
==== Front
Clin Exp Metastasis
Clin Exp Metastasis
Clinical & Experimental Metastasis
0262-0898
1573-7276
Springer Netherlands Dordrecht

37606814
10229
10.1007/s10585-023-10229-3
Review
Lymphatic trafficking of immune cells and insights for cancer metastasis
http://orcid.org/0000-0002-4133-9364
Jackson David G. David.jackson@imm.ox.ac.uk

grid.421962.a 0000 0004 0641 4431 Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS UK
22 8 2023
22 8 2023
2024
41 4 381386
15 5 2023
28 7 2023
© The Author(s) 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
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Most cancers and in particular carcinomas metastasise via the lymphatics to draining lymph nodes from where they can potentially achieve systemic dissemination by invasion of high endothelial blood venules (HEVs) in the paracortex [1, 2]. Currently however, the mechanisms by which tumours invade and migrate within the lymphatics are incompletely understood, although it seems likely they exploit at least some of the normal physiological mechanisms used by immune cells to access lymphatic capillaries and traffic to draining lymph nodes in the course of immune surveillance, immune modulation and the resolution of inflammation [3, 4]. Typically these include directional guidance via chemotaxis, haptotaxis and durotaxis, adhesion to the vessel surface via receptors including integrins, and junctional re-modelling by MMPs (Matrix MetalloProteinases) and ADAMs (A Disintegrin And Metalloproteinases) [5–7]. This short review focusses on a newly emerging mechanism for lymphatic entry that involves the large polysaccharide hyaluronan (HA) and its key lymphatic and immune cell receptors respectively LYVE-1 (Lymphatic Vessel Endothelial receptor) and CD44, and outlines recent work which indicates this axis may also be used by some tumours to aid nodal metastasis.

Keywords

Lymphatic
Immune cell
Tumour metastasis
LYVE-1
Hyaluronan
Glycocalyx
http://dx.doi.org/10.13039/501100000265 Medical Research Council MC_UU_00008/2 issue-copyright-statement© Springer Nature B.V. 2024
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pmcArticle

The majority of immune cells that traffic from peripheral tissues to afferent lymphatics effect their entry within the first 200 μm of initial blind-ended capillaries at the distinctive overlapping junctions between the oakleaf shaped endothelial cells [5]. Here, and to a certain extent in adjoining lymphatic pre-collectors the interdigitating membrane flaps of such cells are “buttoned” at their sides by the adherens-junction protein VE-cadherin (Vascular Endothelial cadherin) and tight junction proteins including Claudin-5, ZO-1 (Zonula Occludens-1), ESAM (Endothelial Selective Adhesion Molecule) and JAM-A (Junctional Adhesion Molecule-A), while their tips are lined with PECAM-1 (Platelet Endothelial Cell Adhesion Molecule-1, CD31), and the lymphatic endothelial HA receptor LYVE-1 [5, 8–10] to form discrete junctional “portals” of approximately 0.5–1 μm through which individual immune cells can enter by pushing and squeezing [5, 11–14]. As predicted from its location in such portals, we recently demonstrated that LYVE-1 plays a key role in the entry of antigen presenting Dendritic cells (DCs) and macrophages to initial capillaries by engaging with its ligand HA, anchored in the surface glycocalyx of the incoming immune cells by the closely related leucocyte receptor CD44 [15–17]. This role of LYVE-1 has similarities to the one played by CD44 in mediating the exit of T cells from inflamed blood capillaries. There however, the HA glycocalyx is present on the (luminal) endothelium, where it serves to capture activated circulating T cells (which also express CD44 but lack an HA coat) by forming a CD44:HA:CD44 sandwich [18–20]. Synthesized primarily by HA synthase-2 (HAS2) in DCs and macrophages, the nascent HA chains associate with CD44 in intracellular vesicles, from which the bound complexes are then exported to the immune cell surface to form a glycocalyx of some 200-300 nm thickness as observed by high resolution (Airyscan) confocal microscopy [17]. Conclusive evidence that LYVE-1:HA interactions can be critical for vessel entry in vivo came from studies tracking the migration of fluorescently labelled DCs in oxazolone hypersensitized skin, which demonstrated that Lyve1 gene deletion or mAb blockade led to a peri-lymphatic accumulation of DCs in the dermis and a consequent delay or inhibition of their trafficking to downstream axial LNs respectively [16]. Likewise, deletion of CD44 or enzymatic depletion of the HA glycocalyx resulted in a marked reduction in DC nodal migration compared to controls. Moreover, the significance of LYVE-1 • HA mediated DC migration for in vivo immune function was underscored by experiments with mice immunised intradermally with influenza virus nucleoprotein or ovalbumin peptide as model vaccines. These showed that both Lyve1 gene deletion and mAb blockade disrupted the generation of DC primed peptide-specific CD4 and CD8 T-cell responses in downstream lymph nodes, confirming that in vivo, the LYVE-1• HA mediated entry of immune cells to lymphatics can be rate-limiting for protective immunity ([16] and reviewed in Johnson et al. [14]). The critical importance of LYVE-1 for immune cell trafficking has been further reinforced by the discovery that the process is controlled by the Circadian clock gene BMAL1 which directly regulates the expression of LYVE-1, CCL21 and CCR7 in lymphatic endothelium to facilitate maximal DC migration during the sleeping hours, when the immune activity of lymph nodes is at its highest [21, 22].

