Abstract LB-277: Abnormal lymphatic drainage pathway and function in mice with lymph node metastases

Abstract

Abstract The lymphatic system provides a major route of cancer cell dissemination from the primary lesion site, to regional draining lymph nodes (LNs), through the lymphatic to blood vasculatures, and ultimately to distant sites of metastasis. However, to date there has been no in vivo imaging technique available to demonstrate functional and structural changes of overall lymphatic system in response to tumor growth and metastasis. In order to elucidate whether there are spatial and temporal changes in lymphatic function and architecture during tumor progression, we employed a dynamic near-infrared (NIR) fluorescence imaging technique. C6/Lacz rat glioma cells were implanted intradermally into the tail at 1 to 2 cm caudal to the rectum or in the right hindlimb in balb/c nude mice. Mice with a tumor in the tail were imaged at three weeks post implantation and mice with a tumor in the hindlimb at two and three weeks after tumor inoculation. Dynamic NIR imaging with 200 ms exposure time was conducted after intradermal injection of indocyanine green (ICG) to the base of the mouse tail for a hindlimb tumor model and to the tail 2cm away from the tail tip for a tail tumor model. Our imaging data in mice with a tail tumor show no uptake of fluorophore in the lymphatic capillaries in the skin above the tumor, which is in agreement with previous reports. In addition, our results show greater staining of lymphatic capillary network to the distal tumor periphery, dilated and tortuous collecting lymphatic vessels, and reduced or loss of propulsive lymphatic flow. Moreover, altered lymphatic drainage patterns and abnormal lymphatic flow from the collecting lymphatic vessel to the lymphatic capillaries at the distal tumor margin were detected. In a hindlimb tumor model, the lymphatic drainage pattern transiently changed with progressive disease. Mice with either the inguinal (primary) or axillary (secondary) LN metastasis showed dilated and leaky fluorescent lymphatic vessels, which circumvented the primary tumor and often the inguinal LN with a tumor and drained to the brachial LN. In one mouse with the inguinal and axillary LN metastases, ICG-labeled lymph drained across the midline of the animal body and thus to the left axillary LN. Magnified fluorescent images also show diffuse dye patterns. In addition, reduced lymphatic contractile function was seen in mice with LN metastasis. In summary, we showed in an animal model that gross cancer metastasis to the draining LNs is accompanied by abnormal lymphatic drainage pathway as well as reduced functional lymph propulsion in comparison to tumor-free mice. Therefore, this emerging NIR fluorescence imaging technology can be used to non-invasively and quantitatively detect functional lymphatic changes associated with cancer, which may enable accurate nodal staging of cancer patients and provide new approaches to diagnoses and therapies against cancer metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-277.