The team at the Max Delbrück Center for Molecular Medicine at the Helmholtz Association (MDC) created new blood vessels (a process called angiogenesis) for tumors in lymph nodes compared with tumors elsewhere in the body, such as the colon or lungs. different. ) was published in the journal Cancer Research. Scientists from the MDC laboratories of Dr. Armin Rehm, Dr. Uta Höpken and Professor Holger Gerhardt participated in the project. The research team identified potentially more effective treatment targets to slow tumor growth in lymphoma patients.
Lymphoma is a cancer of the lymphatic system, including the lymph nodes, spleen and bone marrow. Lymphoma patients with increased markers of vascular development generally have poorer survival. They have also been unsuccessful in inhibiting blood vessel development in other cancer types.
"We hypothesized that tumors in lymph nodes are completely different from solid tumors because lymph nodes provide such a supportive microenvironment for blood-borne tumor cells," said Dr. Uta Höpken, head of microenvironmental regulation at the MDC Autoimmune and Cancer Laboratory. MDC Transforms Tumors "It's absolutely surprising that there still aren't any of the usual suspects involved," said Dr. Armin Rehm, head of the immunology laboratory.
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The blood vessels in early-stage lymphoma are unusually dense and irregular, with many more branches than those in healthy lymph nodes. Branching patterns were not observed in solid tumors, infected lymph nodes, or developing organs, which are often other sites of neovascularization.
To uncover the unique signaling pathways that drive this development, the team conducted analyzes using genetically modified mouse models that develop lymphoma, as well as mice implanted with lymphoma cancer cells. They studied gene expression patterns to understand which genes and proteins were most active during the initial stages of tumor development.
The culprits typically associated with tumor angiogenesis—inflammation, low oxygen levels, and signaling between the base and tips of blood vessels known as Notch signaling—did not appear in the results.
A group of proteins called vascular endothelial growth factors (VEGFs) are thought to be major drivers of normal blood vessel development as well as tumor angiogenesis. In most solid tumors, VEGF-A, a protein that mediates this process, binds to its receptor, VEGFR-2.
In the early stages of lymphoma, the team found that VEGF-C is the most active protein. When they tried blocking the VEGFR-2 receptor to inhibit VEGF-C activity, nothing changed.
But when the researchers blocked another receptor, VEGFR-3, the growth of blood vessels was significantly slowed. They also disrupted receptors for a small protein called lymphotoxin, which is normally required for normal lymph node development and also helps slow blood vessel growth.
The team used two drugs already approved for autoimmune diseases to inhibit this pathway. They confirmed that the treatment was also effective on human cells. Although not clinicians themselves, the researchers hope the treatment may be used in clinical trials to study its effectiveness in human patients. "If some cancer cells survive chemotherapy, it may be possible to prevent recurrence by addressing these pathways with immunotherapy," Rehm said.