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

Volk-Draper, Lisa D.; Hall, Kelly; Wilber, Andrew; Ran, Sophia

doi:10.1371/journal.pone.0179257

Cited by 28 publications

(63 citation statements)

References 57 publications

(152 reference statements)

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“…In our studies performed in tumor-bearing immunocompetent and immunodeficient mice, we often observe a transiently reduced growth upon injection of TLR4-differentiated myeloid progenitors. However, tumor growth resumes at later stages along with substantial increase in lymph node metastasis which correlates with injection of myeloid-derived progenitors [18]. These studies suggest that development of either TLR4-suppressing or TLR4-activating therapeutic strategies should take into account the impact of modulators on all TLR4-positive cells at both tumor and systemic organs.…”

Section: Cellular and Molecular Consequences Of Tlr4 Activation In Thmentioning

confidence: 84%

“…Osteoclasts, macrophage-like cells in the bone marrow, also express TLR4 [13]. Embryonic stem cells [14] as well as adult hematopoietic-myeloid [15], lymphoid [15], mesenchymal [16], blood vascular endothelial [17], and lymphatic endothelial [18] progenitors all express TLR4 and signaling components of this pathway. Among non-hematopoietic cells, TLR4 is expressed in blood vascular [19] and lymphatic [20] endothelia as well as at low concentration in fibroblasts [21], keratinocytes [22], and epithelial cells of most normal organs including the colon [23], intestine [24], ovary [25], kidney [26], and lungs [27].…”

Section: Tlr4 Expression In Normal Organsmentioning

confidence: 99%

“…Given the TLR4 role in homeostasis, it is not surprising that it activates and induces differentiation of BM-derived progenitors from myeloid and lymphoid lineages [15], mesenchymal stem cells [16], blood vascular endothelial progenitors [17], lymphatic endothelial progenitors [18], and local tissue epithelial stem cells [14]. Chemokines recruiting these progenitors are produced by local stroma and epithelium as demonstrated by TLR4-dependent upregulation of a variety of cytokines in inflamed fibroblasts [42], hepatic stellate cells [44], as well as intestinal [45], alveolar [27], ovarian [25], and renal [26] epithelial cells.…”

Section: Physiological Functions Of Tlr4 In Normal Organsmentioning

confidence: 99%

“…The requirement for MD2 turned out to be particularly contentious as several studies reported an exclusive specificity of mouse but not human MD2 in supporting PXL-induced signaling [142,143]. The implication would be that PXL affects only cells from the mouse specie, but this contradicts extensive evidence demonstrating functional LPSmimetic effects of PXL on human tumor cells ( Table 2) and normal monocytes [18]. One group found that PXL does bind to human TLR4/MD2 complex but acts as an antagonist [143].…”

Section: Chemotherapeutic Drug Paclitaxel As a Tlr4 Ligand And A Prommentioning

confidence: 99%

“…The effects on host immune and hematopoietic cells are not straightforward as improved DC functions are counterbalanced by increased generation of myeloid-derived suppressor cells [171] that inhibit antitumor responses. TLR4 activation of BM immature myeloid cells leads to generation of provascular progenitors [17,18] that increase tumor vessel formation and metastasis [136,172]. Lung recruitment of the host BM-derived myeloid cells by TLR4 ligands SAA3 in combination with S100A8/A9 has been shown to create a pulmonary pre-metastatic niche, thus ensuring successful establishment of tumor lesions in distant organs [147].…”

Section: Cellular and Molecular Consequences Of Tlr4 Activation In Thmentioning

confidence: 99%

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TLR4-Induced Inflammation Is a Key Promoter of Tumor Growth, Vascularization, and Metastasis

Ran¹,

Bhattarai²,

Patel³

et al. 2020

Translational Studies on Inflammation

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Toll-like receptor-4 (TLR4) is a powerful pathway best known for inducing inflammation in response to bacteria-produced lipopolysaccharide. TLR4 is also activated by endogenous ligands produced by host-damaged cells and a chemo-drug paclitaxel. Under normal conditions, TLR4 is expressed mainly in macrophages and, at a lower level, in epithelial, endothelial, and stromal cells. Activated TLR4 significantly increases inflammatory cytokines and enhances cell proliferation, migration, invasion, and survival. While these functions in normal cells are essential for host defense and tissue repair, TLR4 overexpression in malignant cells promotes tumor growth and metastasis. This is because pro-oncogenic effects of activated TLR4 in tumor cells are amplified by similar event in TLR4-positive tumor-associated cells including endothelial cells and their mobilized progenitors. The collective activation of multiple cell types within the tumor promotes chemoresistance and metastasis. Here, we summarize the current knowledge of the TLR4 pathway and its functional outcomes in normal and tumor cells. We also discuss its underappreciated role in supporting tumor progression through vascular activation and recruitment of endothelial progenitors. The review considers several open questions regarding the impact of TLR4-mediated pro-and antitumor effects, structural requirements for recognition of the TLR4 complex, and a potential contribution of chemotherapy to tumor spread.

