A mathematical model of tumour angiogenesis: growth, regression and regrowth

Cancerous tumours have the ability to recruit new blood vessels through a process called angiogenesis. By stimulating vascular growth, tumours get connected to the circulatory system, receive nutrients and open a way to colonize distant organs. Tumour-induced vascular networks become unstable in the absence of tumour angiogenic factors (TAFs). They may undergo alternating stages of growth, regression and regrowth. Following a phase-field methodology, we propose a model of tumour angiogenesis that reproduces the aforementioned features and highlights the importance of vascular regression and regrowth. In contrast with previous theories which focus on vessel remodelling due to the absence of flow, we model an alternative regression mechanism based on the dependency of tumour-induced vascular networks on TAFs. The model captures capillaries at full scale, the plastic dynamics of tumour-induced vessel networks at long time scales, and shows the key role played by filopodia during angiogenesis. The predictions of our model are in agreement with in vivo experiments and may prove useful for the design of antiangiogenic therapies.

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Pericytes promote selective vessel regression to regulate vascular patterning

Blood ◽

10.1182/blood-2011-01-332338 ◽

2012 ◽

Vol 120 (7) ◽

pp. 1516-1527 ◽

Cited By ~ 68

Author(s):

Nicole Simonavicius ◽

Matthew Ashenden ◽

Antoinette van Weverwijk ◽

Siân Lax ◽

David L. Huso ◽

...

Keyword(s):

Endothelial Cell ◽

Network Formation ◽

Mouse Tumor ◽

Vascular Patterning ◽

Sprouting Angiogenesis ◽

Antiangiogenic Therapies ◽

Basement Membrane Component ◽

Vessel Regression ◽

Vessel Networks

Abstract Blood vessel networks form in a 2-step process of sprouting angiogenesis followed by selective branch regression and stabilization of remaining vessels. Pericytes are known to function in stabilizing blood vessels, but their role in vascular sprouting and selective vessel regression is poorly understood. The endosialin (CD248) receptor is expressed by pericytes associated with newly forming but not stable quiescent vessels. In the present study, we used the Endosialin−/− mouse as a means to uncover novel roles for pericytes during the process of vascular network formation. We demonstrate in a postnatal retina model that Endosialin−/− mice have normal vascular sprouting but are defective in selective vessel regression, leading to increased vessel density. Examination of the Endosialin−/− mouse tumor vasculature revealed an equivalent phenotype, indicating that pericytes perform a hitherto unidentified function to promote vessel destabilization and regression in vivo in both physiologic and pathologic angiogenesis. Mechanistically, Endosialin−/− mice have no defect in pericyte recruitment. Rather, endosialin binding to an endothelial associated, but not a pericyte associated, basement membrane component induces endothelial cell apoptosis and detachment. The results of the present study advance our understanding of pericyte biology and pericyte/endothelial cell cooperation during vascular patterning and have implications for the design of both pro- and antiangiogenic therapies.

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The Application of the Cold Atmospheric Plasma-Activated Solutions in Cancer Treatment

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666170731115233 ◽

2018 ◽

Vol 18 (6) ◽

pp. 769-775 ◽

Cited By ~ 13

Author(s):

Dayun Yan ◽

Jonathan H. Sherman ◽

Michael Keidar

Keyword(s):

Cancer Treatment ◽

Atmospheric Plasma ◽

Current Status ◽

Cold Atmospheric Plasma ◽

Anti Cancer ◽

Long Time ◽

Key Topics ◽

The Common

Background: Over the past five years, the cold atmospheric plasma-activated solutions (PAS) have shown their promissing application in cancer treatment. Similar as the common direct cold plasma treatment, PAS shows a selective anti-cancer capacity in vitro and in vivo. However, different from the direct cold atmospheric plasma (CAP) treatment, PAS can be stored for a long time and can be used without dependence on a CAP device. The research on PAS is gradually becoming a hot topic in plasma medicine. Objectives: In this review, we gave a concise but comprehensive summary on key topics about PAS including the development, current status, as well as the main conclusions about the anti-cancer mechanism achieved in past years. The approaches to make strong and stable PAS are also summarized.

