Cancer is known to spread via the lymphatic system as well as the circulatory system, but the degree to which the lymphatic system contributes to metastasis remains an open question. To address this question—and explore the therapeutic potential of restricting the lymphatic route—scientists from the University of Heidelberg and the German Cancer Research Center (DKFZ) modeled intratumoral lymphatics in mice. They also tried “regressing established intratumoral lymphatics” by interfering with a signaling pathway that sustains lymph endothelial cells.

The researchers discovered that an antibody against a signaling molecule of the vascular system causes the lymphatic vessels in the tumor to die, suppresses metastasis, and thus prolongs the survival of the mice. The results have now been published in the journal Cancer Discovery, in an article titled, “Timed Ang2-targeted therapy identifies the Angiopoietin-Tie pathway as key regulator of fatal lymphogenous metastasis.”

The article describes how the scientists arrived at a new approach that may block the dangerous colonization and spread of tumor cells. First, the scientists found a way to model lymphogenous metastasis in mice. Next, they identified a therapeutic target to restrict lymphogenous tumor cell dissemination. Finally, they demonstrated that neutralizing the target significantly improved survival in model animals.

“Here, we established a GEMM fragment-based tumor model uniquely sustaining a functional network of intratumoral lymphatics that facilitates seeding of fatal peripheral metastases,” the article’s authors wrote. “Multi-regimen survival studies and correlative patient data identified primary tumor-derived Angiopoietin-2 (Ang2) as a potent therapeutic target to restrict lymphogenous tumor cell dissemination.

Until now, it has been difficult to study the complicated architecture of a tumor and its spread in a living organism. The Heidelberg and DKFZ team led by Hellmut Augustin, PhD, senior author of the current study, has now succeeded in developing a suitable model system.

“The key to this was a direct transplantation of tumor tissue from one mouse to another without prior cell culture,” explained Nicolas Gengenbacher, a researcher on the Heidelberg and DKFZ team, and first author of the current study. “In this model, the natural tissue structure was preserved, and the cancerous tumors were able to form functional lymph vessels that were connected to the lymphatic system—a prerequisite for lymphogenic metastasis.”

Using these animals, the researchers were able to confirm that cancer cells often migrate via the lymph vessels first into nearby lymph nodes and from there continue to metastasize into vital organs. The surgical removal of the primary tumor enabled the researchers to simulate a disease situation that corresponded to that of a cancer patient after surgery: Daughter tumors and not the primary tumor became crucial for survival.

In their search for ways to prevent the development of metastases, the research team focused on the cells that line the lymph vessels from the inside, the so-called lymph endothelial cells. Endothelial cells control many important properties of the blood and lymph vessels and produce numerous signaling molecules and growth factors.

“Mechanistically, tumor-associated lymphatic endothelial cells (EC), in contrast to blood vascular EC, were found to be critically addicted to the Angiopoietin-Tie pathway,” the article’s authors detailed. “Genetic manipulation experiments in combination with single-cell mapping revealed agonistically-acting Ang2/Tie2-signaling as key regulator of lymphatic maintenance.”

Essentially, the researchers found that the messenger substance angiopoietin 2 ensures the survival of lymph endothelial cells in tumors. An antibody that blocks angiopoietin-2 caused the lymph vessels in the tumor to selectively die. This interrupted the transport pathways for cancer cells to detach and prevented them from spreading to nearby lymph nodes. As a result, fewer daughter tumors formed in distant organs and the mice survived significantly longer.

Histological image of blood vessels (green) and lymph vessels (orange) in a cross-section of a tumor. Right: Treatment with an angiopoietin-2-blocking antibody leads to the death of the tumor lymph vessels and prevents the spread of tumor cells via the lymph vessel system. [H. Augustin / German Cancer Research Center]
“Acute presurgical Ang2-neutralization was sufficient to prolong survival by regressing established intratumoral lymphatics,” the article’s authors noted. “[Hence, we identified] a novel therapeutic regimen that warrants further clinical evaluation.”

Malignant cells often remain in the body after cancer surgery and can be the starting point for a relapse of the disease. “Surprisingly, we were able to effectively prevent the spread of tumors in the mice even when we blocked angiopoietin-2 only shortly before tumor surgery,” added Augustin. “However, we have only been able to show that angiopoietin-2 blockade has a therapeutic effect within this treatment window in experimental animals. Whether this approach also helps in humans against the spread of tumors must be clarified in further investigations.”

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