Lymphatic mapping of mice with systemic lymphoproliferative disorder: Usefulness as an inter-lymph node metastasis model of cancer

Shao, Liang; Mori, Shiro; Yagishita, Yoko; Okuno, Tatsuki; Hatakeyama, Yuriko; Sato, Takuma; Kodama, Tetsuya

doi:10.1016/j.jim.2013.01.004

Cited by 53 publications

(95 citation statements)

References 20 publications

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“…Many investigators are rather loose in their identification and naming of the LNs in experimental mice, especially those associated with the gastrointestinal tract. Recognizing this problem, Van den Broech et al proposed adopting a more precise designation of murine LNs (11), one which was recently validated in an independent study (23). According to this nomenclature, the gastrointestinal tract is serviced by a set of nodes, termed (proximally to distally): the gastric, pancreaticoduodenal, jejeunal, colic, and caudal mesenteric LNs.…”

Section: Discussionmentioning

confidence: 99%

Endoscopic photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut

Morton

Sefik

Upadhyay

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

164

144

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Given mounting evidence of the importance of gut-microbiota/ immune-cell interactions in immune homeostasis and responsiveness, surprisingly little is known about leukocyte movements to, and especially from, the gut. We address this topic in a minimally perturbant manner using Kaede transgenic mice, which universally express a photoconvertible fluorescent reporter. Transcutaneous exposure of the cervical lymph nodes to violet light permitted punctual tagging of immune cells specifically therein, and subsequent monitoring of their immigration to the intestine; endoscopic flashing of the descending colon allowed specific labeling of intestinal leukocytes and tracking of their emigration. Our data reveal an unexpectedly broad movement of leukocyte subsets to and from the gut at steady state, encompassing all lymphoid and myeloid populations examined. Nonetheless, different subsets showed different trafficking proclivities (e.g., regulatory T cells were more restrained than conventional T cells in their exodus from the cervical lymph nodes). The novel endoscopic approach enabled us to evidence gut-derived Th17 cells in the spleens of K/BxN mice at the onset of their genetically determined arthritis, thereby furnishing a critical mechanistic link between the intestinal microbiota, namely segmented filamentous bacteria, and an extraintestinal autoinflammatory disease. mucosal immunology | cell migration | autoimmunity | imaging

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Section: Discussionmentioning

confidence: 99%

Endoscopic photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut

Morton

Sefik

Upadhyay

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

164

144

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“…The concept is to inject drugs, before surgical resection, into upstream LNs within the dissection area, so that these drugs are delivered to downstream LNs outside the dissection area. To demonstrate proof of concept, we have developed MXH10/Mo-lpr/lpr (MXH10/Mo/lpr) inbred mice [1][2][3][4], and metastatic tumor cell lines able to grow in the mice. The phenotype of the lpr (lymphproliferation) gene is characterized by the accumulation of a large number of polyclonal CD4 -CD8 -T cells in the LNs and spleen [5]; the lpr gene is recognized as a "promoting factor" for collagen disease in MRL mice due to Fas-mediated apoptotic insufficiency, and the causative genes of collagen disease are considered to be the background genes of MRL mice [6].…”

Section: Introductionmentioning

confidence: 99%

“…MXH/lpr mice were generated using two different parental inbred strains as progenitors, MRL/lpr (H-2 k haplotype) and C3H/lpr (H-2 k ). MXH10/Mo/lpr mice do not develop severe glomerulonephritis and vasculitis, in contrast to MRL/MpJ-lpr/lpr (MRL/lpr) mice [8], and thus their life span is longer than that of MRL/lpr mice [3]. Conventional mice have LNs with diameters of 1-2 mm, far smaller than those of patients.…”

Section: Introductionmentioning

confidence: 99%

Visualization of fluid drainage pathways in lymphatic vessels and lymph nodes using a mouse model to test a lymphatic drug delivery system

