scholarly journals Mammary tumour cells remodel the bone marrow vascular microenvironment to support metastasis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Raymond K. H. Yip ◽  
Joel S. Rimes ◽  
Bianca D. Capaldo ◽  
François Vaillant ◽  
Kellie A. Mouchemore ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Large Scale ◽  
Three Dimensional ◽  
Tumour Microenvironment ◽  
Metastatic Lesion ◽  
Tumour Cells ◽  
Mammary Tumour ◽  
Independent Manner ◽  
Tumour Metastasis

AbstractBone marrow is a preferred metastatic site for multiple solid tumours and is associated with poor prognosis and significant morbidity. Accumulating evidence indicates that cancer cells colonise specialised niches within the bone marrow to support their long-term propagation, but the precise location and mechanisms that mediate niche interactions are unknown. Using breast cancer as a model of solid tumour metastasis to the bone marrow, we applied large-scale quantitative three-dimensional imaging to characterise temporal changes in the bone marrow microenvironment during disease progression. We show that mouse mammary tumour cells preferentially home to a pre-existing metaphyseal domain enriched for type H vessels. Metastatic lesion outgrowth rapidly remodelled the local vasculature through extensive sprouting to establish a tumour-supportive microenvironment. The evolution of this tumour microenvironment reflects direct remodelling of the vascular endothelium through tumour-derived granulocyte-colony stimulating factor (G-CSF) in a hematopoietic cell-independent manner. Therapeutic targeting of the metastatic niche by blocking G-CSF receptor inhibited pathological blood vessel remodelling and reduced bone metastasis burden. These findings elucidate a mechanism of ‘host’ microenvironment hijacking by mammary tumour cells to subvert the local microvasculature to form a specialised, pro-tumorigenic niche.

Long-term Follow-up of Bladder Cancer Patients with Disseminated Tumour Cells in Bone Marrow

2011 ◽  
Vol 60 (2) ◽  
pp. 231-238 ◽  
Author(s):  
Margitta Retz ◽  
Jens Rotering ◽  
Roman Nawroth ◽  
Alexander Buchner ◽  
Michael Stöckle ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bladder Cancer ◽  
Cancer Patients ◽  
Tumour Cells ◽  
Long Term Follow Up ◽  
Disseminated Tumour Cells

Hepatocyte Aggregate Culture Technique for Bioreactors in Hybrid Liver Support Systems

1993 ◽  
Vol 16 (12) ◽  
pp. 843-846 ◽  
Author(s):  
J.C. Gerlach ◽  
K. Klöppel ◽  
C. MÜller ◽  
N. Schnoy ◽  
M.D. Smith ◽  
...  
Keyword(s):  
High Performance ◽  
Large Scale ◽  
Support Systems ◽  
Three Dimensional ◽  
Culture Technique ◽  
Dimensional Structure ◽  
Cell Aggregates ◽  
Liver Support ◽  
Aggregate Culture

Utilizing a modified culture technique for hepatocytes, a high performance suspension culture is possible in which hepatocytes spontaneously form cell aggregates. The aggregates of 20-100 cells have been histologically confirmed to hold a three-dimensional structure, they show a long-term external metabolism and a survival time comparable with standard adhesion cultures. This technique has several advantages in the construction of large scale bioreactors for hybrid liver support systems.

scholarly journals Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner

Blood ◽  
2014 ◽  
Vol 123 (20) ◽  
pp. 3105-3115 ◽  
Author(s):  
Lijian Shao ◽  
Wei Feng ◽  
Hongliang Li ◽  
David Gardner ◽  
Yi Luo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Total Body Irradiation ◽  
Bone Marrow Suppression ◽  
Premature Senescence ◽  
Independent Manner ◽  
Telomere Shortening ◽  
Key Points ◽  
Total Body

Key Points Total body irradiation causes long-term bone marrow suppression by selectively inducing HSC senescence. The induction of HSC senescence is independent of telomere shortening and p16Ink4a and Arf.

Replicative Senescence-Associated Gene Expression Changes In Human MSPCs Independent of Genomic Variations

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4775-4775
Author(s):  
Katharina Schallmoser ◽  
Christina Bartmann ◽  
Eva Rohde ◽  
Simone Bork ◽  
Christian Guelly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Bone Marrow ◽  
Large Scale ◽  
Replicative Senescence ◽  
Genomic Stability ◽  
The State ◽  
Efficient Treatment ◽  
The Impact

