Lymphadenectomy promotes tumor growth and cancer cell dissemination in the spontaneous RET mouse model of human uveal melanoma

Abstract

Resection of infiltrated tumor-draining lymph nodes (TDLNs) is a standard practice for the treatment of several cancers including breast cancer and melanoma. However, many randomized prospective trials have failed to show convincing clinical benefits associated with LN removal and the role of TDLNs in cancer dissemination is poorly understood. Here, we found in a well-characterized spontaneous mouse model of uveal melanoma that the growth of the primary tumor was accompanied by increased lymphangiogenesis and cancer cell colonization in the LNs draining the eyes. But, unexpectedly, early resection of the TDLNs increased the growth of the primary tumor and associated blood vessels as well as promoted cancer cell survival and dissemination. These effects were accompanied by increased tumor cell proliferation and expression of phosphorylated AKT. Topical application of a broad anti-inflammatory agent, Tobradex, or an oral treatment with cyclooxygenase-2 specific inhibitor, Celecoxib, reversed tumor progression observed after complete lymphadenectomy. Our study confirms the importance of tumor homeostasis in cancer progression by showing the enhancing effects of TDLN removal on tumor growth and cancer cell dissemination, and suggests that TDLN resection may only be beneficial if used in combination with anti-inflammatory drugs such as Tobradex and Celecoxib.

Bidirectional Crosstalk between Lymphatic Endothelial Cell and T Cell and Its Implications in Tumor Immunity

“…One of the cardinal functions of lymphatic vessel is to transport components of the local tissue containing interstitial solutes, cytokines, growth factors, and immune cells to the downstream LN for the maintenance of tissue fluid homeostasis and peripheral immune tolerance. Tumor cells can “hijack” the lymphatic and induce the expansion of lymphatic vessels for their dissemination, colonization, and the formation of metastasis in the tumor-draining LNs ( 101 , 102 ) (Figure 1 ). Via the lymphatic route, tumor cells can also modify the microenvironment of the metastatic organs from the distal sites before their arrival—referred to premetastatic niche.…”

“…In another model of dermal lymphatic insufficiency (K14-VEGFR3-Ig mice), implanted melanoma grew robustly and exhibited marked reduction in leukocyte infiltration compared with those implanted in control mice, suggesting that lymphatic vessels are essential for the generation of tumor immune responses ( 125 ). In addition, we showed in a spontaneous mouse model of uveal melanoma that early resection of TDLNs promotes primary tumor growth, cancer cell dissemination, and metastasis ( 102 ). Even though we did not examine the role of immune responses in the absence of tumor-draining LNs, it is plausible that uncontrollable growth of primary tumor may be due to the lack of antitumor immunity since the depletion of CD8 + T cells accelerates tumor growth and dissemination in the same model ( 126 ).…”

Animal Models of Uveal Melanoma: Methods, Applicability, and Limitations

“…with early tumor cell dissemination to local and distant organs [ 82 ]. As initial melanocytic lesions are mostly found within the uvea, this model was used for investigations on early local and distant tumor growth as well as dissemination [ 83 , 84 ]. Schiffner and coworkers described a Tg(Grm1) transgenic mouse breed, with spontaneous skin melanoma, which exhibited pigmented choroidal proliferation mimicking spontaneous uveal melanoma [ 85 ].…”