Kodama

Hatakeyama

Kato

et al. 2014

Biomed. Opt. Express

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Curing/preventing micrometastasis to lymph nodes (LNs) located outside the surgically resected area is essential for improving the morbidity and mortality associated with breast cancer and head and neck cancer. However, no lymphatic therapy system exists that can deliver drugs to LNs located outside the dissection area. Here, we demonstrate proof of concept for a drug delivery system using MXH10/Mo-lpr/lpr mice that exhibit systemic lymphadenopathy, with some peripheral LNs being as large as 10 mm in diameter. We report that a fluorescent solution injected into the subiliac LN (defined as the upstream LN within the dissection area) was delivered successfully to the proper axillary LN (defined as the downstream LN outside the dissection area) through the lymphatic vessels. Our results suggest that this approach could be used before surgical resection to deliver drugs to downstream LNs outside the dissection area. We anticipate that our methodology could be applied clinically, before surgical resection, to cure/prevent micrometastasis in LNs outside the dissection area, using techniques such as ultrasound-guided internal jugular vein catheterization.

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“…In a tail lymphedema model, for example, the induced edema was significantly worse in RAMP3−/− mice than in WT mice. Histological analysis revealed abnormal dilatation of lymphatic vessels similar to that seen clinically when there is a malfunction of lymphatic drainage, such as after lymph node resection [30,31]. On the other hand, the numbers of CD31-positive blood vessels and LYVE-1-positive lymphatic vessels were unaffected by RAMP3 deletion, indicating that progression of angiogenesis and lymphangiogenesis was not altered.…”

Section: Discussionmentioning

confidence: 53%

“…For that reason, dysfunction of lymphatic drainage would likely prolong the inflammation in RAMP3−/− mice. In addition, mast cells were recently shown to contribute to innate immunity and tissue repair, though they can be detrimental when chronically stimulated [31]. Consequently, the increased numbers of mast cells seen in RAMP3−/− mice may also have contributed to the prolonged inflammation and edema.…”

Section: Discussionmentioning

confidence: 99%

Functional differentiation of RAMP2 and RAMP3 in their regulation of the vascular system

Yamauchi

Sakurai

Kamiyoshi

et al. 2014

Journal of Molecular and Cellular Cardiology

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Adrenomedullin (AM) is a vasoactive peptide that possesses various bioactivities. AM receptors are dimers consisting of CLR with one of two accessory proteins, RAMP2 or RAMP3. The functional difference between CLR/RAMP2 and CLR/RAMP3 and the relationship between the two receptors remain unclear. To address these issues, we generated RAMP2 and RAMP3 knockout (−/−) mice and have been studying their physiological activities in the vascular system. AM−/− and RAMP2−/− mice die in utero due to blood vessel abnormalities, which is indicative of their essential roles in vascular development. In contrast, RAMP3−/− mice were born normally without any major abnormalities. In adult RAMP3−/− mice, postnatal angiogenesis was normal, but lymphangiography using indocyanine green (ICG) showed delayed drainage of subcutaneous lymphatic vessels. Moreover, chyle transport by intestinal lymphatics was delayed in RAMP3−/− mice, which also showed more severe interstitial edema than wild-type mice in a tail lymphedema model, with characteristic dilatation of lymphatic capillaries and accumulation of inflammatory cells. In scratch-wound assays, migration of isolated RAMP3−/ − lymphatic endothelial cells was delayed as compared to wild-type cells, and AM administration failed to enhance the re-endothelialization. The delay in re-endothelialization was due to a primary migration defect rather than a decrease in proliferation. These results suggest that RAMP3 regulates drainage through lymphatic vessels, and that the AM-RAMP3 system could be a novel therapeutic target for controlling postoperative lymphedema.

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Lymphatic mapping of mice with systemic lymphoproliferative disorder: Usefulness as an inter-lymph node metastasis model of cancer

Cited by 53 publications

References 20 publications

Endoscopic photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut

Endoscopic photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut

Visualization of fluid drainage pathways in lymphatic vessels and lymph nodes using a mouse model to test a lymphatic drug delivery system

Functional differentiation of RAMP2 and RAMP3 in their regulation of the vascular system

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