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Section: Cellular and Molecular Consequences Of Tlr4 Activation In Thmentioning

confidence: 84%

Section: Tlr4 Expression In Normal Organsmentioning

confidence: 99%

Section: Physiological Functions Of Tlr4 In Normal Organsmentioning

confidence: 99%

Section: Chemotherapeutic Drug Paclitaxel As a Tlr4 Ligand And A Prommentioning

confidence: 99%

Section: Cellular and Molecular Consequences Of Tlr4 Activation In Thmentioning

confidence: 99%

See 3 more Smart Citations

TLR4-Induced Inflammation Is a Key Promoter of Tumor Growth, Vascularization, and Metastasis

Ran¹,

Bhattarai²,

Patel³

et al. 2020

Translational Studies on Inflammation

Self Cite

View full text Add to dashboard Cite

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Lymphatic Endothelial Cell Progenitors in the Tumor Microenvironment

Ran

Volk-Draper

2020

Advances in Experimental Medicine and Biology

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Tumor lymphatics play a key role in cancer progression as they are solely responsible for transporting malignant cells to regional lymph nodes (LNs), a process that precedes and promotes systemic lethal spread. It is broadly accepted that tumor lymphatic sprouting is induced mainly by soluble factors derived from tumor-associated macrophages (TAMs) and malignant cells. However, emerging evidence strongly suggests that a subset of TAMs, myeloid-lymphatic endothelial cell progenitors (M-LECP), also contribute to the expansion of lymphatics through both secretion of paracrine factors and a self-autonomous mode. M-LECP are derived from bone marrow (BM) precursors of the monocyte-macrophage lineage and characterized by unique coexpression of markers identifying lymphatic endothelial cells (LEC), stem cells, M2-type macrophages, and myeloid-derived immunosuppressive cells. This review describes current evidence for the origin of M-LECP in the bone marrow, their recruitment tumors and intratumoral trafficking, similarities to other TAM subsets, and mechanisms promoting tumor lymphatics. We also describe M-LECP integration into preexisting lymphatic vessels and discuss potential mechanisms and significance of this event. We conclude that improved mechanistic understanding of M-LECP functions within the tumor environment may lead to new therapeutic approaches to suppress tumor lymphangiogenesis and metastasis to lymph nodes.

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Chemotherapy-induced metastasis: mechanisms and translational opportunities

Karagiannis

Condeelis

Oktay

2018

Clin Exp Metastasis

109

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Tumors often overcome the cytotoxic effects of chemotherapy through either acquired or environment-mediated drug resistance. In addition, signals from the microenvironment obfuscate the beneficial effects of chemotherapy and may facilitate progression and metastatic dissemination. Seminal mediators in chemotherapy-induced metastasis appear to be a wide range of hematopoietic, mesenchymal and immune progenitor cells, originating from the bone marrow. The actual purpose of these cells is to orchestrate the repair response to the cytotoxic damage of chemotherapy. However, these repair responses are exploited by tumor cells at every step of the metastatic cascade, ranging from tumor cell invasion, intravasation and hematogenous dissemination to extravasation and effective colonization at the metastatic site. A better understanding of the mechanistic underpinnings of chemotherapy-induced metastasis will allow us to better predict which patients are more likely to exhibit pro-metastatic responses to chemotherapy and will help develop new therapeutic strategies to neutralize chemotherapy-driven prometastatic changes.

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

Cited by 28 publications

References 57 publications

TLR4-Induced Inflammation Is a Key Promoter of Tumor Growth, Vascularization, and Metastasis

TLR4-Induced Inflammation Is a Key Promoter of Tumor Growth, Vascularization, and Metastasis

Lymphatic Endothelial Cell Progenitors in the Tumor Microenvironment

Chemotherapy-induced metastasis: mechanisms and translational opportunities

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