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Genome wide effects of oleic acid on cultured bovine granulosa cells: evidence for the activation of pathways favoring folliculo-luteal transition

BMC Genomics ◽

10.1186/s12864-021-07817-6 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Vengala Rao Yenuganti ◽

Dirk Koczan ◽

Jens Vanselow

Keyword(s):

Oleic Acid ◽

Granulosa Cells ◽

System Development ◽

Circulatory System ◽

Bioinformatic Analysis ◽

Negative Energy ◽

Tissue Remodelling ◽

Gonadotropin Secretion ◽

Genome Wide

Abstract Background Metabolic stress, as negative energy balance on one hand or obesity on the other hand can lead to increased levels of free fatty acids in the plasma and follicular fluid of animals and humans. In an earlier study, we showed that increased oleic acid (OA) concentrations affected the function of cultured bovine granulosa cells (GCs). Here, we focus on genome wide effects of increased OA concentrations. Results Our data showed that 413 genes were affected, of which 197 were down- and 216 up-regulated. Specifically, the expression of FSH-regulated functional key genes, CCND2, LHCGR, INHA and CYP19A1 and 17-β-estradiol (E2) production were reduced by OA treatment, whereas the expression of the fatty acid transporter CD36 was increased and the morphology of the cells was changed due to lipid droplet accumulation. Bioinformatic analysis revealed that associated pathways of the putative upstream regulators “FSH” and “Cg (choriogonadotropin)” were inhibited and activated, respectively. Down-regulated genes are over-represented in GO terms “reproductive structure/system development”, “ovulation cycle process”, and “(positive) regulation of gonadotropin secretion”, whereas up-regulated genes are involved in “circulatory system development”, “vasculature development”, “angiogenesis” or “extracellular matrix/structure organization”. Conclusions From these data we conclude that besides inhibiting GC functionality, increased OA levels seemingly promote angiogenesis and tissue remodelling, thus suggestively initiating a premature fulliculo-luteal transition. In vivo this may lead to impeded folliculogenesis and ovulation, and cause sub-fertility.

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Inhibition of CCL7 derived from Mo-MDSCs prevents metastatic progression from latency in colorectal cancer

Cell Death and Disease ◽

10.1038/s41419-021-03698-5 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Xiaoli Ren ◽

Jianbiao Xiao ◽

Wanning Zhang ◽

Feifei Wang ◽

Yongrong Yan ◽

...

Keyword(s):

Colorectal Cancer ◽

Suppressor Cells ◽

Metastatic Progression ◽

Ht29 Cells ◽

Metastatic Cells ◽

Long Time ◽

Mice Liver ◽

Short Time ◽

Related Proteins

AbstractIn colorectal cancer (CRC), overt metastases often appear after years of latency. But the signals that cause micro-metastatic cells to remain indolent, thereby enabling them to survive for extended periods of time, are unclear. Immunofluorescence and co-immunoprecipitation assays were used to explore the co-localization of CCL7 and CCR2. Immunohistochemical (IHC) assays were employed to detect the characters of metastatic HT29 cells in mice liver. Flow cytometry assays were performed to detect the immune cells. Bruberin vivo MS FX Pro Imager was used to observe the liver metastasis of CRC in mice. Quantitative real-time PCR (qRT-PCR) and western blot were employed to detect the expressions of related proteins. Trace RNA sequencing was employed to identify differentially expressed genes in MDSCs from liver micro-M and macro-M of CRC in mice. Here, we firstly constructed the vitro dormant cell models and metastatic dormant animal models of colorectal cancer. Then we found that myeloid-derived suppressor cells (MDSCs) were increased significantly from liver micro-metastases to macro-metastases of CRC in mice. Moreover, monocytic MDSCs (Mo-MDSC) significantly promoted the dormant activation of micro-metastatic cells compared to polymorphonuclear MDSCs (PMN-MDSC). Mechanistically, CCL7 secreted by Mo-MDSCs bound with membrane protein CCR2 of micro-metastatic cells and then stimulated the JAK/STAT3 pathway to activate the dormant cells. Low-dose administration of CCL7 and MDSCs inhibitors in vivo could significantly maintain the CRC metastatic cells dormant status for a long time to reduce metastasis or recurrence after radical operation. Clinically, the level of CCL7 in blood was positively related to the number of Mo-MDSCs in CCR patients, and highly linked with the short-time recurrence and distant metastasis. CCL7 secreted by Mo-MDSCs plays an important role in initiating the outgrowth of metastatic latent CRC cells. Inhibition of CCL7 might provide a potential therapeutic strategy for the prevention of metastasis recurrence.

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Lankesterella (Apicomplexa, Lankesterellidae) Blood Parasites of Passeriform Birds: Prevalence, Molecular and Morphological Characterization, with Notes on Sporozoite Persistence In Vivo and Development In Vitro

Animals ◽

10.3390/ani11051451 ◽

2021 ◽

Vol 11 (5) ◽

pp. 1451

Author(s):

Carolina Romeiro Fernandes Chagas ◽

Josef Harl ◽

Vytautas Preikša ◽

Dovilė Bukauskaitė ◽

Mikas Ilgūnas ◽

...