As regards the precise molecular mechanism of HA-mediated entry, we have observed that contact with the DC glycocalyx triggers redistribution of LYVE-1 into ring-like assemblages termed transmigratory cups in the underlying endothelium, owing to their similarity to structures that form around T-cells during exit across blood vascular endothelium [23–25]. Coincident with engaging LYVE-1 in these cups, we reported that migrating DCs undergo polarisation to form a uropod at the trailing edge, in which CD44 is concentrated with its bound HA glycocalyx, and a leading edge or lamellipodium that extends to explore the surrounding endothelial surface for potential sites of transit, most likely at tri-cellular junctions [17]. Hence, the adhesive interface between HA and LYVE-1 likely provides a flexible foothold for the DC to attach to the outer surface of a lymphatic capillary while the actomyosin machinery provides the tractive force for transit to the vessel lumen either through amoeboid motility or adhesion to integrins at the leading edge, directionally guided by a haptotactic gradient of the chemokine CCL21 in the perilymphatic matrix via its signaling receptor CCR7 [26]. Additionally, DCs can trigger localised discharge of CCL21 from lymphatic endothelium to guide their own transmigration, through Ca2+ triggered exocytosis of the chemokine from pre-stored depots in trans Golgi vesicles [27, 28]. Indeed, the LYVE-1 HA axis appears to regulate such discharge, insofar as engagement of DCs via LYVE-1 can induce CCL21 secretion from LECs, and release of CCL21 from dermal lymphatic capillaries is disrupted in Lyve1−/− mice. (Johnson and Jackson unpublished). Besides DCs, our ongoing investigations have confirmed that tissue macrophages also utilize their HA glycocalyx to mediate exit from inflamed tissue to afferent lymphatics via LYVE-1, notably during the phase of resolution that enables restoration of normal homeostasis in tissues such as the infarcted heart and peritoneum [29, 30].

Of course, the LYVE-1 HA axis is not the only one to play a role in lymphatic entry. With the exception of DCs and macrophages, most other immune cell populations appear to lack a HA glycocalyx, and must instead initiate lymphatic transit by other mechanisms. In the case of TEM and TREG cells for example, it has been reported that entry involves the chemotactic lipid Sphingosine 1-P along with lymphotoxin (LTα1β3) and its receptor LTβR [31, 32]. Neutrophils, the first responders to tissue injury can adhere to the vessel endothelium via β2 integrins and transmigrate through the combined actions of the matrix metalloproteinases MMP8 and MMP9, the serine protease neutrophil elastase and the arachidonate-derived chemorepellent, 12,hydroxyeicosatetraenoate (12(S)HETE) that together promote junctional retraction [33, 34]. Furthermore, it appears likely that both these populations, which migrate primarily in response to inflammation, can enter dermal lymphatics through downstream collectors which lack LYVE-1 and have conventional tight (zippered) endothelial junctions rather than buttoned junctions. Here, it has been reported that the process of entry is mediated by adhesion between integrins on the immune cells and VCAM-1 (Vascular Endothelial Adhesion Molecule – 1) and ICAM-1 (Intercellular Adhesion Molecule – 1) in the inflamed endothelium [35–40]. Notably, it was shown that such integrin dependent transit through downstream collectors is also used by DCs, most likely to accelerate their passage to downstream lymph nodes in inflamed tissues [35]. Indeed integrin-mediated adhesion may even combine with HA-mediated adhesion for DC entry at initial capillaries or pre-collectors, as both ICAM-1 and VCAM-1 have been observed to co-localise with LYVE-1 during transmigration via transmigratory cups [36, 37]. Hence, while the individual mechanisms used to initiate lymphatic entry can differ between immune cell types, they can also vary according to the tissue context. Moreover, the overall process actually involves a series of steps that likely involve contributions from a number of different adhesion receptors and their ligands including ALCAM (Activated Leukocyte Cell Adhesion Molecule), L1CAM, CD99, Mannose receptor, 41-BB/CD137 and CLEVER-1(Combined Lymphatic Endothelial and Vascular Endothelial Receptor − 1), as well as chemokines, chemoattractants and proteinases that together activate signaling pathways leading to the loss of VE-cadherin and junctional retraction [7, 41].