Abstract Abstract 4775 Background: Based on promising experimental studies with mesenchymal stem and progenitor cells (MSPCs) multiple clinical trials have been initiated. In previous studies we have observed genomic stability of MSPCs after efficient short-term expansion in a humanized GMP compliant system with pooled human platelet lysate (pHPL) replacing fetal bovine serum (FBS) as the cell culture supplement (Schallmoser K. and Strunk D., Journal of Visualized Experiments (32) DOI: 10.3791/1523, 2009). Notably, depending on culture protocols, an extensive propagation with highly variable cell culture duration may be necessary to yield enough MSPCs for therapy. The decline in proliferation rates of MSPCs in the course of the different long-term expansion procedures may indicate a propensity for replicative senescence which may hamper long term functionality in vivo. We have therefore initiated a molecular profiling of senescence-associated regulated genes to determine the state of senescence before MSPC transplantation. Methods: Human bone marrow-derived MSPCs were cultured following a highly efficient two-passage protocol (primary culture of unseparated bone marrow and subsequent large scale expansion; Schallmoser K. et al., Tissue Engineering 14:185-196, 2008) compared to conventional serial passaging in three different growth conditions with regularly more then four passages to obtain comparable final cell numbers. Culture media were either supplemented with FBS in different concentrations or pHPL. Gene expression changes were tested by microarray analysis and selected targets were reanalyzed by quantitative real-time PCR. The genomic stability of MSPCs after long-term culture was determined by array comparative genomic hybridization (CGH). Results: Despite high proliferation rate large scale expanded MSPCs showed genomic stability in array CGH. Long-term MSPC growth induced similar gene expression changes in MSPCs irrespective of isolation and expansion conditions. In particular, genes involved in cell differentiation, apoptosis and cell death were up-regulated, whereas genes involved in mitosis and proliferation were down-regulated. Furthermore, overlapping senescence-associated gene expression changes were found in all MSPC preparations. The genomic copy number variations detected in MSPCs of early and late passages in all culture conditions did not coincide with differentially expressed genes. Conclusion: Our data indicate that MSPC expansion can induce gene expression changes independent of isolation and FBS-supplemented as well as FBS-free expansion conditions. A panel of genes will be presented that might offer a practicable approach to assess MSPC quality with regard to the state of replicative senescence in advance of therapeutic application. Determining the impact of senescence acquired during cell expansion on the therapeutic potential of MSCPs for both immune modulation and organ regeneration may help to develop more efficient treatment strategies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Activation of blood coagulation in cancer: implications for tumour progression

2013 ◽  
Vol 33 (5) ◽  
Author(s):  
Luize G. Lima ◽  
Robson Q. Monteiro
Keyword(s):  
Blood Coagulation ◽  
Tumour Progression ◽  
Primary Tumour ◽  
Tumour Microenvironment ◽  
Tumour Cells ◽  
Protease Activated Receptors ◽  
Tumour Metastasis ◽  
Coagulation Proteins ◽  
Associated Proteins ◽  
Cancer Associated Thrombosis

Several studies have suggested a role for blood coagulation proteins in tumour progression. Herein, we discuss (1) the activation of the blood clotting cascade in the tumour microenvironment and its impact on primary tumour growth; (2) the intravascular activation of blood coagulation and its impact on tumour metastasis and cancer-associated thrombosis; and (3) antitumour therapies that target blood-coagulation-associated proteins. Expression levels of the clotting initiator protein TF (tissue factor) have been correlated with tumour cell aggressiveness. Simultaneous TF expression and PS (phosphatidylserine) exposure by tumour cells promote the extravascular activation of blood coagulation. The generation of blood coagulation enzymes in the tumour microenvironment may trigger the activation of PARs (protease-activated receptors). In particular, PAR1 and PAR2 have been associated with many aspects of tumour biology. The procoagulant activity of circulating tumour cells favours metastasis, whereas the release of TF-bearing MVs (microvesicles) into the circulation has been correlated with cancer-associated thrombosis. Given the role of coagulation proteins in tumour progression, it has been proposed that they could be targets for the development of new antitumour therapies.

Ionizing Radiation Induces Hematopoietic Stem Cell Senescence and Long-Term Bone Marrow Suppression in a p16Ink4a/Arf-Independent manner

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1345-1345
Author(s):  
Lijian Shao ◽  
Wei Feng ◽  
Hongliang Li ◽  
Yong Wang ◽  
Norman Sharpless ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Ionizing Radiation ◽  
Hematopoietic Stem Cell ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Sublethal Dose ◽  
Independent Manner ◽  
Hematopoietic Stem

