal mice and cultured in vitro with HV-68 to assess S100A8 and S100A9 mRNA and protein expression. In vivo studies were performed using groups of mice that were mock treated or infected with HV-68. After viral latency was established, 4 T1 breast cancer cells were transplanted in mice. When primary breast tumors were present mice were euthanized and cells isolated for phenotyping of myeloid cell populations using FACS, and for ex vivo analysis of suppressor activity. Serum from these animals was also collected to quantify S100A8 and S100A9 levels. Results In vitro studies demonstrated that direct exposure of myeloid cells to HV-68 did not induce increased expression of S100A8 or S100A9 mRNAs or secreted protein. HV-68 infected mice with metastatic breast cancer disease had no increases in S100A8/A9 levels and no significant increases in the numbers or activation of CD11b+Gr-1+MDSCs when compared to mock treated mice with breast cancer. Conclusions Together these studies are consistent with the notion that expanded myeloid derived suppressor cells do not play a role in gammaherpesvirus-exacerbated breast cancer metastases. The mechanisms responsible for HV-68 induced exacerbation of metastatic breast cancer remain unclear.
Characterization of Omental Immune Aggregates during Establishment of a Latent Gammaherpesvirus Infection  [PDF]
Kathleen S. Gray, Christopher M. Collins, Samuel H. Speck
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043196
Abstract: Herpesviruses are characterized by their ability to establish lifelong latent infection. The gammaherpesvirus subfamily is distinguished by lymphotropism, establishing and maintaining latent infection predominantly in B lymphocytes. Consequently, gammaherpesvirus pathogenesis is closely linked to normal B cell physiology. Murine gammaherpesvirus 68 (MHV68) pathogenesis in laboratory mice has been extensively studied as a model system to gain insights into the nature of gammaherpesvirus infection in B cells and their associated lymphoid compartments. In addition to B cells, MHV68 infection of macrophages contributes significantly to the frequency of viral genome-positive cells in the peritoneal cavity throughout latency. The omentum, a sheet of richly-vascularized adipose tissue, resides in the peritoneal cavity and contains clusters of immune cell aggregates termed milky spots. Although the value of the omentum in surgical wound-healing has long been appreciated, the unique properties of this tissue and its contribution to both innate and adaptive immunity have only recently been recognized. To determine whether the omentum plays a role in gammaherpesvirus pathogenesis we examined this site during early MHV68 infection and long-term latency. Following intraperitoneal infection, immune aggregates within the omentum expanded in size and number and contained virus-infected cells. Notably, a germinal-center B cell population appeared in the omentum of infected animals with earlier kinetics and greater magnitude than that observed in the spleen. Furthermore, the omentum harbored a stable frequency of viral genome-positive cells through early and into long-term latency, while removal of the omentum prior to infection resulted in a slight decrease in the establishment of splenic latency following intraperitoneal infection. These data provide the first evidence that the omentum is a site of chronic MHV68 infection that may contribute to the maintenance of chronic infection.
Perturbation of Lytic and Latent Gammaherpesvirus Infection in the Absence of the Inhibitory Receptor CEACAM1  [PDF]
Heiko Adler, Susanne El-Gogo, Simone Guggemoos, Wolfgang Zimmermann, Nicole Beauchemin, Robert Kammerer
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006317
Abstract: Control of gammaherpesvirus infections requires a complex, well orchestrated immune response regulated by positive and negative co-signaling molecules. While the impact of co-stimulatory molecules has been addressed in various studies, the role of co-inhibitory receptors has not been tested. The ITIM-bearing CEACAM1 is an inhibitory receptor expressed by a variety of immune cells, including B, T and NK cells. Using Ceacam1?/? mice, we analyzed the in vivo function of CEACAM1 during acute and latent murine gammaherpesvirus 68 (MHV-68) infection. During acute lytic replication, we observed lower virus titers in the lungs of Ceacam1?/? mice than in WT mice. In contrast, during latency amplification, Ceacam1?/? mice displayed increased splenomegaly and a higher latent viral load in the spleen. Analysis of the immune response revealed increased virus-specific antibody levels in Ceacam1?/? mice, while the magnitude of the T cell-mediated antiviral immune response was reduced. These findings suggest that inhibitory receptors can modulate the efficacy of immune responses against gammaherpesvirus infections.
Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles
Robert Klopfleisch, Dido Lenze, Michael Hummel, Achim D Gruber
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-618
Abstract: Messenger RNA expression profiles of twenty-seven lymph node metastasis positive or negative canine mammary carcinomas were established by microarray analysis. Differentially expressed genes were functionally characterized and associated with molecular pathways. The findings were also correlated with published data on human breast cancer.Metastatic canine mammary carcinomas had 1,011 significantly differentially expressed genes when compared to non-metastatic carcinomas. Metastatic carcinomas had a significant up-regulation of genes associated with cell cycle regulation, matrix modulation, protein folding and proteasomal degradation whereas cell differentiation genes, growth factor pathway genes and regulators of actin organization were significantly down-regulated. Interestingly, 265 of the 1,011 differentially expressed canine genes are also related to human breast cancer and, vice versa, parts of a human prognostic gene signature were identified in the expression profiles of the metastatic canine tumors.Metastatic canine mammary carcinomas can be discriminated from non-metastatic carcinomas by their gene expression profiles. More than one third of the differentially expressed genes are also described of relevance for human breast cancer. Many of the differentially expressed genes are linked to functions and pathways which appear to be relevant for the induction and maintenance of metastatic progression and may represent new therapeutic targets. Furthermore, dogs are in some aspects suitable as a translational model for human breast tumors in order to identify prognostic molecular signatures and potential therapeutic targets.Canine mammary tumor (CMT) is the most common cancer among female dogs and often becomes fatal due to the development of distant metastases [1-3]. Metastasis to the regional lymph node is an early step in metastasis and one of the most important prognostic factors in the diagnosis of CMT, a criterion that is also valid for human breast cancer
Characterization of the MDSC Proteome Associated with Metastatic Murine Mammary Tumors Using Label-Free Mass Spectrometry and Shotgun Proteomics  [PDF]
Angela M. Boutté,W. Hayes McDonald,Yu Shyr,Li Yang,P. Charles Lin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022446
Abstract: Expansion of Gr-1+/CD11b+ myeloid derived suppressor cells (MDSCs) is governed by the presence of increasingly metastatic, malignant primary tumors. Metastasis, not the primary tumor, is often the cause of mortality. This study sought to fully characterize the MDSC proteome in response to metastatic and non-metastatic mammary tumors using label-free mass spectrometry shotgun proteomics in a mouse model with tumor cell lines, 67NR and 4T1, derived from the same tumor. 67NR cells form only primary mammary tumors, whereas 4T1 cells readily metastasize to the lungs, lymph nodes, and blood. Overall analysis identified a total of 2825 protein groups with a 0.78% false discovery rate. Of the 2814 true identifications, 43 proteins were exclusive to the 67NR group, 153 were exclusive to the 4T1 group, and 2618 were shared. Among the shared cohort, 26 proteins were increased and 31 were decreased in the metastatic 4T1 cohort compared to non-metastatic 67NR controls after filtering. MDSCs selectively express proteins involved in the γ-glutamyl transferase, glutathione synthase pathways, CREB transcription factor signaling, and other pathways involved in platelet aggregation, as well as lipid and amino acid metabolism, in response to highly metastatic 4T1 tumors. Cell cycle regulation dominated protein pathways and ontological groups of the 67NR non-metastatic group. Not only does this study provide a starting point to identify potential biomarkers of metastasis expressed by MDSCs; it identifies critical pathways that are unique to non-metastatic and metastatic conditions. Therapeutic interventions aimed at these pathways in MDSC may offer a new route to control malignancy and metastasis.