The use of the LYVE-1·HA adhesion axis by DCs and macrophages for lymphatic entry can be reconciled with the unusual mechanics of the binding interaction and its tissue context. Unlike CD44, to which individual HA chains bind through conventional ”sticking” interactions, the HA chains can “slide” through the cleft-like binding site in LYVE-1, a process that likely equips DCs and macrophages for their fluid-like crawling on lymphatic endothelium and subsequent transmigration in the low shear environment of initial lymphatics [10, 42]. Likewise, the absence of an HA glycocalyx from T cells and neutrophils likely reflects the fact they reside mainly in the blood circulation where the firmer binding properties of CD44 enable their extravasation at sites of tissue injury by adhesion to endothelial HA in the face of rapid blood flow.

The HA pericellular coat in tumours - a potential role in nodal metastasis?

Besides being a feature of tissue based immune cell populations as already discussed, the assembly of an HA glycocalyx or pericellular coat is also a property of other less motile cell types such as fibroblasts, chondrocytes and epithelial cells, where the large polyanionic nature of the sugar polymer acts as a barrier modulating cell:cell contact, as well as a means of tissue anchorage via proteoglycans in the extracellular matrix [43]. Importantly, the HA pericellular coat can be radically altered during cell transformation. Notably, its expansion through upregulation of HAS gene expression and HA deposition are hallmarks of epithelial to mesenchymal transition [44], a fundamental process in carcinoma progression by which tumour cells acquire enhanced migratory capacity [45]. Furthermore, elevated levels of both HA and CD44 are common amongst “aggressive” and metastatic cancers and associated with poor survival [46, 47].

There is now growing evidence to suggest this tumour cell HA coat can contribute to metastasis by facilitating lymphatic invasion of either individual tumour cells or tumour emboli via LYVE-1, perhaps in a similar manner to the trafficking of immune cells. Most if not all tumours grow in close proximity to host lymphatics or generate new peritumoral or even intratumoral lymphatics, both of which have LYVE-1 lined endothelial junctions. Moreover, in immunostained paraffin tissue sections of breast cancer, a CD44-associated pericellular HA matrix has been observed on tumour emboli invading such lymphatic vessels [48], while in vitro cultured breast tumour lines have been reported to adhere via HA to LYVE-1 in transfected fibroblasts [49]. Extending upon these observations, our own more recent studies indicate that assembly of a dense CD44 anchored HA glycocalyx is a consistent feature of metastatic MDA MB 231 and MCF-7 breast carcinomas but not poorly metastasizing SKBR3 cells, and that MDA MB 231 and MCF-7 cells both adhere and transit human LEC monolayers via LYVE-1 transmigratory cups similar to those formed by transmigrating DCs (Johnson and Jackson unpublished). Curiously, such findings chime with those from a previous ultrastructural study in mice where detailed electron microscopic imaging suggested that prostate adenocarcinomas, colon carcinomas and B16 melanomas extend filopodia-like protrusions towards lymphatic vessels during invasion, and that the endothelial cells simultaneously extend transmigratory cup-like projections around the transiting tumour cells [50]. Moreover, in further studies with the mouse 4T1 mammary carcinoma line that can spread directly from the first draining lymph nodes to the blood circulation in Balb/c animals by invading HEVs [51, 52] we found the initial invasion of local lymphatics and metastasis to draining inguinal lymph nodes is both reliant on HA and LYVE-1 and severely impaired in Lyve1−/−mice (Johnson LA and Jackson DG unpublished). It is tempting to speculate that subsequent colonisation of these inguinal nodes by 4T1 as well as invasion of blood vessels for systemic dissemination of the tumour involves yet further interactions with LYVE-1, given its abundance in the sinuses that must be traversed to reach the HEVs; however, this remains to be investigated.

In summary, both tissue-based immune cells and metastatic tumours employ similar adhesive interactions between their endogenous HA surface glycocalyx and the endothelial receptor LYVE-1 to enter afferent lymphatics and migrate to downstream lymph nodes - the former to promote immunity and its resolution and the latter for systemic dissemination (Fig. 1). Accordingly, LYVE-1 is a potential target for the therapeutic blockade of both immune based disorders and cancer metastasis. Regarding the latter however, one important caveat is that lymphatic trafficking is pivotal to the generation of anti-tumour immunity and its disruption would therefore be undesirable. Hence, LYVE-1 blockade might be most effective for the treatment of early-stage cancers, when administered after primary tumour resection, prior to nodal dissemination and local immune activation. Further studies will no doubt help to clarify these issues.

