Lymphatic Vessels in Tumor Dissemination versus Immunotherapy

Vaahtomeri, Kari; Alitalo, Kari

doi:10.1158/0008-5472.can-20-0156

Cited by 50 publications

(29 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tumor lymphatic vessels connect primary tumor cells and lymph nodes. Consequently, cancer cells invade the lymph nodes to move to other organs [29]. In the present study, we found that TGF-β signaling is involved in lymphatic drainage, in addition to confirming structural abnormalities of lymphatic vessels by the loss of LEC-specific TGF-β signaling.…”

Section: Discussionsupporting

confidence: 78%

Endothelial-specific depletion of TGF-β signaling affects lymphatic function

et al. 2021

View full text Add to dashboard Cite

Background Transforming growth factor (TGF)-β is a multifunctional cytokine involved in cell differentiation, cell proliferation, and tissue homeostasis. Although TGF-β signaling is essential for maintaining blood vessel functions, little is known about the role of TGF-β in lymphatic homeostasis. Methods To delineate the role of TGF-β signaling in lymphatic vessels, TβRIIfl/fl mice were crossed with Prox1-CreERT2 mice to generate TβRIIfl/fl; Prox1-CreERT2 mice. The TβRII gene in the lymphatic endothelial cells (LECs) of the conditional knockout TβRIIiΔLEC mice was selectively deleted using tamoxifen. The effects of TβRII gene deletion on embryonic lymphangiogenesis, postnatal lymphatic structure and drainage function, tumor lymphangiogenesis, and lymphatic tumor metastasis were investigated. Results Deficiency of LEC-specific TGF-β signaling in embryos, where lymphangiogenesis is active, caused dorsal edema with dilated lymphatic vessels at E13.5. Postnatal mice in which lymphatic vessels had already been formed displayed dilation and increased bifurcator of lymphatic vessels after tamoxifen administration. Similar dilation was also observed in tumor lymphatic vessels. The drainage of FITC-dextran, which was subcutaneously injected into the soles of the feet of the mice, was reduced in TβRIIiΔLEC mice. Furthermore, Lewis lung carcinoma cells constitutively expressing GFP (LLC-GFP) transplanted into the footpads of the mice showed reduced patellar lymph node metastasis. Conclusion These data suggest that TGF-β signaling in LECs maintains the structure of lymphatic vessels and lymphatic homeostasis, in addition to promoting tumor lymphatic metastasis. Therefore, suppression of TGF-β signaling in LECs might be effective in inhibiting cancer metastasis.

show abstract

Section: Discussionsupporting

confidence: 78%

Endothelial-specific depletion of TGF-β signaling affects lymphatic function

et al. 2021

View full text Add to dashboard Cite

show abstract

“…During cancer progression lymphatic vessels can play dual roles (reviewed in Oliver et al, 2020 ; Petrova and Koh, 2020 ; Vaahtomeri and Alitalo, 2020 ). On the one hand, they promote tumor metastasis by providing malignant cells with an escape conduit for dissemination toward the lymph nodes and distal metastatic niches.…”

Section: Structure and Functions Of The Lymphatic Systemmentioning

confidence: 99%

“…Once the solid tumor becomes vascularized, there is a rapid switch from a dormant to a malignant state that promotes further growth and tissue dissemination ( Lugano et al, 2020 ). In addition to blood ECs, lymphatic vessels are also present in the tumor microenvironment, and are considered to play an active role in primary tumor progression, metastatic spread and immunomodulation ( Stacker et al, 2014 ; Garnier et al, 2019 ; Oliver et al, 2020 ; Petrova and Koh, 2020 ; Vaahtomeri and Alitalo, 2020 ). On the one hand, tumor-associated lymphatics uptake the interstitial fluid containing cells and macromolecules of tumor mass origin, and drain them to the sentinel lymph node.…”

Section: Formation Of Cancer-associated Lymphaticsmentioning

confidence: 99%

Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis

Gutierrez-Miranda

Yaniv

2020

Front. Physiol.

View full text Add to dashboard Cite

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.

show abstract

“…13 In addition to facilitating tumor metastasis, increased tumor-associated lymphangiogenesis may also modulate immune response as the major function of lymphatic system is to transport tumor antigens by dendritic cells to lymph nodes, presenting to T-lymphocytes and initiate adaptive immune response. 14 Therefore, lymphangiogenesis can enhance the efficacy of immunotherapy in some tumor models. However, since tumors can produce immunosuppressive molecules to attenuate anti-tumor immunity, lymphangiogenesis may still serve as a pro-metastatic function in cancer progression (Figure 1).…”

Section: Lymphatic Metastasis and Lymphangiogenesis In Cancer Progressionmentioning

confidence: 99%

Regulation of lymphangiogenesis by extracellular vesicles in cancer metastasis

Wang

Tsai

2021

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Metastasis is not only one of the hallmarks of cancer but, unfortunately, it also is the most accurate biomarker for poor prognosis. Cancer cells metastasize through two different but eventually merged routes, the vasculature and lymphatic systems. The processes of cancer metastasis through blood vessel have been extensively studied and are well documented in the literature. In contrast, metastasis through the lymphatic system is less studied. Most people believe that cancer cells metastasize through lymphatic vessel are passive because the lymphatic system is thought to be a sewage draining system that collects whatever appears in the tissue fluid. It was recently found that cancer cells disseminated from lymphatic vessels are protected from being destroyed by our body’s defense system. Furthermore, some cancer cells or cancer-associated immune cells secrete lymphangiogenic factors to recruit lymphatic vessel infiltration to the tumor region, a process known as lymphangiogenesis. To ensure the efficiency of lymphangiogenesis, the lymphangiogenic mediators are carried or packed by nanometer-sized particles named extracellular vesicles. Extracellular vesicles are lipid bilayer particles released from eventually every single cell, including bacterium, with diameters ranging from 30 nm (exosome) to several micrometers (apoptotic body). Components carried by extracellular vesicles include but are not limited to DNA, RNA, protein, fatty acid, and other metabolites. Recent studies suggest that cancer cells not only secrete more extracellular vesicles but also upload critical mediators required for lymphatic metastasis onto extracellular vesicles. This review will summarize recent advances in cancer lymphatic metastasis and how cancer cells regulate this process via extracellular vesicle-dependent lymphangiogenesis.

show abstract

Lymphatic Vessels in Tumor Dissemination versus Immunotherapy

Cited by 50 publications

References 14 publications

Endothelial-specific depletion of TGF-β signaling affects lymphatic function

Endothelial-specific depletion of TGF-β signaling affects lymphatic function

Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis

Regulation of lymphangiogenesis by extracellular vesicles in cancer metastasis

Contact Info

Product

Resources

About