Keyword(s):

Morphological Characterization ◽

Life Cycles ◽

Diagnostic Methods ◽

Host Cells ◽

Blood Parasites ◽

Serinus Canaria ◽

Long Time ◽

Development In Vitro

Recent studies confirmed that some Hepatozoon-like blood parasites (Apicomplexa) of birds are closely related to the amphibian parasite Lankesterella minima. Little is known about the biology of these pathogens in birds, including their distribution, life cycles, specificity, vectors, and molecular characterization. Using blood samples of 641 birds from 16 species, we (i) determined the prevalence and molecular diversity of Lankesterella parasites in naturally infected birds; (ii) investigated the development of Lankesterella kabeeni in laboratory-reared mosquitoes, Culex pipiens forma molestus and Aedes aegypti; and (iii) tested experimentally the susceptibility of domestic canaries, Serinus canaria, to this parasite. This study combined molecular and morphological diagnostic methods and determined 11% prevalence of Lankesterella parasites in Acrocephalidae birds; 16 Lankesterella lineages with a certain degree of host specificity and two new species (Lankesterella vacuolata n. sp. and Lankesterella macrovacuolata n. sp.) were found and characterized. Lankesterella kabeeni (formerly Hepatozoon kabeeni) was re-described. Serinus canaria were resistant after various experimental exposures. Lankesterella sporozoites rapidly escaped from host cells in vitro. Sporozoites persisted for a long time in infected mosquitoes (up to 42 days post exposure). Our study demonstrated a high diversity of Lankesterella parasites in birds, and showed that several avian Hepatozoon-like parasites, in fact, belong to Lankesterella genus.

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Persistent luminescent nanoparticles for super-long time in vivo and in situ imaging with repeatable excitation

Journal of Luminescence ◽

10.1016/j.jlumin.2013.08.070 ◽

2014 ◽

Vol 145 ◽

pp. 838-842 ◽

Cited By ~ 28

Author(s):

Meng Sun ◽

Zhan-Jun Li ◽

Chun-Lin Liu ◽

Hai-Xia Fu ◽

Jiang-Shan Shen ◽

...

Keyword(s):

Long Time ◽

Luminescent Nanoparticles ◽

In Situ Imaging

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Patterning Vascular Networks In Vivo for Tissue Engineering Applications

Tissue Engineering Part C Methods ◽

10.1089/ten.tec.2014.0258 ◽

2015 ◽

Vol 21 (5) ◽

pp. 509-517 ◽

Cited By ~ 26

Author(s):

Ritika R. Chaturvedi ◽

Kelly R. Stevens ◽

Ricardo D. Solorzano ◽

Robert E. Schwartz ◽

Jeroen Eyckmans ◽

...

Keyword(s):

Tissue Engineering ◽

Vascular Networks ◽

Engineering Applications

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Abstract 18332: EphrinB2/EphB4 Signaling controls the Dose-Dependent Switch between Normal and Aberrant Angiogenesis by VEGF

Circulation ◽

10.1161/circ.130.suppl_2.18332 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Elena Groppa ◽

Veronica Sacchi ◽

Sime Brkic ◽

Marianna Trani ◽

Michael Heberer ◽

...

Keyword(s):

Growth Factor ◽

Longitudinal Splitting ◽

Vascular Growth ◽

Over Expression ◽

Capillary Networks ◽

Endothelial Proliferation ◽

Mouse Limb ◽

Normal Networks ◽

Endothelial Growth Factor

Vascular Endothelial Growth Factor-A (VEGF) is the master regulator of vascular growth and it can induce either normal or aberrant angiogenesis depending on its dose in the microenvironment around each producing cell in vivo, and not on the total amount. However, stimulation of pericyte recruitment by co-expression of Platelet Derived Growth Factor-BB (PDGF-BB) could prevent aberrant structures despite heterogeneous and high VEGF levels and switch to homogeneously normal angiogenesis. Here we dissected the role of specific pericyte-mediated signaling pathways in the switch between normal and aberrant angiogenesis by VEGF. Monoclonal populations of transduced myoblasts were used to homogeneously express specific VEGF doses, inducing either normal or aberrant angiogenesis, and were further transduced to secrete soluble blockers of the TGFβ-1/TGFβ-R, Tie2/Angiopoietin or EphB4/EphrinB2 pathways (LAP, sTie2Fc and sEphB4, respectively). Two weeks after implantation into mouse limb muscles, neither TGFβ nor Angiopoietin blockade altered the normal angiogenesis by low VEGF, whereas EphrinB2/EphB4 inhibition caused a switch to aberrant angioma-like structures, similar to the effects of blocking pericyte recruitment. Conversely, gain-of-function of EphB4 signaling by systemic treatment with recombinant EphrinB2-Fc completely prevented aberrant angiogenesis by high VEGF levels and yielded normal networks of mature capillaries. We recently found that VEGF over-expression in muscle induces angiogenesis without sprouting, but by circumferential enlargement and longitudinal splitting (intussusception). EphB4 inhibition increased both endothelial proliferation and the diameter of initial enlargements induced by low VEGF (4 days), leading to a failure of splitting and progressive angioma growth. However, it did not interfere with pericyte recruitment, contrary to high VEGF alone. Conversely, EphB4 stimulation decreased both endothelial proliferation and the diameter of enlargements induced by high VEGF to values similar to low VEGF alone, and accelerated splitting into pericyte-covered capillary networks. In conclusion, EphrinB2/EphB4 signaling can prevent VEGF-induced aberrant angiogenesis by regulating intussusception.