Estrogen receptor alpha deletion enhances the metastatic phenotype of Ron overexpressing mammary tumors in mice
Aaron M Marshall, Rebecca J McClaine, Devikala Gurusamy, Jerilyn K Gray, Kara E Lewnard, Sohaib A Khan, Susan E Waltz
Molecular Cancer , 2012, DOI: 10.1186/1476-4598-11-2
Abstract: Here, we report that Ron expression is correlated with in situ, estrogen receptor alpha (ERα)-positive tumors, and is higher in breast tumors following neoadjuvant tamoxifen therapy. We also demonstrate that the majority of mammary tumors isolated from transgenic mice with mammary specific-Ron overexpression (MMTV-Ron mice), exhibit appreciable ER expression. Moreover, genetic-ablation of ERα, in the context of Ron overexpression, leads to delayed mammary tumor initiation and growth, but also results in an increased metastasis.Ron receptor overexpression is associated with ERα-positive human and murine breast tumors. In addition, loss of ERα on a Ron overexpressing background in mice leads to the development of breast tumors which grow slower but which exhibit more metastasis and suggests that targeting of ERα, as in the case of tamoxifen therapy, may reduce the growth of Ron overexpressing breast cancers but may cause these tumors to be more metastatic.To date, the most successful pharmacological therapies specifically targeting breast cancer include anti-estrogens and receptor tyrosine kinase (RTK) modulating drugs [1]. Accordingly, there have been numerous studies examining signaling paradigms between estrogen and RTK signaling pathways [2-4] which have provided evidence that RTKs are able to activate estrogen receptor alpha (ERα) in breast cancers independent of its ligand estrogen. This activation of ERα by RTKs leads to an ERα transcriptional program that enhances cell survival. The dependency of this activation on the RTK ligand is still an area of active investigation. More importantly, however, this signaling crosstalk between RTKs and ERα may predict resistance to anti-estrogen hormonal therapies, including tamoxifen [2,5]. Specifically, studies have shown that activation of EGFR, Her2, cMet, IGFR, RET and recently, Ron RTK, lead to phosphorylation and activation of ERα which enhances survival of breast cancer in the presence of anti-estrogen therapy [4,6-
Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes
Rosalyn D Ferguson, Ruslan Novosyadlyy, Yvonne Fierz, Nyosha Alikhani, Hui Sun, Shoshana Yakar, Derek LeRoith
Breast Cancer Research , 2012, DOI: 10.1186/bcr3089
Abstract: Using a hyperinsulinemic mouse model (MKR+/+) and the metastatic, c-Myc-transformed mammary carcinoma cell line Mvt1, we investigated how high systemic insulin levels would affect the progression of orthotopically inoculated primary mammary tumors to lung metastases.We found that orthotopically injected Mvt1 cells gave rise to larger mammary tumors and to a significantly higher mean number of pulmonary macrometastases in hyperinsulinemic mice over a period of six weeks (hyperinsulinemic, 19.4 ± 2.7 vs. control, 4.0 ± 1.3). When Mvt1-mediated mammary tumors were allowed to develop and metastasize for approximately two weeks and were then surgically removed, hyperinsulinemic mice demonstrated a significantly higher number of lung metastases after a four-week period (hyperinsulinemic, 25.1 ± 4.6 vs. control, 7.4 ± 0.42). Similarly, when Mvt1 cells were injected intravenously, hyperinsulinemic mice demonstrated a significantly higher metastatic burden in the lung than controls after a three-week period (hyperinsulinemic, 6.0 ± 1.63 vs. control, 1.5 ± 0.68). Analysis of Mvt1 cells both in vitro and in vivo revealed a significant up-regulation of the transcription factor c-Myc under hyperinsulinemic conditions, suggesting that hyperinsulinemia may promote c-Myc signaling in breast cancer. Furthermore, insulin-lowering therapy using the beta-adrenergic receptor agonist CL-316243 reduced metastatic burden in hyperinsulinemic mice to control levels.Hyperinsulinemia in a mouse model promotes breast cancer metastasis to the lung. Therapies to reduce insulin levels in hyperinsulinemic patients suffering from breast cancer could lessen the likelihood of metastatic progression.Breast cancer incidence and progression are affected by several lifestyle factors, such as hormone therapy, body mass index, dietary intake and physical activity [1]. Type 2 diabetes (T2D) is an emerging major health concern, affecting around 285 million adults worldwide and predicted to affect up to 439 mi
Decreased Autocrine EGFR Signaling in Metastatic Breast Cancer Cells Inhibits Tumor Growth in Bone and Mammary Fat Pad  [PDF]
Nicole K. Nickerson,Khalid S. Mohammad,Jennifer L. Gilmore,Erin Crismore,Angela Bruzzaniti,Theresa A. Guise,John Foley
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030255
Abstract: Breast cancer metastasis to bone triggers a vicious cycle of tumor growth linked to osteolysis. Breast cancer cells and osteoblasts express the epidermal growth factor receptor (EGFR) and produce ErbB family ligands, suggesting participation of these growth factors in autocrine and paracrine signaling within the bone microenvironment. EGFR ligand expression was profiled in the bone metastatic MDA-MB-231 cells (MDA-231), and agonist-induced signaling was examined in both breast cancer and osteoblast-like cells. Both paracrine and autocrine EGFR signaling were inhibited with a neutralizing amphiregulin antibody, PAR34, whereas shRNA to the EGFR was used to specifically block autocrine signaling in MDA-231 cells. The impact of these was evaluated with proliferation, migration and gene expression assays. Breast cancer metastasis to bone was modeled in female athymic nude mice with intratibial inoculation of MDA-231 cells, and cancer cell-bone marrow co-cultures. EGFR knockdown, but not PAR34 treatment, decreased osteoclasts formed in vitro (p<0.01), reduced osteolytic lesion tumor volume (p<0.01), increased survivorship in vivo (p<0.001), and resulted in decreased MDA-231 growth in the fat pad (p<0.01). Fat pad shEGFR-MDA-231 tumors produced in nude mice had increased necrotic areas and decreased CD31-positive vasculature. shEGFR-MDA-231 cells also produced decreased levels of the proangiogenic molecules macrophage colony stimulating factor-1 (MCSF-1) and matrix metalloproteinase 9 (MMP9), both of which were decreased by EGFR inhibitors in a panel of EGFR-positive breast cancer cells. Thus, inhibiting autocrine EGFR signaling in breast cancer cells may provide a means for reducing paracrine factor production that facilitates microenvironment support in the bone and mammary gland.
