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Search Results: 1 - 10 of 90320 matches for " Jeffrey W Pollard "
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Tumour-stromal interactions: Transforming growth factor-beta isoforms and hepatocyte growth factor/scatter factor in mammary gland ductal morphogenesis
Jeffrey W Pollard
Breast Cancer Research , 2001, DOI: 10.1186/bcr301
Abstract: The development of the mammary gland largely occurs postnatally. Initially, the ductal system begins to develop from the nipple, and is characterized by specialized structures - the terminal end buds (TEBs) – capping the end of the ducts. TEBs grow out across the fat pad and, by bifurcation, lay down by puberty the minimally branched structure that covers the fat pad, at which point the TEBs disappear. Throughout the estrus cycle there is modest development of the ductal system, but it is during pregnancy that a dramatic outgrowth of secondary branches occurs that, together with the formation of the lobuloalveolar structures, results in the milk-producing gland. Once weaning has occurred, this fully developed structure regresses to a virgin-like state.It has been well established that these events are under the control of a complex interplay of circulating hormones, particularly estrogen, progesterone, glucocorticoids and prolactin gene family members [1]. However, it has also become clear that local mesenchymal–epithelial interactions are essential for mammary development, and that many of these are mediated by growth factors that are often synthesized in response to the circulating hormones. These include wnt family proteins, TGF-α, fibroblast growth factors, insulin-like growth factors, epidermal growth factor [2], colony stimulating factor-1 [3], and – the subjects of the present review – the TGF-β family of proteins and HGF/SF.The three classical members of the TGF-β family belong to a much larger family. In humans this family contains almost 30 members, including bone morphogenic proteins, activins, and Mullerian inhibiting substance [4]. These TGF-β family members have profound effects during development, regulating cell fate by affecting proliferation, differentiation and cell death, and therefore they are important for the development of many tissues.All three of the classical TGF-β isoforms (TGF-βs) activate intracellular responses by binding to and hetero
New tricks for metastasis-associated macrophages
Bin-Zhi Qian, Jeffrey W Pollard
Breast Cancer Research , 2012, DOI: 10.1186/bcr3143
Abstract: Metastasis is the major cause of breast cancer lethality. In target organs, a series of events are required for the establishment of metastatic tumor cells. These events include: adherence to the blood vessel, extravasation, survival, establishment of micrometastases, and persistent growth into macrometastases. While tumor cell intrinsic factors can enhance metastatic efficiency and site selection [1], metastasis also relies on interactions between spreading tumor cells and host factors in the target organ [2]. These host factors include cytokines/growth factors, extracellular matrix, platelets, and different stromal and immune cells [2]. Particularly, a population of metastasis-associated macrophages has been identified that promotes breast cancer metastasis [3]. These cells, derived from a subset of inflammatory monocytic precursor cells, promote tumor cell extravasation through vascular endothelial growth factor production and their subsequent survival and growth [3,4].Chen and colleagues have provided a new mechanism for the metastasis-promoting function of metastasis-associated macrophages through their adherence to tumor cells that provides survival signals to the tumor cells [5]. Previous studies from this group compared gene expression changes of subclones of a human mammary carcinoma cell line, MDA-MB-231, which have differential metastatic efficiencies to target organs when introduced into the circulation of immune-deficient mice [6]. The hypothesis being that certain genes are preferentially expressed by cells with higher metastatic efficiency and that if their expression is correlated with poor prognosis and metastatic disease, this gene is likely to contribute to the metastatic process in patients. Based on this idea, a lung metastasis gene expression signature was identified by comparing subclones selected for lung metastasis with the parental MDA-MB-231 line and those subclones selected for metastasis to bone or brain [6]. The focus of the current stu
Absence of Colony Stimulation Factor-1 Receptor Results in Loss of Microglia, Disrupted Brain Development and Olfactory Deficits
Bryna Erblich, Liyin Zhu, Anne M. Etgen, Kostantin Dobrenis, Jeffrey W. Pollard
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026317
Abstract: The brain contains numerous mononuclear phagocytes called microglia. These cells express the transmembrane tyrosine kinase receptor for the macrophage growth factor colony stimulating factor-1 (CSF-1R). Using a CSF-1R-GFP reporter mouse strain combined with lineage defining antibody staining we show in the postnatal mouse brain that CSF-1R is expressed only in microglia and not neurons, astrocytes or glial cells. To study CSF-1R function we used mice homozygous for a null mutation in the Csflr gene. In these mice microglia are >99% depleted at embryonic day 16 and day 1 post-partum brain. At three weeks of age this microglial depletion continues in most regions of the brain although some contain clusters of rounded microglia. Despite the loss of microglia, embryonic brain development appears normal but during the post-natal period the brain architecture becomes perturbed with enlarged ventricles and regionally compressed parenchyma, phenotypes most prominent in the olfactory bulb and cortex. In the cortex there is increased neuronal density, elevated numbers of astrocytes but reduced numbers of oligodendrocytes. Csf1r nulls rarely survive to adulthood and therefore to study the role of CSF-1R in olfaction we used the viable null mutants in the Csf1 (Csf1op) gene that encodes one of the two known CSF-1R ligands. Food-finding experiments indicate that olfactory capacity is significantly impaired in the absence of CSF-1. CSF-1R is therefore required for the development of microglia, for a fully functional olfactory system and the maintenance of normal brain structure.
