Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine

Olmeda, David; Cerezo-Wallis, Daniela; Riveiro-Falkenbach, Erica; Pennacchi, Paula Comune; Contreras-Alcalde, Marta; Ibarz, Nuria; Cifdaloz, Metehan; Catena, Xavier; Calvo, Tonantzin G.; Cañón, Estela; Alonso-Curbelo, Direna; Suárez, Javier; Osterloh, Lisa; Graña, Osvaldo; Mulero, Francisca; Megı́as, Diego; Cañamero, Marta; Martı́nez-Torrecuadrada, Jorge L.; Mondal, Chandrani; Martino, Julie Di; Lora, David; Martínez-Corral, Inés; Bravo‐Cordero, Jose Javier; Muñoz, Javier; Puig, Susana; Ortiz‐Romero, Pablo L.; Rodríguez-Peralto, José L.; Ortega, Sagrario; Soengas, Marı́a S.

doi:10.1038/nature22977

Cited by 132 publications

(184 citation statements)

References 43 publications

(57 reference statements)

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“…72 In a more recent study, the angiogenic effect of exosomes derived from two oral squamous cell carcinoma cell lines (SCC15 and HSC3) was found to increase HUVEC migration and tube formation. 73 Thus, many different EV proteins, including but not limited to CD97, 74 the heparin-binding factor midkine, 75 and annexin II, 76 have been shown to support angiogenesis in cancer models by affecting different mechanisms.…”

Section: Ev On Tumor Microvesselsmentioning

confidence: 99%

Extracellular vesicles and microvascular pathology: Decoding the active dialogue

Hosseini‐Beheshti

Grau

2018

Microcirculation

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Extracellular vesicles (EV) are a heterogeneous collection of membrane‐surrounded structures released from all studied cells, under both physiological and pathological conditions. These nano‐size vesicles carry complex cargoes including different classes of proteins, lipids and nucleic acids and are known to act as a communication and signalling vesicles in various cellular process. In addition to their role in development and progression of pathological disorders which make them potentially great biomarkers, EV have beneficial effects, as they take part in homeostasis. In this review we have analysed the evidence for the role of microvesicles and exosomes secreted from other cells on microvascular endothelium (EV uptake) as well as the role of endothelial‐derived vesicles on their neighbouring and distant cells (EV release).

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Section: Ev On Tumor Microvesselsmentioning

confidence: 99%

Extracellular vesicles and microvascular pathology: Decoding the active dialogue

Hosseini‐Beheshti

Grau

2018

Microcirculation

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“…In some circumstances, cancer cells have co-opted some of the signalling molecules of the innate immune system, including chemokines and their receptors (such as CXCL12–CXCR4 and CCL21–CCR7 mentioned above), to facilitate invasion, migration, and metastasis. As advances in non-invasive imaging technologies improve and allow us to visualise the lymphatics with greater resolution, and with the development of new tools such as the ‘MetAlert’ mice 171 , which serve to visualise lymphovascular niches in whole animals, we can begin to study the function of tumour-associated lymphatics on metastatic dissemination as well as during therapeutic response.…”

Section: Going With the Flow: Intravasation Into Blood And Lymphaticsmentioning

confidence: 99%

Recent advances in understanding the complexities of metastasis

et al. 2018

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Tumour metastasis is a dynamic and systemic process. It is no longer seen as a tumour cell-autonomous program but as a multifaceted and complex series of events, which is influenced by the intrinsic cellular mutational burden of cancer cells and the numerous bidirectional interactions between malignant and non-malignant cells and fine-tuned by the various extrinsic cues of the extracellular matrix. In cancer biology, metastasis as a process is one of the most technically challenging aspects of cancer biology to study. As a result, new platforms and technologies are continually being developed to better understand this process. In this review, we discuss some of the recent advances in metastasis and how the information gleaned is re-shaping our understanding of metastatic dissemination.