Fig. 1 Involvement of LYVE-1 and hyaluronan glycocalyx in entry of immune cells and tumours to initial lymphatics. Pictorial images showing potential similarity between mechanisms used by normal immune cells and tumour cells to enter lymphatic capillaries by means of LYVE-1 and hyaluronan glycocalyx. Panels depict a blind-ended lymphatic in each case containing multiple LYVE-1 lined entry portals (red stippling). Entry of dendritic cells (DC), macrophages (M) and tumour cells (T) involves clustering of the glycocalyx and formation of LYVE-1 enriched transmigratory cups that facilitate transit to the vessel lumen

Author contributions

Not applicable. Single author.

Funding

This work was funded by the UK Medical Research Council under Core Grant MC_UU_00008/2.

Data Availability

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Presented at the 9th International Congress on Cancer Metastasis through the Lymphovascular System, May 4–6, 2023, in San Francisco, CA. To be published in a Special Issue of Clinical and Experimental Metastasis: Molecular Mechanisms of Cancer Metastasis.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Zhou H, Lei PJ, Padera TP (2021) Progression of Metastasis through Lymphatic System. Cells 10
2. Houvenaeghel G Cohen M Classe JM Reyal F Mazouni C Chopin N Martinez A Darai E Coutant C Colombo PE Lymphovascular invasion has a significant prognostic impact in patients with early breast cancer, results from a large, national, multicenter, retrospective cohort study ESMO Open 2021 6 100316 10.1016/j.esmoop.2021.100316 34864349
Houvenaeghel G, Cohen M, Classe JM, Reyal F, Mazouni C, Chopin N, Martinez A, Darai E, Coutant C, Colombo PE et al (2021) Lymphovascular invasion has a significant prognostic impact in patients with early breast cancer, results from a large, national, multicenter, retrospective cohort study. ESMO Open 6:10031634864349 10.1016/j.esmoop.2021.100316
3. Tamburini BAJ Padera TP Lund AW Editorial: regulation of Immune function by the lymphatic vasculature Front Immunol 2019 10 2597 10.3389/fimmu.2019.02597 31781105
Tamburini BAJ, Padera TP, Lund AW (2019) Editorial: regulation of Immune function by the lymphatic vasculature. Front Immunol 10:259731781105 10.3389/fimmu.2019.02597
4. Fujimoto N, Dieterich LC (2021) Mechanisms and Clinical Significance of Tumor Lymphatic Invasion. Cells 10
5. Baluk P Fuxe J Hashizume H Romano T Lashnits E Butz S Vestweber D Corada M Molendini C Dejana E Functionally specialized junctions between endothelial cells of lymphatic vessels J Exp Med 2007 204 2349 2362 10.1084/jem.20062596 17846148
Baluk P, Fuxe J, Hashizume H, Romano T, Lashnits E, Butz S, Vestweber D, Corada M, Molendini C, Dejana E et al (2007) Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med 204:2349–236217846148 10.1084/jem.20062596
6. Lammermann T Bader BL Monkley SJ Worbs T Wedlich-Soldner R Hirsch K Keller M Forster R Critchley DR Fassler R Rapid leukocyte migration by integrin-independent flowing and squeezing Nature 2008 453 51 55 10.1038/nature06887 18451854
Lammermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Soldner R, Hirsch K, Keller M, Forster R, Critchley DR, Fassler R et al (2008) Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453:51–5518451854 10.1038/nature06887
7. Jackson DG (2019) Leucocyte trafficking via the lymphatic vasculature - mechanisms and consequences. Front Immunol 10
8. Yao LC Baluk P Srinivasan RS Oliver G McDonald DM Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation Am J Pathol 2012 180 2561 2575 10.1016/j.ajpath.2012.02.019 22538088
Yao LC, Baluk P, Srinivasan RS, Oliver G, McDonald DM (2012) Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation. Am J Pathol 180:2561–257522538088 10.1016/j.ajpath.2012.02.019
9. Banerji S Ni J Wang SX Clasper S Su J Tammi R Jones M Jackson DG LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan J Cell Biol 1999 144 789 801 10.1083/jcb.144.4.789 10037799
Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, Jackson DG (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144:789–80110037799 10.1083/jcb.144.4.789