Abstract Abstract 1345 Many patients receiving chemotherapy and/or ionizing radiation (IR) develop residual (or long-term) bone marrow (BM) injury that can not only limit the success of cancer treatment but also adversely affect their quality of life. Although residual BM injury has been largely attributed to the induction of hematopoietic stem cell (HSC) senescence, neither the molecular mechanisms by which chemotherapy and/or IR induce HSC senescence have been clearly defined, nor has an effective treatment been developed to ameliorate the injury. The Ink4a-Arf locus encodes two important tumor suppressors, p16Ink4a (p16) and Arf. Both of them have been implicated in mediating the induction of cellular senscence in a variety of cells including HSCs. Therefore, we examined the role of p16 and/or Arf in IR-induced HSC senescence and long-term BM suppression using a total body irradiation (TBI) mouse model. The results from our studies show that exposure of wild-type (WT) mice to a sublethal dose (6 Gy) of TBI induces HSC senescence and long-term BM suppression. The induction of HSC senescence is not associated with a reduction in telemore length in HSCs and their progeny, but is associated with significant increases in the production of reactive oxygen species (ROS), the expression of p16 and Arf mRNA, and the activity of senescence-associated β-galacotosidase (SA-β-gal) in HSCs. However, genetical deletion of Ink4a and/or Arf has no effect on TBI-induced HSC senescence, as HSCs from the Ink4a and/or Arf knockout mice after exposure to TBI exhibit similar changes as those seen in the cells from irradiated WT mice in comparison with the cells from un-irradiated mice with correspondent genotypes. In addition, TBI-induced long-term BM suppression is also not attenuated by the deletion of the Ink4a and/or Arf genes. These findings suggest that IR induces HSC senescence and long-term BM suppression in a p16Ink4a/Arf-independent manner. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A High-Capacity Ammonium Vanadate Cathode for Zinc-Ion Battery

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Qifei Li ◽  
Xianhong Rui ◽  
Dong Chen ◽  
Yuezhan Feng ◽  
Ni Xiao ◽  
...  
Keyword(s):  
Large Scale ◽  
Three Dimensional ◽  
High Capacity ◽  
Cycling Performance ◽  
Zinc Ion ◽  
First Principles Calculations ◽  
Diffusion Channel ◽  
Ion Storage ◽  
Ion Intercalation

AbstractGiven the advantages of being abundant in resources, environmental benign and highly safe, rechargeable zinc-ion batteries (ZIBs) enter the global spotlight for their potential utilization in large-scale energy storage. Despite their preliminary success, zinc-ion storage that is able to deliver capacity > 400 mAh g−1 remains a great challenge. Here, we demonstrate the viability of NH4V4O10 (NVO) as high-capacity cathode that breaks through the bottleneck of ZIBs in limited capacity. The first-principles calculations reveal that layered NVO is a good host to provide fast Zn2+ ions diffusion channel along its [010] direction in the interlayer space. On the other hand, to further enhance Zn2+ ion intercalation kinetics and long-term cycling stability, a three-dimensional (3D) flower-like architecture that is self-assembled by NVO nanobelts (3D-NVO) is rationally designed and fabricated through a microwave-assisted hydrothermal method. As a result, such 3D-NVO cathode possesses high capacity (485 mAh g−1) and superior long-term cycling performance (3000 times) at 10 A g−1 (~ 50 s to full discharge/charge). Additionally, based on the excellent 3D-NVO cathode, a quasi-solid-state ZIB with capacity of 378 mAh g−1 is developed.

scholarly journals Structural geology and geophysics as a support to build a hydrogeologic model of granite rock

Solid Earth ◽  
2016 ◽  
Vol 7 (3) ◽  
pp. 881-895 ◽  
Author(s):  
Lurdes Martinez-Landa ◽  
Jesús Carrera ◽  
Andrés Pérez-Estaún ◽  
Paloma Gómez ◽  
Carmen Bajos
Keyword(s):  
Structural Geology ◽  
Large Scale ◽  
Preferential Flow ◽  
Three Dimensional ◽  
Pumping Test ◽  
Discrete Elements ◽  
Flow Paths ◽  
Preferential Flow Paths

Abstract. A method developed for low-permeability fractured media was applied to understand the hydrogeology of a mine excavated in a granitic pluton. This method includes (1) identifying the main groundwater-conducting features of the medium, such as the mine, dykes, and large fractures, (2) implementing this factors as discrete elements into a three-dimensional numerical model, and (3) calibrating these factors against hydraulic data . A key question is how to identify preferential flow paths in the first step. Here, we propose a combination of several techniques. Structural geology, together with borehole sampling, geophysics, hydrogeochemistry, and local hydraulic tests aided in locating all structures. Integration of these data yielded a conceptual model of the site. A preliminary calibration of the model was performed against short-term (< 1 day) pumping tests, which facilitated the characterization of some of the fractures. The hydraulic properties were then used for other fractures that, according to geophysics and structural geology, belonged to the same families. Model validity was tested by blind prediction of a long-term (4 months) large-scale (1 km) pumping test from the mine, which yielded excellent agreement with the observations. Model results confirmed the sparsely fractured nature of the pluton, which has not been subjected to glacial loading–unloading cycles and whose waters are of Na-HCO3 type.

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