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“…By analyzing the course of enhanced GFP (EGFP)-luciferase VEGFR3 reporter mice after implantation with nine different mCherry-labeled melanoma lines, Olmeda et al found that early local and systemic VEGFR3- luc activation, and not VEGFC expression or VEGFR3-luc restricted to primary tumors, positively correlated with increased lymphatic vessel density at lymph nodes and tumor metastasis[47]. Moreover, surgical removal of tumors led to a decrease in systemic VEGFR3- luc.…”

Section: Lymphatic Imaging Using Transgenic Fluorescent Reporter Micementioning

confidence: 99%

“…VEGFR3-Luc expression locally and systemically, IV. systemic VEGFR3-Luc expression with or without local primary tumor expression) observed as well as their correlations to tumoral metastasis to lymph nodes or distant organs[47]. …”

Section: Lymphatic Imaging Using Transgenic Fluorescent Reporter Micementioning

confidence: 99%

Fluorescent reporter transgenic mice for in vivo live imaging of angiogenesis and lymphangiogenesis

et al. 2018

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The study of lymphangiogenesis is an emerging science that has revealed the lymphatic system as a central player in many pathological conditions including cancer metastasis, lymphedema, and organ graft rejection. A thorough understanding of the mechanisms of lymphatic growth will play a key role in the development of therapeutic strategies against these conditions. Despite the known potential of this field, the study of lymphatics has historically lagged behind that of hemangiogenesis. Until recently, significant strides in lymphatic studies were impeded by a lack of lymphatic-specific markers and suitable experimental models compared to those of the more immediately visible blood vasculature. Lymphangiogenesis has also been shown to be a key phenomenon in developmental biological processes, such as cell proliferation, guided migration, differentiation, and cell-to-cell communication, making lymphatic-specific visualization techniques highly desirable and desperately needed. Imaging modalities including immunohistochemistry and in situ hybridization are limited by the need to sacrifice animal models for tissue harvesting at every experimental time point. Moreover, the processes of mounting and staining harvested tissues may introduce artifacts that can confound results. These traditional methods for investigating lymphatic and blood vasculature are associated with several problems including animal variability (e.g., between mice) when replicating lymphatic growth environments and the cost concerns of prolonged, labor-intensive studies, all of which complicate the study of dynamic lymphatic processes. With the discovery of lymphatic-specific markers, researchers have been able to develop several lymphatic and blood vessel-specific, promoter-driven, fluorescent-reporter transgenic mice for visualization of lymphatics in vivo and in vitro. For instance, GFP, mOrange, tdTomato, and other fluorescent proteins can be expressed under control of a lymphatic-specific marker like Prospero-related homeobox 1 (Prox1), which is a highly conserved transcription factor for determining embryonic organogenesis in vertebrates that is implicated in lymphangiogenesis as well as several human cancers. Importantly, Prox1-null mouse embryos develop without lymphatic vessels. In human adults, Prox1 maintains lymphatic endothelial cells and upregulates proteins associated with lymphangiogenesis (e.g., VEGFR-3) and downregulates angiogenesis-associated gene expression (e.g., STAT6). To visualize lymphatic development in the context of angiogenesis, dual fluorescent-transgenic reporters, like Prox1-GFP/Flt1-DsRed mice, have been bred to characterize lymphatic and blood vessels simultaneously in vivo. In this review, we discuss the trends in lymphatic visualization and the potential usage of transgenic breeds in hemangiogenesis and lymphangiogenesis research to understand spatial and temporal correlations between vascular development and pathological progression.

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Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine

Cited by 132 publications

References 43 publications

Extracellular vesicles and microvascular pathology: Decoding the active dialogue

Extracellular vesicles and microvascular pathology: Decoding the active dialogue

Recent advances in understanding the complexities of metastasis

Fluorescent reporter transgenic mice for in vivo live imaging of angiogenesis and lymphangiogenesis

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