10. Jackson DG Hyaluronan in the lymphatics: the key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking Matrix Biol 2019 78–79 219 235 10.1016/j.matbio.2018.02.001 29425695
Jackson DG (2019) Hyaluronan in the lymphatics: the key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking. Matrix Biol 78–79:219–23529425695 10.1016/j.matbio.2018.02.001
11. Pflicke H Sixt M Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels J Exp Med 2009 206 2925 2935 10.1084/jem.20091739 19995949
Pflicke H, Sixt M (2009) Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J Exp Med 206:2925–293519995949 10.1084/jem.20091739
12. Tal O Lim HY Gurevich I Milo I Shipony Z Ng LG Angeli V Shakhar G DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling J Exp Med 2011 208 2141 2153 10.1084/jem.20102392 21930767
Tal O, Lim HY, Gurevich I, Milo I, Shipony Z, Ng LG, Angeli V, Shakhar G (2011) DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling. J Exp Med 208:2141–215321930767 10.1084/jem.20102392
13. Zhang F Zarkada G Yi S Eichmann A Lymphatic endothelial cell junctions: Molecular Regulation in Physiology and Diseases Front Physiol 2020 11 509 10.3389/fphys.2020.00509 32547411
Zhang F, Zarkada G, Yi S, Eichmann A (2020) Lymphatic endothelial cell junctions: Molecular Regulation in Physiology and Diseases. Front Physiol 11:50932547411 10.3389/fphys.2020.00509
14. Johnson LA, Jackson DG (2021) Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System. Cells 10
15. Lawrance W Banerji S Day AJ Bhattacharjee S Jackson DG Binding of Hyaluronan to the native lymphatic vessel endothelial receptor LYVE-1 is critically dependent on receptor clustering and Hyaluronan Organization J Biol Chem 2016 291 8014 8030 10.1074/jbc.M115.708305 26823460
Lawrance W, Banerji S, Day AJ, Bhattacharjee S, Jackson DG (2016) Binding of Hyaluronan to the native lymphatic vessel endothelial receptor LYVE-1 is critically dependent on receptor clustering and Hyaluronan Organization. J Biol Chem 291:8014–803026823460 10.1074/jbc.M115.708305
16. Johnson LA Lawrance W Roshorn YM Hanke T Banerji S Jackson DG The lymphatic vessel endothelial receptor LYVE-1 mediates dendritic cell entry to the afferent lymphatics via transmigratory cups that engage the leukocyte hyaluronan glycocalyx Nat Immunol 2017 18 762 770 10.1038/ni.3750 28504698
Johnson LA, Lawrance W, Roshorn YM, Hanke T, Banerji S, Jackson DG (2017) The lymphatic vessel endothelial receptor LYVE-1 mediates dendritic cell entry to the afferent lymphatics via transmigratory cups that engage the leukocyte hyaluronan glycocalyx. Nat Immunol 18:762–77028504698 10.1038/ni.3750
17. Johnson LA, Banerji S, Lagerholm BC, Jackson DG (2021) Dendritic cell entry to lymphatic capillaries is orchestrated by CD44 and the hyaluronan glycocalyx. Life Sci Alliance 4. 10.26508/lsa.202000908
18. DeGrendele HC Estess P Picker LJ Siegelman MH CD44 and its ligand hyaluronate mediate rolling under physiologic flow: a novel lymphocyte-endothelial cell primary adhesion pathway J Exp Med 1996 183 1119 1130 10.1084/jem.183.3.1119 8642254
DeGrendele HC, Estess P, Picker LJ, Siegelman MH (1996) CD44 and its ligand hyaluronate mediate rolling under physiologic flow: a novel lymphocyte-endothelial cell primary adhesion pathway. J Exp Med 183:1119–11308642254 10.1084/jem.183.3.1119
19. Nandi A Estess P Siegelman MH Hyaluronan anchoring and regulation on the surface of vascular endothelial cells is mediated through the functionally active form of CD44 J Biol Chem 2000 275 14939 14948 10.1074/jbc.275.20.14939 10809739
Nandi A, Estess P, Siegelman MH (2000) Hyaluronan anchoring and regulation on the surface of vascular endothelial cells is mediated through the functionally active form of CD44. J Biol Chem 275:14939–1494810809739 10.1074/jbc.275.20.14939
20. Petrey AC de la Motte CA Hyaluronan, a crucial regulator of inflammation Front Immunol 2014 5 101 10.3389/fimmu.2014.00101 24653726
Petrey AC, de la Motte CA (2014) Hyaluronan, a crucial regulator of inflammation. Front Immunol 5:10124653726 10.3389/fimmu.2014.00101
21. Holtkamp SJ Ince LM Barnoud C Schmitt MT Sinturel F Pilorz V Pick R Jemelin S Muhlstadt M Boehncke WH Circadian clocks guide dendritic cells into skin lymphatics Nat Immunol 2021 22 1375 1381 10.1038/s41590-021-01040-x 34663979
