Lead author, Dr. David Lyden, Stavros S. Niarchos Professor of Pediatric Cardiology and a professor of pediatrics and cell and developmental biology at Weill Cornell Medicine.
Scientists have traditionally taken a tumor-focused view of melanoma, in which cells from the tumor break off and travel to nearby lymph nodes, as cancer metastasizes. . Dr Lyden, who is also a member of the Gale and Ira Drukier Children’s Health Institute and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, said: “What our study showed was lymph nodes. mechanically prepare for future metastases. “There are a lot of changes going on in the lymph node even before the tumor cells get there. We call it the pre-metastasis lymph node.”
Using a mouse model, the lead author, Dr Héctor Peinado, head of the Laboratory of Metastasis and Microbiology, Molecular Oncology Program at the Spanish National Center for Cancer Research (CNIO) in Madrid , Spain, examined the release of exosomes from melanoma cells. Exosomes, also known as extracellular vesicles, are small packages containing various elements and proteins that are secreted by cells and that travel through the lymphatic and blood vessels to distant locations where they can be taken up by cells. other reception.
Dr Peinado, who was previously a postdoctoral associate in Dr. Lyden’s laboratory where much of this work began, discovered that the NGFR protein is released in melanocyte-secreted exosomes out and into the lymph nodes. The protein is then taken up by lymphatic endothelial cells, or cells lining the lymphatic vessels, where it reprograms the lymph node to form new lymphatic vessels. This process, called lymphangiogenesis, encourages the spread of cancer. “The more vessels a lymph node has, the more tumor cells can get in,” says Dr. Lyden.
Furthermore, NGFR increases the secretion of the intracellular adhesion molecule protein 1, which encourages tumor cells to bind to lymphatic vessels, which also encourages metastasis, Dr. Lyden said.
Dr. Peinado also studied how the presence of proteins called integrins on the surface of exsomes determines where metastatic melanoma cells will bind. In this paper, the researchers found that the alpha integral is more important for the spread to the lymph nodes than it is to other organs such as the liver.
Overall, while the lymph nodes are believed to be where the immune system is activated and ready to fight cancer cells, the processes outlined in the study demonstrate that the lymph nodes are immunocompromised. epidemic, which could have implications for disease prognosis, Dr. Lyden said.
When someone has melanoma, doctors will check the sentinel lymph node, or the first node where the tumor is likely to spread, to see if it contains cancer cells. “However, examining the key lymph nodes for tumor cells is not yet complete,” says Dr. Lyden. Additional information such as the presence of NGFR or lymphangiogenesis may indicate a poor prognosis for the patient, meaning that they may require aggressive treatment.
The research could also have implications for drug development. In a mouse model, Dr. Peinado used a small molecule inhibitor called THX-B to prevent NGFR from binding to lymphatic endothelial cells, helping to prevent lymph node metastasis. “This drug needs a lot of testing,” says Dr. Lyden. “But ultimately, I think an NGFR inhibitor could be used in a clinical setting.”
The researchers followed the findings in a mouse model by studying lymph node tissue from 44 patients with stage III or IV melanoma and found that NGFR expression was higher in metastatic lymph node tissues. significantly compared with the original skin lesions. A review of 25 other patients with stage III melanoma revealed a significant increase in the frequency of NGFR-positive tumor cells in lymph node metastasis compared with melanoma of origin.
“People with metastatic disease actually have very high NGFR expression,” says Dr. Lyden. “So at all stages, whether it’s anterior metastasis or total lymph node metastasis, it seems that the molecule is heavily upregulated in patients with a worse prognosis.”
The researchers aimed to validate their findings on a larger number of patients. “We also wanted to determine if we could use a simple blood test to see if exosomes carry NGFR,” Dr. Lyden said. “This will help doctors look at NGFR exosomes over time during therapy to see how treatments should be adjusted.”