Selective Depletion of Eosinophils or Neutrophils in Mice Impacts the Efficiency of Apoptotic Cell Clearance in the Thymus
Hye-Jung Kim,Eric S. Alonzo,Guillaume Dorothee,Jeffrey W. Pollard,Derek B. Sant'Angelo
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011439
Abstract: Developing thymocytes undergo a rigorous selection process to ensure that the mature T cell population expresses a T cell receptor (TCR) repertoire that can functionally interact with major histocompatibility complexes (MHC). Over 90% of thymocytes fail this selection process and die. A small number of macrophages within the thymus are responsible for clearing the large number of dying thymocytes that must be continuously cleared. We studied the capacity of thymic macrophages to clear apoptotic cells under acute circumstances. This was done by synchronously inducing cell death in the thymus and then monitoring the clearance of apoptotic thymocytes. Interestingly, acute cell death was shown to recruit large numbers of CD11b+ cells into the thymus. In the absence of a minor CSF-1 dependent population of macrophages, the recruitment of these CD11b+ cells into the thymus was greatly reduced and the clearance of apoptotic cells was disrupted. To assess a possible role for the CD11b+ cells in the clearance of apoptotic cells, we analyzed mice deficient for eosinophils and mice with defective trafficking of neutrophils. Failure to attract either eosinophils or neutrophils to the thymus resulted in the impaired clearance of apoptotic cells. These results suggested that there is crosstalk between cells of the innate immune system that is necessary for maximizing the efficiency of apoptotic cell removal.
Requirement of macrophages and eosinophils and their cytokines/chemokines for mammary gland development
Valérie Gouon-Evans, Elaine Y Lin, Jeffrey W Pollard
Breast Cancer Research , 2002, DOI: 10.1186/bcr441
Abstract: It is well established that epithelial/mesenchymal interactions are important for postnatal development of the mammary ductal tree and its differentiation during pregnancy into a milk-producing structure [1]. The mesenchyme contains a heterogeneous group of cells [2] and several of these, such as fat cells and fibroblasts, are capable of producing factors that can promote the growth of epithelial cells [3-6]. This review focuses on the role of two types of migrant hematopoietic cells, macrophages and eosinophils, that have been recently found to accumulate extensively around terminal end buds (TEBs) during the pubertal burst of ductal growth [7]. Their chemoattractant factors and their roles in mammary cancer are also discussed.The stroma of the mammary gland is composed of various cells including adipocytes, fibroblasts, endothelial cells, nerve cells and migratory leukocytes [8]. Immunohistochemical analysis using anti-F4/80 antibody revealed two cell types, macrophages and eosinophils, whose recruitment to the postnatal mammary gland closely parallels the formation and outgrowth of terminal end buds (TEBs) (Fig. 1a,1b,1c,1d,1e) [7]. Although F4/80 was originally described as a murine macrophage-restricted cell-surface glycoprotein [9], it is also expressed in eosinophils (see Fig. 1c), which can be independently identified by their specific eosinophilic cytoplasmic granules (see Fig. 1d). The distribution of macrophages and eosinophils around TEBs overlaps, although macrophages are mostly recruited to the neck while eosinophils are more numerous around the head of the TEB. When other leukocyte-lineage markers such as B220, CD3 and Gr-1 are used, neither B cells, T cells nor neutrophils are detected in the vicinity of epithelial structures in the developing mammary gland during puberty, even though they are present in the lymph node localized in the middle of the fourth abdominal mammary gland. Macrophages and eosinophils are also found during pregnancy and lactat
A Distinct Macrophage Population Mediates Metastatic Breast Cancer Cell Extravasation, Establishment and Growth
Binzhi Qian, Yan Deng, Jae Hong Im, Ruth J. Muschel, Yiyu Zou, Jiufeng Li, Richard A. Lang, Jeffrey W. Pollard
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006562
Abstract: Background The stromal microenvironment and particularly the macrophage component of primary tumors influence their malignant potential. However, at the metastatic site the role of these cells and their mechanism of actions for establishment and growth of metastases remain largely unknown. Methodology/Principal Findings Using animal models of breast cancer metastasis, we show that a population of host macrophages displaying a distinct phenotype is recruited to extravasating pulmonary metastatic cells regardless of species of origin. Ablation of this macrophage population through three independent means (genetic and chemical) showed that these macrophages are required for efficient metastatic seeding and growth. Importantly, even after metastatic growth is established, ablation of this macrophage population inhibited subsequent growth. Furthermore, imaging of intact lungs revealed that macrophages are required for efficient tumor cell extravasation. Conclusion/Significance These data indicate a direct enhancement of metastatic growth by macrophages through their effects on tumor cell extravasation, survival and subsequent growth and identifies these cells as a new therapeutic target for treatment of metastatic disease.
Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors
Evanthia T Roussos, Yarong Wang, Jeffrey B Wyckoff, Rani S Sellers, Weigang Wang, Jiufeng Li, Jeffrey W Pollard, Frank B Gertler, John S Condeelis
Breast Cancer Research , 2010, DOI: 10.1186/bcr2784
Abstract: To investigate the role of Mena in tumor progression and metastasis, Mena deficient mice were intercrossed with mice carrying a transgene expressing the polyoma middle T oncoprotein, driven by the mouse mammary tumor virus. The progeny were investigated for the effects of Mena deficiency on tumor progression via staging of primary mammary tumors and by evaluation of morbidity. Stages of metastatic progression were investigated using an in vivo invasion assay, intravital multiphoton microscopy, circulating tumor cell burden, and lung metastases. Mammary gland development was studied in whole mount mammary glands of wild type and Mena deficient mice.Mena deficiency decreased morbidity and metastatic dissemination. Loss of Mena increased mammary tumor latency but had no affect on mammary tumor burden or histologic progression to carcinoma. Elimination of Mena also significantly decreased epidermal growth factor (EGF) induced in vivo invasion, in vivo motility, intravasation and metastasis. Non-tumor bearing mice deficient for Mena also showed defects in mammary gland terminal end bud formation and branching.Deficiency of Mena decreases metastasis by slowing tumor progression and reducing tumor cell invasion and intravasation. Mena deficiency during development causes defects in invasive processes involved in mammary gland development. These findings suggest that functional intervention targeting Mena in breast cancer patients may provide a valuable treatment option to delay tumor progression and decrease invasion and metastatic spread leading to an improved prognostic outcome.Metastasis is the primary cause of death from breast cancer, the most common form of cancer affecting women in the United States, and the second leading cause of cancer related deaths in women around the world [1]. Tumor cells make use of different cellular processes to execute the steps of metastasis: invasion, intravasation, extravasation, tumor cell dissemination, extravasation and growth of di
Contribution of CXCL12 secretion to invasion of breast cancer cells
Pamela J Boimel, Tatiana Smirnova, Zhen Zhou, Jeffrey Wyckoff, Haein Park, Salvatore J Coniglio, Bin-Zhi Qian, E Richard Stanley, Dianne Cox, Jeffrey W Pollard, William J Muller, John Condeelis, Jeffrey E Segall
Breast Cancer Research , 2012, DOI: 10.1186/bcr3108
Abstract: We studied invasion in the tumor microenvironment using multiphoton intravital imaging, in vivo invasion and intravasation assays. CXCL12 signaling was altered by using the CXCR4 inhibitor AMD3100 or by increasing CXCL12 expression. The role of macrophage signaling in vivo was determined using a colony-stimulating factor 1 receptor (CSF-1R) blocking antibody.The Neu-YD strain was reduced in invasion, intravasation and metastasis compared to the Neu-YB and Neu deletion mutant (activated receptor) strains. Remarkably, in the Neu-YB strain, in vivo invasion to epidermal growth factor was dependent on both CXCL12-CXCR4 and CSF1-CSF-1R signaling. Neu-YB tumors had increased macrophage and microvessel density. Overexpression of CXCL12 in rat mammary adenocarcinoma cells increased in vivo invasion as well as microvessel and macrophage density.Expression of CXCL12 by tumor cells results in increased macrophage and microvessel density and in vivo invasiveness.Neu (HER2/ErbB2) is overexpressed in 25% to 30% of human breast cancer, correlating with a poor prognosis [1]. Neu is a member of the ErbB family of receptor tyrosine kinases, which are important mediators of signal transduction for proliferation, survival, apoptosis, motility and invasion of cells. The ErbB receptors, consisting of ErbB1 (epidermal growth factor receptor (EGFR)), Her2/Neu (ErbB2), ErbB3 and ErbB4, can homodimerize and heterodimerize, mediating ligand specificity and various signal transduction pathways [2]. At low expression levels, Neu is unlikely to homodimerize [3]; however, it is the preferred binding partner for the other ErbB receptor tyrosine kinases and mediates the activation of potent signal transduction pathways [4,5].At high expression levels, Neu can homodimerize [6,7], and the correlation of high levels of expression with poor prognosis and clinical significance as a pharmacological target has made the Neu receptor and its contributions to metastasis and tumorigenesis important areas of s