Holtkamp SJ, Ince LM, Barnoud C, Schmitt MT, Sinturel F, Pilorz V, Pick R, Jemelin S, Muhlstadt M, Boehncke WH et al (2021) Circadian clocks guide dendritic cells into skin lymphatics. Nat Immunol 22:1375–138134663979 10.1038/s41590-021-01040-x
22. Wang C Barnoud C Cenerenti M Sun M Caffa I Kizil B Bill R Liu Y Pick R Garnier L Dendritic cells direct circadian anti-tumour immune responses Nature 2023 614 136 143 10.1038/s41586-022-05605-0 36470303
Wang C, Barnoud C, Cenerenti M, Sun M, Caffa I, Kizil B, Bill R, Liu Y, Pick R, Garnier L et al (2023) Dendritic cells direct circadian anti-tumour immune responses. Nature 614:136–14336470303 10.1038/s41586-022-05605-0
23. Carman CV Springer TA A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them J Cell Biol 2004 167 377 388 10.1083/jcb.200404129 15504916
Carman CV, Springer TA (2004) A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J Cell Biol 167:377–38815504916 10.1083/jcb.200404129
24. Millan J Hewlett L Glyn M Toomre D Clark P Ridley AJ Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains Nat Cell Biol 2006 8 113 123 10.1038/ncb1356 16429128
Millan J, Hewlett L, Glyn M, Toomre D, Clark P, Ridley AJ (2006) Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains. Nat Cell Biol 8:113–12316429128 10.1038/ncb1356
25. Nieminen M Henttinen T Merinen M Marttila-Ichihara F Eriksson JE Jalkanen S Vimentin function in lymphocyte adhesion and transcellular migration Nat Cell Biol 2006 8 156 162 10.1038/ncb1355 16429129
Nieminen M, Henttinen T, Merinen M, Marttila-Ichihara F, Eriksson JE, Jalkanen S (2006) Vimentin function in lymphocyte adhesion and transcellular migration. Nat Cell Biol 8:156–16216429129 10.1038/ncb1355
26. Weber M Hauschild R Schwarz J Moussion C de Vries I Legler DF Luther SA Bollenbach T Sixt M Interstitial dendritic cell guidance by haptotactic chemokine gradients Science 2013 339 328 332 10.1126/science.1228456 23329049
Weber M, Hauschild R, Schwarz J, Moussion C, de Vries I, Legler DF, Luther SA, Bollenbach T, Sixt M (2013) Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science 339:328–33223329049 10.1126/science.1228456
27. Vaahtomeri K Brown M Hauschild R De Vries I Leithner AF Mehling M Kaufmann WA Sixt M Locally triggered release of the chemokine CCL21 promotes dendritic cell transmigration across lymphatic endothelia Cell Rep 2017 19 902 909 10.1016/j.celrep.2017.04.027 28467903
Vaahtomeri K, Brown M, Hauschild R, De Vries I, Leithner AF, Mehling M, Kaufmann WA, Sixt M (2017) Locally triggered release of the chemokine CCL21 promotes dendritic cell transmigration across lymphatic endothelia. Cell Rep 19:902–90928467903 10.1016/j.celrep.2017.04.027
28. Vaahtomeri K Moussion C Hauschild R Sixt M Shape and function of interstitial chemokine CCL21 gradients are Independent of Heparan Sulfates produced by lymphatic endothelium Front Immunol 2021 12 630002 10.3389/fimmu.2021.630002 33717158
Vaahtomeri K, Moussion C, Hauschild R, Sixt M (2021) Shape and function of interstitial chemokine CCL21 gradients are Independent of Heparan Sulfates produced by lymphatic endothelium. Front Immunol 12:63000233717158 10.3389/fimmu.2021.630002
29. Vieira JM Norman S Del Villa C Cahill TJ Barnette DN Gunadasa-Rohling M Johnson LA Greaves DR Carr CA Jackson DG The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction J Clin Invest 2018 128 3402 3412 10.1172/JCI97192 29985167
Vieira JM, Norman S, Del Villa C, Cahill TJ, Barnette DN, Gunadasa-Rohling M, Johnson LA, Greaves DR, Carr CA, Jackson DG et al (2018) The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction. J Clin Invest 128:3402–341229985167 10.1172/JCI97192
30. Ravaud C, Ved N, Jackson DG, Vieira JM, Riley PR (2021) Lymphatic clearance of Immune cells in Cardiovascular Disease. Cells 10
31. Brinkman CC Iwami D Hritzo MK Xiong Y Ahmad S Simon T Hippen KL Blazar BR Bromberg JS Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration Nat Commun 2016 7 12021 10.1038/ncomms12021 27323847
Brinkman CC, Iwami D, Hritzo MK, Xiong Y, Ahmad S, Simon T, Hippen KL, Blazar BR, Bromberg JS (2016) Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration. Nat Commun 7:1202127323847 10.1038/ncomms12021
