Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells

Follain, Gautier; Osmani, Naël; Azevedo, Ana Sofia; Allio, Guillaume; Mercier, Luc; Karreman, Matthia A.; Solecki, Gergely; García-León, María J.; Lefèbvre, Olivier; Fekonja, Nina; Hille, Claudia; Chabannes, Vincent; Dollé, Guillaume; Metivet, Thibaut; Hovsepian, François Der; Prud'Homme, Christophe; Pichot, Angélique; Paul, Nicodéme; Carapito, Raphaël; Bahram, Seiamak; Ruthensteiner, Bernhard; Kemmling, André; Siemonsen, Susanne; Schneider, Tanja; Fiehler, Jens; Glatzel, Markus; Winkler, Frank; Schwab, Yannick; Pantel, Klaus; Harlepp, Sébastien; Goetz, Jacky G.

doi:10.1016/j.devcel.2018.02.015

Cited by 252 publications

(222 citation statements)

References 78 publications

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“…37 38 2. RESULTS AND DISCUSSION 39 40 We employed a well-established methodology developed by our group to quantify the extravasation 41 efficiency of TCs in the MVNs 30 . MVNs were formed in microfluidic devices using primary human 42 umbilical vein ECs (HUVEC) and normal human lung fibroblasts (nHLF) from pooled donors.…”

Section: Introductionmentioning

confidence: 99%

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

Offeddu

Hajal

Foley

et al. 2020

Preprint

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The glycocalyx on tumor cells has been recently identified as an important driver for cancer progression, possibly providing critical opportunities for treatment. Metastasis, in particular, is often the limiting step in the survival to cancer, yet our understanding of how tumor cells escape the vascular system to initiate metastatic sites remains limited. Using an in vitro model of the human microvasculature, we assess here the importance of the tumor and vascular glycocalyces during tumor cell extravasation. Through selective manipulation of individual components of the glycocalyx, we reveal a novel mechanism whereby tumor cells prepare an adhesive vascular niche by depositing components of the glycocalyx along the endothelium. Accumulated hyaluronic acid shed by tumor cells subsequently mediates adhesion to the endothelium via the glycoprotein CD44. Transendothelial migration and invasion into the stroma occurs through binding of the isoform CD44v to components of the sub-endothelial extra-cellular matrix. Targeting of the hyaluronic acid-CD44 glycocalyx complex results in significant reduction in the extravasation of tumor cells. These studies provide evidence of tumor cells repurposing the glycocalyx to promote adhesive interactions leading to cancer progression. Such glycocalyx-mediated mechanisms may be therapeutically targeted to hinder metastasis and improve patient survival.

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Section: Introductionmentioning

confidence: 99%

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

Offeddu

Hajal

Foley

et al. 2020

Preprint

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“…In order for distant metastases to occur, a so-called "invasion-metastasis cascade" takes place: CTCs lose adherence to the primary tumor, intravasate into the vasculature, migrate in the venous circulation, arrest at specific capillary sites, extravasate, invade parenchymal tissue, and eventually form metastatic tumors. Numerous host and tumor factors influence each of these steps, and it has recently become clear that only a small fraction of CTCs from carcinomas, which in humans are much more common than sarcomas, remain viable and capable of forming metastases after entry into the vasculature (15). Carcinoma cells that are likely to disseminate undergo epithelial to mesenchymal transition (EMT), acquiring the ability to invade endothelium and digest extracellular matrix, among other functional properties (16,17).…”

