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Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis.

ABSTRACT: 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 non-endothelial 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.

SUBMITTER: Gutierrez-Miranda L

PROVIDER: S-EPMC7541848 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis.

Gutierrez-Miranda Laura L Yaniv Karina K

Frontiers in physiology 20200924

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 ...[more]

PMID: 33071831

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Project description:BACKGROUND:Infiltration into lymphatic vessels is a critical step in breast cancer metastasis. Lymphatics undergo changes that facilitate metastasis as a result of activation of the cells lining lymphatic vessels, lymphatic endothelial cells (LECs). Inhibition of activation by targeting VEGFR3 can reduce invasion toward lymphatics. To best benefit patients, this approach should be coupled with standard of care that slows tumor growth, such as chemotherapy. Little is known about how chemotherapies, like docetaxel, may influence lymphatics and conversely, how lymphatics can alter responses to therapy. METHODS:A novel 3D in vitro co-culture model of the human breast tumor microenvironment was employed to examine the contribution of LECs to tumor invasion and viability with docetaxel and anti-VEGFR3, using three cell lines, MDA-MB-231, HCC38, and HCC1806. In vivo, the 4T1 mouse model of breast carcinoma was used to examine the efficacy of combinatorial therapy with docetaxel and anti-VEGFR3 on lymph node metastasis and tumor growth. Lymphangiogenesis in these mice was analyzed by immunohistochemistry and flow cytometry. Luminex analysis was used to measure expression of lymphangiogenic cytokines. RESULTS:In vitro, tumor cell invasion significantly increased with docetaxel when LECs were present; this effect was attenuated by inhibition of VEGFR3. LECs reduced docetaxel-induced cell death independent of VEGFR3. In vivo, docetaxel significantly increased breast cancer metastasis to the lymph node. Docetaxel and anti-VEGFR3 combination therapy reduced lymph node and lung metastasis in 4T1 and synergized to reduce tumor growth. Docetaxel induced VEGFR3-dependent vessel enlargement, lymphangiogenesis, and expansion of the LEC population in the peritumoral microenvironment, but not tumor-free stroma. Docetaxel caused an upregulation in pro-lymphangiogenic factors including VEGFC and TNF-? in the tumor microenvironment in vivo. CONCLUSIONS:Here we present a counter-therapeutic effect of docetaxel chemotherapy that triggers cancer cells to elicit lymphangiogenesis. In turn, lymphatics reduce cancer response to docetaxel by altering the cytokine milieu in breast cancer. These changes lead to an increase in tumor cell invasion and survival under docetaxel treatment, ultimately reducing docetaxel efficacy. These docetaxel-induced effects can be mitigated by anti-VEGFR3 therapy, resulting in a synergism between these treatments that reduces tumor growth and metastasis.

Dataset Information

Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis.

Publications

Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis.

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