32. Piao W Xiong Y Famulski K Brinkman CC Li L Toney N Wagner C Saxena V Simon T Bromberg JS Regulation of T cell afferent lymphatic migration by targeting LTbetaR-mediated non-classical NFkappaB signaling Nat Commun 2018 9 3020 10.1038/s41467-018-05412-0 30069025
Piao W, Xiong Y, Famulski K, Brinkman CC, Li L, Toney N, Wagner C, Saxena V, Simon T, Bromberg JS (2018) Regulation of T cell afferent lymphatic migration by targeting LTbetaR-mediated non-classical NFkappaB signaling. Nat Commun 9:302030069025 10.1038/s41467-018-05412-0
33. Hampton HR Bailey J Tomura M Brink R Chtanova T Microbe-dependent lymphatic migration of neutrophils modulates lymphocyte proliferation in lymph nodes Nat Commun 2015 6 7139 10.1038/ncomms8139 25972253
Hampton HR, Bailey J, Tomura M, Brink R, Chtanova T (2015) Microbe-dependent lymphatic migration of neutrophils modulates lymphocyte proliferation in lymph nodes. Nat Commun 6:713925972253 10.1038/ncomms8139
34. Rigby DA Ferguson DJ Johnson LA Jackson DG Neutrophils rapidly transit inflamed lymphatic vessel endothelium via integrin-dependent proteolysis and lipoxin-induced junctional retraction J Leukoc Biol 2015 98 897 912 10.1189/jlb.1HI0415-149R 26216937
Rigby DA, Ferguson DJ, Johnson LA, Jackson DG (2015) Neutrophils rapidly transit inflamed lymphatic vessel endothelium via integrin-dependent proteolysis and lipoxin-induced junctional retraction. J Leukoc Biol 98:897–91226216937 10.1189/jlb.1HI0415-149R
35. Arasa J, Collado-Diaz V, Kritikos I, Medina-Sanchez JD, Friess MC, Sigmund EC, Schineis P, Hunter MC, Tacconi C, Paterson N et al (2021) Upregulation of VCAM-1 in lymphatic collectors supports dendritic cell entry and rapid migration to lymph nodes in inflammation. J Exp Med 218. 10.1084/jem.20201413
36. Johnson LA Clasper S Holt AP Lalor PF Baban D Jackson DG An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium J Exp Med 2006 203 2763 2777 10.1084/jem.20051759 17116732
Johnson LA, Clasper S, Holt AP, Lalor PF, Baban D, Jackson DG (2006) An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J Exp Med 203:2763–277717116732 10.1084/jem.20051759
37. Teijeira A Garasa S Pelaez R Azpilikueta A Ochoa C Marre D Rodrigues M Alfaro C Auba C Valitutti S Lymphatic endothelium forms integrin-engaging 3D structures during DC transit across inflamed lymphatic vessels J Invest Dermatol 2013 133 2276 2285 10.1038/jid.2013.152 23528818
Teijeira A, Garasa S, Pelaez R, Azpilikueta A, Ochoa C, Marre D, Rodrigues M, Alfaro C, Auba C, Valitutti S et al (2013) Lymphatic endothelium forms integrin-engaging 3D structures during DC transit across inflamed lymphatic vessels. J Invest Dermatol 133:2276–228523528818 10.1038/jid.2013.152
38. Hunter MC Teijeira A Halin C T cell trafficking through lymphatic vessels Front Immunol 2016 7 613 10.3389/fimmu.2016.00613 28066423
Hunter MC, Teijeira A, Halin C (2016) T cell trafficking through lymphatic vessels. Front Immunol 7:61328066423 10.3389/fimmu.2016.00613
39. Teijeira A Hunter MC Russo E Proulx ST Frei T Debes GF Coles M Melero I Detmar M Rouzaut A T Cell Migration from Inflamed skin to draining Lymph Nodes requires Intralymphatic crawling supported by ICAM-1/LFA-1 interactions Cell Rep 2017 18 857 865 10.1016/j.celrep.2016.12.078 28122237
Teijeira A, Hunter MC, Russo E, Proulx ST, Frei T, Debes GF, Coles M, Melero I, Detmar M, Rouzaut A et al (2017) T Cell Migration from Inflamed skin to draining Lymph Nodes requires Intralymphatic crawling supported by ICAM-1/LFA-1 interactions. Cell Rep 18:857–86528122237 10.1016/j.celrep.2016.12.078
40. Vigl B Aebischer D Nitschke M Iolyeva M Rothlin T Antsiferova O Halin C Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner Blood 2011 118 205 215 10.1182/blood-2010-12-326447 21596851
Vigl B, Aebischer D, Nitschke M, Iolyeva M, Rothlin T, Antsiferova O, Halin C (2011) Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner. Blood 118:205–21521596851 10.1182/blood-2010-12-326447
41. Arasa J, Collado-Diaz V, Halin C (2021) Structure and Immune Function of Afferent Lymphatics and Their Mechanistic Contribution to Dendritic Cell and T Cell Trafficking. Cells 10
