Possible involvement of tumor-producing VEGF-A in the recruitment of lymphatic endothelial progenitor cells from bone marrow

Tawada, Masahiro; Hayashi, Shinichiro; Ikegame, Yuka; Yoshida, Kazuhiro

doi:10.3892/or.2014.3499

Cited by 17 publications

(26 citation statements)

References 32 publications

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“…Despite multiple reports demonstrating integration of lymphatic progenitors into preexisting lymphatic vessels [12,15,29] and their role in increasing the number of these vessels [25,32], the evidence for impact of progenitors on lymphatic function is still very limited. Specifically, neither endogenous nor exogenous M-LECP were shown to directly affect tumor growth and metastasis.…”

Section: Resultsmentioning

confidence: 99%

“…Such pro-lymphatic reprogramming has been shown for human monocytes isolated from peripheral or cord blood [24,27], human pluripotent stem cell lines [25], mouse embryonic cells [28], mouse BM-derived CD11b + and mononuclear cells [13,16,29], mouse and human mesenchymal stem cells [30] and adipose-derived stem cells [31]. The main criteria for defining differentiated cells as LECP are as follows: 1) expression of specific LEC markers [16,24,25,27]; 2) acquisition of an endothelial-specific cobblestone morphology and/or ability to form tubes when grown in matrigel [16]; 3) demonstrated function in vivo evidenced by integration into lymphatic vessels [12,15,22] and a statistically significant increase in lymphatic vessel density (LVD) in inflammatory and tissue remodeling models [24,25,32]; and 4) evidence for enhanced functionality of new lymphatics such as improved relief from lymphedema [32] and an accelerated rate of healing wounds [25].…”

Section: Introductionmentioning

confidence: 99%

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Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4

et al. 2017

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BackgroundMyeloid-derived lymphatic endothelial cells (M-LECP) are induced by inflammation and play an important role in adult lymphangiogenesis. However, the mechanisms driving M-LECP differentiation are currently unclear. We previously showed that activation of Toll-like receptor-4 (TLR4) induces myeloid-lymphatic transition (MLT) of immortalized mouse myeloid cells. Here the goals were to assess the potential of different TLR4 ligands to induce pro-lymphatic reprogramming in human and mouse primary myeloid cells and to identify transcriptional changes regulating this process.Methodology/Principal findingsHuman and mouse myeloid cells were reprogrammed to the lymphatic phenotype by TLR4 ligands including lipopolysaccharide (LPS), recombinant high mobility group box 1 protein (HMGB1), and paclitaxel. TLR4 induced similar MLT in cells from mice of different strains and immune status. Commonly induced genes were detected by transcriptional profiling in human and mouse myeloid cells from either immunocompetent or immunodeficient mice. Shared trends included: (1) novel expression of lymphatic-specific markers vascular endothelial growth factor receptor-3 (VEGFR-3), lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and podoplanin (PDPN) largely absent prior to induction; (2) lack of notable changes in blood vessel-specific markers; (3) transient expression of VEGFR-3, but sustained increase of vascular endothelial growth factor-C (VEGF-C) and a variety of inflammatory cytokines; (4) dependency of VEGFR-3 upregulation and other LEC genes on NF-κB; and (5) novel expression of lymphatic-specific (e.g., PROX1) and stem/progenitor (e.g., E2F1) transcription factors known for their roles in adult and embryonic vascular formation. M-LECP generated by TLR4 ligands in vitro were functional in vivo as demonstrated by significantly increased lymphatic vessel density and lymphatic metastasis detected in orthotopic breast cancer models.Conclusions/SignificanceWe established a novel TLR4-dependent protocol for in vitro production of functionally competent M-LECP from primary human or mouse myeloid cells and identified many potential regulators of this process. This information can be further exploited for research and therapeutic purposes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4

et al. 2017

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“…In presence of PRDM16, Myf5 + precursor populations acquire brown fat characteristics specific for “classical” brown adipocytes (52). On the other hand, PRDM16 can also influence the fate of Myf5 − precursors present mostly in the white adipocytes to acquire brown-like phenotype expressing “beige-specific” markers (53). We observed significant enrichment of both classical BAT progenitors including Myf5 and Oplah, as well as the beige adipocyte-specific markers Cd137 and Tbx1 during xenograft development, suggesting that both populations increase UCP1 expression as well as contribute to breast tumor development.…”

