Photodynamic Ablation of Lymphatic Vessels and Intralymphatic Cancer Cells Prevents Metastasis

Destruction of lymphatic vessels by photodynamic therapy suppresses metastasis by eradicating both the in-transit tumor cells and their conduit to distant tissues. Shining a Light on Tumor Metastasis Tumor cells have several routes that enable them to move from the primary tumor to distant tissues, a process called metastasis. It is metastasis of the primary tumor that kills most cancer patients. One of the least studied routes of metastasis is the lymphatic system. Many tumors produce vascular endothelial growth factor–C (VEGF-C) or VEGF-D, factors that promote the formation of new lymphatic vessels (lymphangiogenesis). The newly formed lymphatic vessels enable tumor cells to travel from the primary tumor to the regional lymph nodes from whence they can spread throughout the body. In a new study, Tammela and colleagues investigate whether eradicating tumor-associated lymphatic vessels and the tumor cells they contain using photodynamic therapy (PDT) with a light-activated cytotoxic compound could reduce or eliminate tumor metastasis. They selected the mouse ear as their model system because it is easy to image both the lymphatic vessels and the in-transit tumor cells. The mouse ear is also amenable to PDT because it is very thin, thus enabling sufficient tissue penetration by the infrared light that activates the cytotoxic compound (verteporfin). The authors implanted mouse melanoma cells or human lung tumor cells into the mouse ear tip and waited 2 weeks for the primary tumors to become established and to induce lymphangiogenesis. Using immunohistochemistry, they observed that the newly formed lymphatic vessels contained in-transit tumor cells as well as small tumor nodules. Using pathology sections taken from a patient with recurrent melanoma, they confirmed that the tumor-associated lymphatic vessels of cancer patients contain in-transit tumor cells and tumor nodules. But could PDT eliminate both tumor-associated lymphatic vessels and the tumor cells inside them? The authors injected verteporfin in a liposomal preparation intradermally into the mouse ear and showed that this cytotoxic dye accumulated specifically in the lymphatic vessels. When they illuminated the mouse ear with infrared laser light, the lymphatic vessels started to shrink and fragment, and became leaky. Could this treatment prevent relapse when combined with surgery? The authors implanted mouse melanoma cells into the flanks of mice and waited 2 weeks until the tumor cells had become established and had metastasized via the lymphatic vessels to the axillary lymph nodes. They then injected verteporfin into the primary tumor and surrounding tissue and illuminated the whole flank with infrared laser light before surgically removing the primary tumor and lymph nodes. They found that the mice receiving PDT and surgery had a much lower relapse rate than those that underwent surgery alone. But will PDT be useful for eradicating tumor-associated lymphatic vessels deep within the tissues of human cancer patients? Using a pig model, Tammela and colleagues demonstrated that this should be feasible. They injected verteporfin into pig hoofs and then used a special laser catheter inserted at the knee to activate the dye. They showed that the lymphatic system ceased to drain as the vessels fragmented and became clogged, indicating that PDT can target lymphatic vessels deep within the body. PDT using verteporfin is currently used clinically to destroy overgrown blood vessels in the retina of patients with macular degeneration. So it should certainly be feasible to use PDT to destroy tumor-associated lymphatic vessels in cancer patients undergoing surgery. Shining a light deep within the body should ensure that an oft-overlooked conduit for tumor metastasis will remain illuminated. The dissemination of tumor cells to sites far from the primary tumor (metastasis) is the principal cause of death in cancer patients. Tumor-associated lymphatic vessels are a key conduit for metastatic tumor cells, which typically first colonize the lymph nodes. Although the primary tumor and affected lymph nodes can be removed during surgery, tumor cells inside lymphatic vessels are left behind. Here, we show that in-transit tumor cells inside lymphatic vessels in mice bearing mouse melanomas or human lung tumors give rise to metastases. Using photodynamic therapy with the benzoporphyrin derivative verteporfin, we selectively destroyed lymphatic vessels in mice and pigs. Destruction of tumor-associated lymphatic vessels also eradicated intralymphatic tumor cells and prevented metastasis of mouse melanoma cells and subsequent relapse. Photodynamic therapy, when combined with anti-lymphangiogenic therapy, prevented further tumor invasion of lymphatic vessels. These findings highlight the potential of targeting in-transit tumor cells in patients.