Activation of latent metastases in the lung after resection of a metastatic lymph node in a lymph node metastasis mouse model

Shao, Liang; Ouchi, Tomoki; Sakamoto, Maya; Mori, Shiro; Kodama, Tetsuya

doi:10.1016/j.bbrc.2015.03.066

Cited by 30 publications

(45 citation statements)

References 16 publications

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“…Indeed, Evans blue solution injected into the SiLN has been visualized to flow into the TV . A recent study from our group using real-time imaging has demonstrated the flow of a fluorescent solution from the SiLN into both the efferent LV and TV (Shao et al, 2015), suggesting that there are lymphatic and venous system connections in the SiLN.…”

Section: Discussionmentioning

confidence: 97%

“…We have reported models of LN metastasis suitable for the study of diagnostic and treatment methods in both MXH10/Mo/lpr (Shao et al, 2013;Kato et al, 2015;Kodama et al, 2015;Shao et al, 2015) and MRL/MpJ-lpr/lpr (Li et al, 2013a(Li et al, , 2013b mice. In these models, tumor cells were injected into the SiLN to induce metastasis in the PALN through the lymphatic system.…”

Section: Discussionmentioning

confidence: 99%

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Communication between lymphatic and venous systems in mice

Shao

Takeda

Kato

et al. 2015

Journal of Immunological Methods

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Communication between lymphatic and venous systems in mice

Shao

Takeda

Kato

et al. 2015

Journal of Immunological Methods

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“…The experimental procedures were performed under general anesthesia with 2.5% isoflurane in oxygen, and great efforts were made to minimize animal suffering, as previously reported . The time of inoculation was defined as 0 hour.…”

Section: Methodsmentioning

confidence: 99%

“…Because lymph node metastasis results from the proliferation of tumor cells that have invaded into the marginal sinus from the afferent lymphatic vessels, it is possible that these tumor cells invade the blood vessels penetrating the lymph node capsule and enter the blood circulation to reach distant organs, even during the early stages of lymph node metastasis. Our previous studies revealed that tumor cells migrated to the lungs in a relatively short period of time after their inoculation into a mouse lymph node . Therefore, we proposed a new concept of lymph node‐mediated hematogenous metastasis and have been working to clarify the mechanisms driving the onset of distant metastasis .…”

Section: Introductionmentioning

confidence: 99%

“…From another point of view, it has been shown in clinical studies that tumor cells attached to lung blood vessels are not activated for a considerable period of time, but these dormant tumor cells can be activated by surgical intervention, such as lymph node dissection . In preliminary studies, we have created a mouse model in which dormant tumor cells in lung metastatic lesions are activated after lymph node dissection . In this model, the lung metastases were activated after excision of the lymph node into which the tumor cells had been inoculated.…”

Section: Introductionmentioning

confidence: 99%

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Lymph node resection induces the activation of tumor cells in the lungs

et al. 2019

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Lymph node (LN) dissection is a crucial procedure for cancer staging, diagnosis and treatment, and for predicting patient survival. Activation of lung metastatic lesions after LN dissection has been described for head and neck cancer and breast cancer. Preclinical studies have reported that dissection of a tumor‐bearing LN is involved in the activation and rapid growth of latent tumor metastases in distant organs, but it is also important to understand how normal (non‐tumor‐bearing) LN resection influences secondary cancer formation. Here, we describe how the resection of tumor‐bearing and non‐tumor‐bearing LN affects distant metastases in MXH10/Mo‐lpr/lpr mice. Tumor cells were administered intravenously and/or intranodally into the right subiliac lymph node (SiLN) to create a mouse model of lung metastasis. Luciferase imaging revealed that tumor cells in the lung were activated after resection of the SiLN, irrespective of whether it contained tumor cells. No luciferase activity was detected in the lungs of mice that did not undergo LN resection (excluding the intravenous inoculation group). Our results indicate that resection of an LN can activate distant metastases regardless of whether the LN contains tumor cells. Hence, lung metastatic lesions are suppressed while metastatic LN are present but activated after LN resection. If this phenomenon occurs in patients with cancer, it is likely that lung metastatic lesions may be activated by elective LN dissection in clinical N0 cases. The development of minimally invasive cancer therapy without surgery would help to minimize the risk of activation of distant metastatic lesions by LN resection.

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Treatment of false‐negative metastatic lymph nodes by a lymphatic drug delivery system with 5‐fluorouracil

et al. 2019

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Metastatic lymph nodes ( LN s) may be the origin of systemic metastases. It will be important to develop a strategy that prevents systemic metastasis by treating these LN s at an early stage. False‐negative metastatic LN s, which are found during the early stage of metastasis development, are those that contain tumor cells but have a size and shape similar to LN s that do not host tumor cells. Here, we show that 5‐fluorouracil (5‐ FU ), delivered by means of a novel lymphatic drug delivery system ( LDDS ), can treat LN s with false‐negative metastases in a mouse model. The effects of 5‐ FU on four cell lines were investigated using in vitro cytotoxicity and cell survival assays. The therapeutic effects of LDDS ‐administered 5‐ FU on false‐negative metastatic LN s were evaluated using bioluminescence imaging, high‐frequency ultrasound ( US ), and histology in MHX 10/Mo‐ lpr / lpr mice. These experimental animals develop LN s that are similar in size to human LN s. We found that all cell lines showed sensitivity to 5‐ FU in the in vitro assays. Furthermore, a concentration‐dependent effect of 5‐ FU to inhibit tumor growth was observed in tumor cells with low invasive growth characteristics, although a significant reduction in metastatic LN volume was not detected in MHX 10/Mo‐ lpr / lpr mice. Adverse effects of 5‐ FU were not detected. 5‐Fluorouracil administration with a LDDS is an effective treatment method for false‐negative metastatic LN s. We anticipate that the delivery of anticancer drugs by a LDDS will be of great benefit in the prevention and treatment of cancer metastasis via LN s.

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Activation of latent metastases in the lung after resection of a metastatic lymph node in a lymph node metastasis mouse model

Cited by 30 publications

References 16 publications

Communication between lymphatic and venous systems in mice

Communication between lymphatic and venous systems in mice

Lymph node resection induces the activation of tumor cells in the lungs

Treatment of false‐negative metastatic lymph nodes by a lymphatic drug delivery system with 5‐fluorouracil

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