Fine-needle aspiration cytology of extra mammary metastatic lesions in the breast: A retrospective study of 36 cases diagnosed during 18 years  [cached]
Sauer Torill
CytoJournal , 2010,
Abstract: Background: Metastatic tumors in the breast require treatment according to origin and type of tumor. It is important to recognize these lesions in fine-needle aspiration cytology (FNAC) in order to avoid unnecessary mastectomy or non-relevant chemotherapy. The aim of this study was to evaluate the cytological features of metastatic tumors and possible criteria that could alert us as to the possibility of a metastasis from an extra mammary malignancy. Methods: The material included 36 confirmed or suspected metastases in the breast registered in the pathology files at Oslo University Hospital, Ulleval, during 1990-2007. There were a total of 6,325 cases of malignant breast FNAC, representing 30 men and 6,295 women. Smears were evaluated for the amount of material, presence or absence of myoepithelial cells, microcalcifications, mitoses and necrotic material. All carcinomas were graded. Results: There were seven men (7/30 = 23.3%) and 29 women (29/6,295 = 0.46%). The primary tumor was known in 22 cases (22/36 = 61.1%). No other primary tumor was known and metastatic lesion was not initially suspected in 14 cases (14/36 = 38.9%). The most common origin was lung (15/36 = 41.7%). In five cases (5/36 = 13.9%), the origin remained uncertain. Conclusions: Metastases from extra mammary sites are (relatively) common in males (23.3%). In women, metastatic lesions are rare (0.46%). A large proportion of them (88%) are high-grade adenocarcinomas and poorly differentiated carcinomas that may resemble grade 3 ductal carcinomas. Unusual clinical and/or radiological presentation in combination with high-grade malignant cells should alert us to consider the possibility of a metastasis.
Endothelial Cells Support Persistent Gammaherpesvirus 68 Infection  [PDF]
Andrea Luísa Suárez,Linda Faye van Dyk
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.1000152
Abstract: A variety of human diseases are associated with gammaherpesviruses, including neoplasms of lymphocytes (e.g. Burkitt's lymphoma) and endothelial cells (e.g. Kaposi's sarcoma). Gammaherpesvirus infections usually result in either a productive lytic infection, characterized by expression of all viral genes and rapid cell lysis, or latent infection, characterized by limited viral gene expression and no cell lysis. Here, we report characterization of endothelial cell infection with murine gammaherpesvirus 68 (γHV68), a virus phylogenetically related and biologically similar to the human gammaherpesviruses. Endothelial cells supported γHV68 replication in vitro, but were unique in that a significant proportion of the cells escaped lysis, proliferated, and remained viable in culture for an extended time. Upon infection, endothelial cells became non-adherent and altered in size, complexity, and cell-surface protein expression. These cells were uniformly infected and expressed the lytic transcription program based on detection of abundant viral gene transcripts, GFP fluorescence from the viral genome, and viral surface protein expression. Additionally, endothelial cells continued to produce new infectious virions as late as 30 days post-infection. The outcome of this long-term infection was promoted by the γHV68 v-cyclin, because in the absence of the v-cyclin, viability was significantly reduced following infection. Importantly, infected primary endothelial cells also demonstrated increased viability relative to infected primary fibroblasts, and this increased viability was dependent on the v-cyclin. Finally, we provide evidence for infection of endothelial cells in vivo in immune-deficient mice. The extended viability and virus production of infected endothelial cells indicated that endothelial cells provided a source of prolonged virus production and identify a cell-type specific adaptation of gammaherpesvirus replication. While infected endothelial cells would likely be cleared in a healthy individual, persistently infected endothelial cells could provide a source of continued virus replication in immune-compromised individuals, a context in which gammaherpesvirus-associated pathology frequently occurs.
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