Abstract
Tumor-associated lymphatics are postulated to provide a transit route for disseminating metastatic cells. This notion is supported by preclinical findings that inhibition of pro-lymphangiogenic signaling during tumor development reduces cell spread to sentinel lymph nodes (SLNs). However, it is unclear how lymphatics downstream of SLNs contribute to metastatic spread into distal organs, or if modulating distal lymph transport impacts disease progression. Utilizing murine models of metastasis, longitudinal in vivo imaging of lymph transport, and function blocking antibodies against two VEGF family members, we provide evidence that distal lymphatics undergo disease course-dependent up-regulation of lymph transport coincidental with structural remodeling. Inhibition of VEGF-C activity with antibodies against VEGF-C or NRP2 prevented these disease-associated changes. Furthermore, utilizing a novel model of adjuvant treatment, we demonstrate that antagonism of VEGF-C or NRP2 decreases post SLN metastasis. These data support a potential therapeutic strategy for inhibiting distant metastatic dissemination via targeting tumor-associated lymphatic remodeling.
Highlights
Metastatic disease accounts for the majority of deaths associated with solid tumors [1,2]
Lymphogenous spread of tumor cells to sentinel lymph nodes is a signature feature of metastatic disease associated with many solid tumors
While a mechanistic understanding of how pro-lymphangiogenesis signaling promotes cell transport to sentinel lymph nodes (SLNs) has been proposed [23,24,27,28,30,31,34,35,36], little is known regarding the behaviors and contribution of distal lymphatic vessels in the further spread of metastatic tumor cells after they exit SLNs; the latter representing a clinically important question as the majority of patients are diagnosed with existing SLN metastases
Summary
Metastatic disease accounts for the majority of deaths associated with solid tumors [1,2]. Prostate, colon and head and neck squamous cell carcinoma patient populations, tumorassociated (peri- and intra-tumoral) lymphatics exhibit features of remodeling: increased lymphatic endothelial cell proliferation, vessel density and dilation [3,4,5,6,7,8,9,10,11,12]. Within these patient populations tumor cells can be detected in associated lymphatics along with metastatic lesions within draining SLNs–the latter provides direct evidence of metastatic cell transit through lymphatics. There is a high degree of correlation between SLN and distant organ metastases, while primary lymphatic vessel density correlates with metastasis frequency and clinical outcome [13,14,15,16,17,18]
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