Unexpected contribution of lymphatic vessels to promotion of distant metastatic tumor spread

Ma, Qiaoli; Dieterich, Lothar C.; Ikenberg, Kristian; Bachmann, Stephan; Mangana, Johanna; Proulx, Steven T.; Amann, Valerie C; Levesque, Mitchell P.; Dummer, Reinhard; Bałuk, Peter; McDonald, Donald M.; Detmar, Michael

doi:10.1126/sciadv.aat4758

Cited by 77 publications

(72 citation statements)

References 29 publications

(44 reference statements)

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“…55,56 Lymphangiogenesis was also shown to occur in distant organs with established metastases where it promoted further spread of the tumor cells to other organs. 57 Supporting the clinical relevance of our findings, we found that expression of Adora2a and adenosinegenerating ectonucleotidases were positively correlated with the levels of lymphatic or pro-lymphangiogenic markers such as Lyve1, Pdpn or Vegfc, in several types of human tumors. In this context, our findings are highly relevant as they identify a novel pathway that could be targeted to block tumor-associated lymphangiogenesis and sentinel lymph node metastasis.…”

Section: Discussionsupporting

confidence: 85%

Adenosine A2a receptor promotes lymphangiogenesis and lymph node metastasis

et al. 2019

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Section: Discussionsupporting

confidence: 85%

Adenosine A2a receptor promotes lymphangiogenesis and lymph node metastasis

et al. 2019

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“…Typically, they affect the primary tumor tissue as well as draining collecting vessels and lymph nodes (LNs) which can markedly increase in size during tumor progression . In addition, lymphangiogenesis may also occur at distant metastatic sites, where it correlates with poor outcome in patients with melanoma metastasis to the lung . With regard to breast cancer, clinical studies have revealed that the extent of lymphangiogenesis is very heterogenous, as is the correlation with the clinical outcome, probably reflecting the wide spectrum of breast cancer subtypes which differ extensively in their cellular, molecular and pathological characteristics and prognosis.…”

Section: Introductionmentioning

confidence: 99%

“…3 In addition, lymphangiogenesis may also occur at distant metastatic sites, where it correlates with poor outcome in patients with melanoma metastasis to the lung. 4 With regard to breast cancer, clinical studies have revealed that the extent of lymphangiogenesis is very heterogenous, as is the correlation with the clinical outcome, 1,2 probably reflecting the wide spectrum of breast cancer subtypes which differ extensively in their cellular, molecular and pathological characteristics and prognosis. Nonetheless, a recent meta-analysis including a total of an overall positive correlation between lymphatic vessel density, lymphatic invasion and reduced disease-free and overall survival.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional profiling of breast cancer‐associated lymphatic vessels reveals VCAM‐1 as regulator of lymphatic invasion and permeability

Kapaklikaya

Cetintas

Proulx

et al. 2019

Intl Journal of Cancer

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Tumor‐associated lymphangiogenesis and lymphatic invasion of tumor cells correlate with poor outcome in many tumor types, including breast cancer. Various explanations for this correlation have been suggested in the past, including the promotion of lymphatic metastasis and an immune‐inhibitory function of lymphatic endothelial cells (LECs). However, the molecular features of tumor‐associated lymphatic vessels and their implications for tumor progression have been poorly characterized. Here, we report the first transcriptional analysis of tumor‐associated LECs directly isolated from the primary tumor in an orthotopic mouse model of triple negative breast cancer (4T1). Gene expression analysis showed a strong upregulation of inflammation‐associated genes, including endothelial adhesion molecules such as VCAM‐1, in comparison to LECs derived from control tissue. In vitro experiments demonstrated that VCAM‐1 is not involved in the adhesion of tumor cells to LECs but unexpectedly promoted lymphatic permeability by weakening of lymphatic junctions, most likely through a mechanism triggered by interactions with integrin α4 which was also induced in tumor‐associated LECs. In line with this, in vivo blockade of VCAM‐1 reduced lymphatic invasion of 4T1 cells. Taken together, our findings suggest that disruption of lymphatic junctions and increased permeability via tumor‐induced lymphatic VCAM‐1 expression may represent a new target to block lymphatic invasion and metastasis.

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“…VEGFR-3 reporter mice revealed lymphangiogenesis in lymph nodes, liver, lungs, and spleens of tumor-bearing mice [21] before metastatic spread. High lymphatic density and lymphatic invasion in metastatic lungs was associated with poor outcome of melanoma patients [22]. Blocking pro-lymphangiogenic VEGF-C signaling after cancer cell colonization of tumor-draining lymph nodes prevented further spread to lungs [23] and inhibiting lymphangiogenesis in distant organs may prevent further dissemination of metastatic cells.…”

Section: Timingmentioning

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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Unexpected contribution of lymphatic vessels to promotion of distant metastatic tumor spread

Abstract: Lymphatic vessels promote organ-to-organ metastasis in addition to mediating tumor cell dissemination from the primary site.

Cited by 77 publications

References 29 publications

Adenosine A2a receptor promotes lymphangiogenesis and lymph node metastasis

Adenosine A2a receptor promotes lymphangiogenesis and lymph node metastasis

Transcriptional profiling of breast cancer‐associated lymphatic vessels reveals VCAM‐1 as regulator of lymphatic invasion and permeability

Parallels of Resistance between Angiogenesis and Lymphangiogenesis Inhibition in Cancer Therapy

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