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confidence: 99%

Flow Cytometric Detection of Circulating Osteosarcoma Cells in Dogs

et al. 2019

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Osteosarcoma (OSA) is a malignant tumor of middle-aged dogs and adolescent humans. The clinical outcome of OSA has not improved over more than three decades, and dogs typically succumb to metastatic disease within 6 months despite tumor resection through limb amputation and adjuvant chemotherapy. Therefore, undetectable tumor cells with potential to form metastases are present at diagnosis. An assay to identify canine immortalized and primary OSA cells through flow cytometric detection of intracellular collagen 1 (Col I) and osteocalcin was optimized, and applied to blood samples from tumorbearing dogs for detection of circulating tumor cells (CTCs). Spiking variable number of OSA cells into normal dog blood recovered 50-60% of Col I positive cells with high forward and variable side light scatter. An algorithm to exclude nonviable, doublet, and autofluorescent cells was applied to sequential blood samples from three dogs obtained prior to and after limb amputation, and at approximately, triweekly intervals over 121, 142, and 183 days of chemotherapy, respectively. Dogs had >100 CTC/10 6 leukocytes prior to amputation, variably frequent CTC during chemotherapy, and an increase up to 4,000 CTC/10 6 leukocytes within 4 weeks before overt metastases or death. Sorted CTCs were morphologically similar to direct tumor aspirates and positive for Col I. Although preliminary, findings suggest that CTCs are frequent in canine OSA, more numerous than carcinoma CTC in humans, and that an increase in CTC frequency may herald clinical deterioration. This assay may enable enumeration and isolation of OSA CTC for prognostic and functional studies, respectively. OSTEOSARCOMA (OSA) is a primary bone cancer that is common in middle-aged to older, large breed dogs, and less common in humans, where children and young adults are most often affected. Therapy consisting of limb amputation or limbsparing tumor resection followed by chemotherapy (typically platinum or doxorubicin-based) is the gold standard, but the clinical outcome of OSA in dogs and humans remains poor (1-3). Dogs with OSA of the appendicular skeleton treated with amputation and chemotherapy had median survival times (STs) of 235-540 days (4), while in humans 5-year survival has been stagnant at about 60% (5). Although the median ST is relatively homogeneous, the range of ST in dogs with OSA treated identically varies from 2 to >30 months, illustrating that there is extensive heterogeneity in tumor biology and/or host response (6-8). Metastatic disease is the usual cause of spontaneous death or euthanasia, but fewer than 10% of dogs have radiographic evidence of metastasis at the time of diagnosis (2).Computed tomography also lacks sensitivity for identifying metastases, and histologic grading schemes for canine OSA poorly predict biological behavior (9-11).

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“…4C), we sought to investigate the impact of LPHN2 on the extravasation of cancer cells that can be effectively tracked and quantified by using the zebrafish embryo (Follain et al, 2018;Osmani & Goetz, 2019). To this aim, fluorescently-labeled mouse (B16F10) or human (SK-MEL-28) melanoma cells were injected in the duct of Cuvier of Tg(kdrl:EGFP) s843 wild type or lphn2a -/zebrafish embryos and their metastatic extravasation potential was quantified by measuring the number of tumor cells outside the vessels in the caudal plexus where the circulating tumor cells (CTCs) preferentially arrested and extravasated (Follain et al, 2018;Hyenne et al, 2019). We discovered that, likely due to their abnormal inter-EC junctions, lphn2a null zebrafish embryos are more permissive to extravasation of both mouse B16F10 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion

Camillo

Facchinello

Villari

et al. 2020

Preprint

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Dynamic modulation of endothelial cell (EC) adhesion to extracellular matrix (ECM) in response to mechanostimuli is essential for blood vessel patterning and functioning. Yet, the molecular mechanisms involved in this biological process are far to be completely deciphered. Here, we identify the adhesion G protein-coupled receptor (ADGR) Latrophilin 2 (LPHN2) as a novel determinant of vascular morphogenesis and endothelial barrier function. In cultured ECs, endogenous LPHN2 localizes at ECM adhesions, signals through cAMP/Rap1, and, via its fibronectin-leucine-rich transmembrane (FLRT)-binding domain, negatively regulates ECM-elicited haptotaxis. ECs also express endogenous FLRT2 ligand that promotes cAMP/Rap1 signaling and hinders haptotaxis in a LPHN2-dependent manner. Vascular ECs of lphn2a knock-out zebrafish embryos become abnormally stretched, display a hyperactive Hippo mechanosensing pathway, and lack proper intercellular junctions. Indeed, intravascularly injected cancer cells extravasate more easily in lphn2a null animals. Thus, LPHN2 ligands, such as FLRT2, may be therapeutically exploited to interfere with cancer metastatic dissemination.

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Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells

Cited by 252 publications

References 78 publications

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

Flow Cytometric Detection of Circulating Osteosarcoma Cells in Dogs

LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion

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