42. Bano F Banerji S Howarth M Jackson D Richter R A single molecule assay to probe monovalent and multivalent bonds between hyaluronan and its key leukocyte receptor CD44 under force Sci Rep 2016 6 34176 10.1038/srep34176 27679982
Bano F, Banerji S, Howarth M, Jackson D, Richter R (2016) A single molecule assay to probe monovalent and multivalent bonds between hyaluronan and its key leukocyte receptor CD44 under force. Sci Rep 6:3417627679982 10.1038/srep34176
43. Toole BP Hyaluronan: from extracellular glue to pericellular cue Nat Rev Cancer 2004 4 528 539 10.1038/nrc1391 15229478
Toole BP (2004) Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 4:528–53915229478 10.1038/nrc1391
44. Camenisch TD Schroeder JA Bradley J Klewer SE McDonald JA Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2-ErbB3 receptors Nat Med 2002 8 850 855 10.1038/nm742 12134143
Camenisch TD, Schroeder JA, Bradley J, Klewer SE, McDonald JA (2002) Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2-ErbB3 receptors. Nat Med 8:850–85512134143 10.1038/nm742
45. Lu W Kang Y Epithelial-mesenchymal plasticity in Cancer Progression and Metastasis Dev Cell 2019 49 361 374 10.1016/j.devcel.2019.04.010 31063755
Lu W, Kang Y (2019) Epithelial-mesenchymal plasticity in Cancer Progression and Metastasis. Dev Cell 49:361–37431063755 10.1016/j.devcel.2019.04.010
46. Setala LP Tammi MI Tammi RH Eskelinen MJ Lipponen PK Agren UM Parkkinen J Alhava EM Kosma VM Hyaluronan expression in gastric cancer cells is associated with local and nodal spread and reduced survival rate Br J Cancer 1999 79 1133 1138 10.1038/sj.bjc.6690180 10098747
Setala LP, Tammi MI, Tammi RH, Eskelinen MJ, Lipponen PK, Agren UM, Parkkinen J, Alhava EM, Kosma VM (1999) Hyaluronan expression in gastric cancer cells is associated with local and nodal spread and reduced survival rate. Br J Cancer 79:1133–113810098747 10.1038/sj.bjc.6690180
47. Ropponen K Tammi M Parkkinen J Eskelinen M Tammi R Lipponen P Agren U Alhava E Kosma VM Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer Cancer Res 1998 58 342 347 9443415
Ropponen K, Tammi M, Parkkinen J, Eskelinen M, Tammi R, Lipponen P, Agren U, Alhava E, Kosma VM (1998) Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer. Cancer Res 58:342–3479443415
48. Williams CS Leek RD Robson AM Banerji S Prevo R Harris AL Jackson DG Absence of lymphangiogenesis and intratumoural lymph vessels in human metastatic breast cancer J Pathol 2003 200 195 206 10.1002/path.1343 12754740
Williams CS, Leek RD, Robson AM, Banerji S, Prevo R, Harris AL, Jackson DG (2003) Absence of lymphangiogenesis and intratumoural lymph vessels in human metastatic breast cancer. J Pathol 200:195–20612754740 10.1002/path.1343
49. Du Y Liu Y Wang Y He Y Yang C Gao F LYVE-1 enhances the adhesion of HS-578T cells to COS-7 cells via hyaluronan Clin Invest Med 2011 34 E45 54 10.25011/cim.v34i1.14912 21291635
Du Y, Liu Y, Wang Y, He Y, Yang C, Gao F (2011) LYVE-1 enhances the adhesion of HS-578T cells to COS-7 cells via hyaluronan. Clin Invest Med 34:E45–5421291635 10.25011/cim.v34i1.14912
50. Azzali G On the transendothelial passage of tumor cell from extravasal matrix into the lumen of absorbing lymphatic vessel Microvasc Res 2006 72 74 85 10.1016/j.mvr.2006.03.005 16730031
Azzali G (2006) On the transendothelial passage of tumor cell from extravasal matrix into the lumen of absorbing lymphatic vessel. Microvasc Res 72:74–8516730031 10.1016/j.mvr.2006.03.005
51. Brown M Assen FP Leithner A Abe J Schachner H Asfour G Bago-Horvath Z Stein JV Uhrin P Sixt M Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice Science 2018 359 1408 1411 10.1126/science.aal3662 29567714
Brown M, Assen FP, Leithner A, Abe J, Schachner H, Asfour G, Bago-Horvath Z, Stein JV, Uhrin P, Sixt M et al (2018) Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice. Science 359:1408–141129567714 10.1126/science.aal3662
52. Padera TP Kadambi A di Tomaso E Carreira CM Brown EB Boucher Y Choi NC Mathisen D Wain J Mark EJ Lymphatic metastasis in the absence of functional intratumor lymphatics Science 2018 296 1883 1886 10.1126/science.1071420
Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ et al (2018) Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296:1883–188610.1126/science.1071420
