Abstract
The lymphatic system provides an initial route for cancer cell dissemination in many cancers including melanoma. However, it is largely unknown how the lymphatic system changes during tumor progression due in part to the lack of imaging techniques currently available. In this study, we non-invasively imaged changes of lymphatic function and drainage patterns using near-infrared fluorescence (NIRF) imaging. Dynamic NIRF imaging following intradermal injection of indocyanine green (ICG) was conducted in C57BL/6 mice prior to inoculation of B16F10 murine melanoma cells to the dorsal aspect of the left hindpaw for baseline data or directly to the popliteal lymph node (PLN) and until 21 days post-implantation (p.i.). A series of acquired fluorescent images were quantified to measure lymphatic contractile function. Computed tomography (CT) was also performed to measure the volume of tumor-draining lymph nodes (LNs). We observed significant reduction of lymphatic contractility from 7 days p.i. until 21 days p.i.. Altered lymphatic drainage patterns were also detected at 21 days p.i. in mice with tumor in the paw and at 11 days p.i. in mice with tumor in the PLN, due to lymphatic obstruction of normal lymphatic drainages caused by extensive tumor invasion of draining LNs. Since lymphatic function and architecture were progressively altered during tumor growth and metastasis, non-invasive NIRF imaging may provide a new method to stage disease. In addition, this novel technique can be used as a diagnostic method to non-invasively assess lymphatic response as mechanism of therapeutic action.
Highlights
Melanoma is the most lethal skin cancer in large part due to its propensity to metastasize to distant sites
When metastasis is observed within the sentinel LN (SLN), complete lymph nodes (LNs) dissection is performed for regional disease control and cure
It has been postulated that massive LN metastasis can obstruct normal lymph flow and change normal lymphatic drainage pathways
Summary
Melanoma is the most lethal skin cancer in large part due to its propensity to metastasize to distant sites. Because the lymphatic system provides an initial transport route for cancer cell dissemination for melanoma, regional lymph node (LN) metastases are regarded as the first site of metastasis in most cutaneous melanoma patients with tumor progression [1,2]. It has been postulated that massive LN metastasis can obstruct normal lymph flow and change normal lymphatic drainage pathways. It has been reported that metastatic melanoma in patients can block normal lymph flow to the SLN [3,4]. In preclinical studies in mice bearing C6 rat glioma, we demonstrated that extensive tumor invasion of draining LNs can alter or completely block normal lymphatic fluid passage, leading to changes of lymphatic drainage pathways [5]
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