Section: Discussionmentioning

confidence: 99%

“…It has been well demonstrated that breast tumor cells recruit BM-MSCs, hematopoietic cells including macrophages, as well as many other cell types from the host to promote its growth (53–54). Since substantial amount of beige adipose markers of host origin was found in the xenografts, we have been examining whether they were recruited from the microenvironment or from distant sites of the host.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Beige/Brown Adipose Markers from Host and Breast Cancer Cells Influence Xenograft Formation in Mice

Singh

Parveen

Basgen

et al. 2016

Molecular Cancer Research

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The initiation and progression of breast cancer is a complex process that is influenced by heterogeneous cell populations within the tumor microenvironment (TME). Although adipocytes have been shown to promote breast cancer development, adipocyte characteristics involved in this process remain poorly understood. In this study, we demonstrate enrichment of beige/brown adipose markers, contributed from the host as well as tumor cells, in the xenografts from breast cancer cell lines. In addition to uncoupling protein-1 (UCP1) that is exclusively expressed in beige/brown adipocytes, gene expression for classical brown (MYF5, EVA1 and OPLAH), as well as beige (CD137/TNFRSF9 and TBX1) adipocyte markers, were also elevated in the xenografts. Enrichment of beige/brown characteristics in the xenografts was independent of the site of implantation of the breast tumor cells. Early stages of xenografts showed an expansion of a subset of mammary cancer stem cells (MCSCs) that expressed PRDM16, a master regulator of brown adipocyte differentiation. Depletion of UCP1+ or Myf5+ cells significantly reduced tumor development. There was increased COX-2 (MT-CO2) expression, which is known to stimulate formation of beige adipocytes in early xenografts and treatment with a COX-2 inhibitor (SC236) reduced tumor growth. By contrast, treatment with factors that induce brown adipocyte differentiation in vitro led to larger tumors in vivo. A panel of xenografts derived from established breast tumor cells as well as patient-tumor tissues were generated that expressed key brown adipose tissue (BAT)-related markers and contained cells that morphologically resembled brown adipocytes. Implications This is the first report demonstrating that beige /brown adipocyte characteristics could play an important role in breast tumor development and suggest a potential target for therapeutic drug design.

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“…VEGF-A is considered as a molecule that stimulates angiogenesis, mostly via VEGF receptor 2, but also has some potential to stimulate some forms of lymphangiogenesis, especially in inflammation or tumor growth. VEGF-A acts indirectly via macrophages, stimulating the production of VEGF-C and VEGF-D, but it may also directly trigger the expression of Lyve-1 in bone marrow-derived lymphatic endothelial progenitor cells in vitro [35,36]. Overexpression of VEGF-A 164 leads to the formation of giant lymphatic vessels in the mouse ear [37].…”

Section: Discussionmentioning

confidence: 99%

Mouse Proepicardium Exhibits a Sprouting Response to Exogenous Proangiogenic Growth Factors in vitro

Niderla-Bielińska

Ciszek²,

Jankowska‐Steifer³

et al. 2016

J Vasc Res

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Angiogenesis contributes to the generation of the vascular bed but also affects the progression of many diseases, such as tumor growth. Many details of the molecular pathways controlling angiogenesis are still undefined due to the lack of appropriate models. We propose the proepicardial explant as a suitable model for studying certain aspects of angiogenesis. The proepicardium (PE) is a transient embryonic structure that contains a population of undifferentiated endothelial cells (ECs) forming a vascular net continuous with the sinus venosus. In this paper, we show that PE explants give rise to CD31-positive vascular sprouts in the presence of basic fibroblast growth factor (bFGF) and 2 isoforms of vascular endothelial growth factor A (VEGF-A), i.e. VEGF-A₁₂₀ and VEGF-A₁₆₄. Vascular sprouts exhibit differences in number, length, thickness and the number of branches, depending on the combination of growth factors used. Moreover, the ECs of the sprouts express various levels of mRNA for Notch1 and its ligand Dll4. Additionally, stimulation with bFGF/VEGF-A164 upregulates the expression of Lyve-1 antigen in the ECs in the sprouts. In summary, we present a new model for angiogenesis studies involving mouse PE as a source of ECs. We believe that our model may act as a supplementary assay for angiogenesis studies along with the existing models.

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Possible involvement of tumor-producing VEGF-A in the recruitment of lymphatic endothelial progenitor cells from bone marrow

Cited by 17 publications

References 32 publications

Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4

Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4

Increased Expression of Beige/Brown Adipose Markers from Host and Breast Cancer Cells Influence Xenograft Formation in Mice

Mouse Proepicardium Exhibits a Sprouting Response to Exogenous Proangiogenic Growth Factors in vitro

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