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Abstract 290: Haemogenic Endocardium Contribute To Definitive Hematopoiesis During Cardiogenesis

Circulation Research ◽

10.1161/res.113.suppl_1.a290 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Haruko Nakano ◽

Xiaoqian Liu ◽

Armin Arshi ◽

Ben van Handel ◽

Rajkumar Sasidharan ◽

...

Keyword(s):

De Novo ◽

Ex Vivo ◽

Embryonic Stem ◽

Circulatory System ◽

Lineage Tracing ◽

Mouse Heart ◽

Heart Tube ◽

Cardiac Progenitors ◽

Definitive Hematopoiesis

The circulatory system is the first functional organ system that develops during mammalian life. Accumulating evidences suggest that cardiac and endocardial cells can arise from a single common progenitor cell during mammalian cardiogenesis. Notably, these early cardiac progenitors express multiple hematopoietic transcription factors, consistent with previous reports. Indeed, a close relationship among cardiac, endocardial and hematopoietic lineages has been suggested in fly, zebrafish, and embryonic stem cell in vitro differentiation models. However, it is unclear when, where and how this hematopoietic gene program is in operation during in vivo mammalian cardiogenesis. Hematopoietic colony assay suggests that mouse heart explants generate myeloids and erythroids in the absence of circulation, suggesting that the heart tube is a de novo site for the definitive hematopoiesis. Lineage tracing revealed that putative cardiac-derived Nkx2-5+/Isl1+ endocardial cells give rise to CD41+ hematopoietic progenitors that contribute to definitive hematopoiesis in vivo and ex vivo during embryogenesis earlier than in the AGM region. Furthermore, Nkx2-5 and Isl1 are both required for the hemogenic activity of the endocardium. Together, identification of Nkx2-5/Isl1-dependent hemogenic endocardial cells (1) adds hematopoietic component in the cardiogenesis lineage tree, (2) changes the long-held dogma that AGM is the only major source of definitive hematopoiesis in the embryo proper, and (3) represents phylogenetically conserved fundamental mechanism of cardio-vasculo-hematopoietic differentiation pathway during the development of circulatory system.

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Platelets Disseminate Extracellular Vesicles in Lymph in Rheumatoid Arthritis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.119.313698 ◽

2020 ◽

Vol 40 (4) ◽

pp. 929-942 ◽

Cited By ~ 4

Author(s):

Nicolas Tessandier ◽

Imene Melki ◽

Nathalie Cloutier ◽

Isabelle Allaeys ◽

Adam Miszta ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Extracellular Vesicles ◽

Lymphatic System ◽

Circulatory System ◽

Donor Cell ◽

Vascular Leakage ◽

In Vivo Model ◽

Interstitial Tissue ◽

Tissue Fluid

Objective: The lymphatic system is a circulatory system that unidirectionally drains the interstitial tissue fluid back to blood circulation. Although lymph is utilized by leukocytes for immune surveillance, it remains inaccessible to platelets and erythrocytes. Activated cells release submicron extracellular vesicles (EV) that transport molecules from the donor cell. In rheumatoid arthritis, EV accumulate in the joint where they can interact with numerous cellular lineages. However, whether EV can exit the inflamed tissue to recirculate is unknown. Here, we investigated whether vascular leakage that occurs during inflammation could favor EV access to the lymphatic system. Approach and Results: Using an in vivo model of autoimmune inflammatory arthritis, we show that there is an influx of platelet EV, but not EV from erythrocytes or leukocytes, in joint-draining lymph. In contrast to blood platelet EV, lymph platelet EV lacked mitochondrial organelles and failed to promote coagulation. Platelet EV influx in lymph was consistent with joint vascular leakage and implicated the fibrinogen receptor α2bβ 3 and platelet-derived serotonin. Conclusions: These findings show that platelets can disseminate their EV in fluid that is inaccessible to platelets and beyond the joint in this disease.

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