Positron emission tomography agent 2-deoxy-2-[18F]fluoro-D-glucose has a therapeutic potential in breast cancer
Renee M Moadel, Andrew V Nguyen, Elaine Y Lin, Ping Lu, Joseph Mani, M Donald Blaufox, Jeffrey W Pollard, Ekaterina Dadachova
Breast Cancer Research , 2003, DOI: 10.1186/bcr643
Abstract: Polyoma middle T antigen (PyMT) and mouse mammary tumor virus-NeuT transgenic mice with tumors 0.5–1 cm in diameter were imaged with 18F-FDG, and tumor to liver ratios (TLRs) were calculated. The radiotoxicity of 18F-FDG administration was determined in healthy mice. PyMT mice with small (0.15–0.17 cm) and large (more than 1 cm) tumors were treated with 2–4 mCi of 18F-FDG, and control C3H/B6 mice with 3 mCi of 18F-FDG. At 10 days after treatment the tumors and control mammary glands were analyzed for the presence of apoptotic and necrotic cells. Five patients with breast cancer and metastatic disease were evaluated and standardized uptake values (SUVs) in tumors, maximum tolerated dose, and the doses to the tumor were calculated.Doses up to 5 mCi proved to be non-radiotoxic to normal organs. The 18F-FDG uptake in mouse tumors showed an average TLR of 1.6. The treatment of mice resulted in apoptotic cell death in the small tumors. Cell death through the necrotic pathway was seen in large tumors, and was accompanied by tumor fragmentation and infiltration with leukocytes. Normal mammary tissues were not damaged. A human 18F-FDG dose delivering 200 rad to the red marrow (less than 5% damage) was calculated to be 4.76 Ci for a 70 kg woman, and the dose to the tumors was calculated to be 220, 1100 and 2200 rad for SUVs of 1, 5 and 10, respectively.We have shown that positrons delivered by 18F-FDG to mammary tumors have a tumoricidal effect on cancer cells. The study of breast cancer patients suggests that the tumor and normal organ dosimetry of 18F-FDG makes it suitable for therapy of this malignancy.Breast cancer remains a major cause of cancer death in women in the developed world. Novel therapeutic modalities are needed for those patients in whom chemotherapy, hormonal treatment and external radiation therapy are ineffective. 2-Deoxy-2-[18F]fluoro-D-glucose (18F-FDG) is widely used in positron emission tomography (PET) for the evaluation of patients with tumors [1,2].
Temporal stereophotogrammetric analysis of retrogressive thaw slumps on Herschel Island, Yukon Territory
H. Lantuit,W. H. Pollard
Natural Hazards and Earth System Sciences (NHESS) & Discussions (NHESSD) , 2005,
Abstract: The western Canadian Arctic is identified as an area of potentially significant global warming. Thawing permafrost, sea level rise, changing sea ice conditions and increased wave activity will result in accelerated rates of coastal erosion and thermokarst activity in areas of ice-rich permafrost. The Yukon Coastal Plain is widely recognized as one of the most ice-rich and thaw-sensitive areas in the Canadian Arctic. In particular, Herschel Island displays extensive coastal thermokarst. Retrogressive thaw slumps are a common thermokarst landform along the Herschel Island coast that have been increasing in both frequency and extent have in recent years due to increased thawing of massive ground ice and coastal erosion. The volume of sediment and ground ice eroded by retrogressive slump activity and the potential release of climate change related materials like organic carbon, carbon dioxide and methane are largely unknown. The remote setting of Herschel Island, and the Arctic in general, make direct observation of this type of erosion and the analysis of potential climate feedbacks extremely problematic. Remote sensing provides possibly the best solution to this problem. This study looks at two retrogressive thaw slumps located on the western shore of Herschel Island and using stereophotogrammetric methods attempts to (1) develop the first three-dimensional geomorphic analysis of this type of landform, and (2) provide an estimation of the volume of sediment/ground ice eroded through back wasting thermokarst activity. Digital Elevation Models were extracted for the years 1952, 1970 and 2004 and validated using data collected in the field using Kinematic Differential Global Positioning System. Estimates of sediment volumes eroded from retrogressive thaw slumps were found to vary greatly. In one case the total volume of material lost for the 1970–2004 period was approximately 1560000m3. The estimated volume of sediment alone was 360000m3. The temporal analysis of the DEMs suggest that second generation retrogressive thaw slump activity within the floor of a large polycyclic retrogressive thaw slump is possible.
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