Myeloid-Derived Lymphatic Endothelial Cell Progenitors Significantly Contribute to Lymphatic Metastasis in Clinical Breast Cancer

Volk-Draper, Lisa D.; Patel, Radhika R.; Bhattarai, Nihit; Yang, Jie; Wilber, Andrew; DeNardo, David G.; Ran, Sophia

doi:10.1016/j.ajpath.2019.07.006

Cited by 25 publications

(63 citation statements)

References 91 publications

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“…Similarly, bone marrow derived GFP+/CD11+/PDPN+ cells injected into mice bearing EMT6 orthotopic breast carcinomas, augmented as well lymphatic vessel density (Volk-Draper et al, 2017). In a different study, Volk-Draper et al (2019) showed that in vitro TLR4-mediated differentiated M-LECP inoculated in different breast cancer mice models were able to increase LYVE1+ lymphatic density, thereby resulting in a substantial increment in lymphatic metastasis. Moreover, other studies have reported the effect of blocking of myeloid cells in tumor lymphatic vasculature.…”

Section: The Cellular Origins Of Cancer Lymphaticsmentioning

confidence: 94%

“…A follow-up study suggested that the tumors might boost the release of myeloid precursors, since CD14+ monocytes expressing LEC specific markers were abundant, albeit being nearly absent in healthy donors. In addition, M-LECPs expressing high levels of LYVE1, PDPN, PROX1 and VEGFR3 were uniquely detected in the lymph vessels of breast cancer tissue and their density correlated with the development of lymphatic metastasis in breast cancer patients (Volk-Draper et al, 2019).…”

Section: The Cellular Origins Of Cancer Lymphaticsmentioning

confidence: 95%

“…Moreover, other studies have reported the effect of blocking of myeloid cells in tumor lymphatic vasculature. Inhibition of bone marrow myeloid cell recruitment abolished M-LECPs integration into the lymphatic vessels and reduced tumor lymphatic vessel density (Volk-Draper et al, 2019). Systemic depletion of macrophages in an orthotopic urinary bladder cancer (OUBC) model also caused a decrease in tumor LYVE1+ lymphatic vessel density (Yang et al, 2011).…”

Section: The Cellular Origins Of Cancer Lymphaticsmentioning

confidence: 99%

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Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis

Gutierrez-Miranda

Yaniv

2020

Front. Physiol.

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The lymphatic system plays important roles in physiological and pathological conditions. During cancer progression in particular, lymphangiogenesis can exert both positive and negative effects. While the formation of tumor associated lymphatic vessels correlates with metastatic dissemination, increased severity and poor patient prognosis, the presence of functional lymphatics is regarded as beneficial for anti-tumor immunity and cancer immunotherapy delivery. Therefore, a profound understanding of the cellular origins of tumor lymphatics and the molecular mechanisms controlling their formation is required in order to improve current strategies to control malignant spread. Data accumulated over the last decades have led to a controversy regarding the cellular sources of tumor-associated lymphatic vessels and the putative contribution of nonendothelial cells to this process. Although it is widely accepted that lymphatic endothelial cells (LECs) arise mainly from pre-existing lymphatic vessels, additional contribution from bone marrow-derived cells, myeloid precursors and terminally differentiated macrophages, has also been claimed. Here, we review recent findings describing new origins of LECs during embryonic development and discuss their relevance to cancer lymphangiogenesis.

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Section: The Cellular Origins Of Cancer Lymphaticsmentioning

confidence: 94%

Section: The Cellular Origins Of Cancer Lymphaticsmentioning

confidence: 95%

Section: The Cellular Origins Of Cancer Lymphaticsmentioning

confidence: 99%

See 1 more Smart Citation

Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis

Gutierrez-Miranda

Yaniv

2020

Front. Physiol.

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“…Similarly, lymphatic beds may consist of LECs derived from heterogeneous sources. Recent findings [46] show that the level of circulating myeloid derived lymphatic endothelial progenitor cells, as determined by co-staining of myeloid and LEC markers, strongly correlate with lymphatic metastasis in breast cancer patients. These progenitor cells were shown to incorporate into lymphatic vessels in human and mouse tumors ( Figure 1).…”

Section: Metastasis Independent Of Lymphatic Endothelial Cell Sproutingmentioning

confidence: 99%

“…TAMs are also associated with high lymphatic vessel density and lymphatic metastasis (Figure 1). Macrophages may contribute directly to the lymphatic vasculature through transdifferentiation [49], progenitor differentiation [46], and vascular mimicry [62,63] or indirectly by secretion of pro-lymphangiogenic factors [64]. VEGF-C acts as a chemotactic factor for VEGFR-3 expressing macrophages [65].…”

Section: Myeloid Cell Recruitmentmentioning

confidence: 99%

Parallels of Resistance between Angiogenesis and Lymphangiogenesis Inhibition in Cancer Therapy

Jones

2020

Cells

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Metastasis is the primary cause of cancer-related mortality. Cancer cells primarily metastasize via blood and lymphatic vessels to colonize lymph nodes and distant organs, leading to worse prognosis. Thus, strategies to limit blood and lymphatic spread of cancer have been a focal point of cancer research for several decades. Resistance to FDA-approved anti-angiogenic therapies designed to limit blood vessel growth has emerged as a significant clinical challenge. However, there are no FDA-approved drugs that target tumor lymphangiogenesis, despite the consequences of metastasis through the lymphatic system. This review highlights several of the key resistance mechanisms to anti-angiogenic therapy and potential challenges facing anti-lymphangiogenic therapy. Blood and lymphatic vessels are more than just conduits for nutrient, fluid, and cancer cell transport. Recent studies have elucidated how these vasculatures often regulate immune responses. Vessels that are abnormal or compromised by tumor cells can lead to immunosuppression. Therapies designed to improve lymphatic vessel function while limiting metastasis may represent a viable approach to enhance immunotherapy and limit cancer progression.

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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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Myeloid-Derived Lymphatic Endothelial Cell Progenitors Significantly Contribute to Lymphatic Metastasis in Clinical Breast Cancer

Cited by 25 publications

References 91 publications

Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis

Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis

Parallels of Resistance between Angiogenesis and Lymphangiogenesis Inhibition in Cancer Therapy

Lymphatic Endothelial Cell Progenitors in the Tumor Microenvironment

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