15 April 2020

The creation of new blood vessels in the lymph nodes during lymphoma is different from that of tumours in other parts of the body, according to a German study.

The work was led by researchers at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin. They believe their results, published in the journal Cancer Research, point to potential targets for treatment which could be more effective at slowing tumour growth for lymphoma patients.

Dr Uta Höpken, of the MDC's Microenvironmental Regulation in Autoimmunity and Cancer Lab, said the study was based on the hypothesis that tumours in lymph nodes are different from solid tumours because the lymph nodes provide a very supportive environment for blood-borne tumour cells.

Blood vessels in early lymphoma are unusually dense and irregular, with more branching than found in blood vessels of healthy lymph nodes. This kind of branching has not been observed in solid tumours, in infected lymph nodes or in developing organs, which are other typical sites of new blood vessel development, or angiogenesis.

To learn more about the mechanism behind this unique pattern, the team analysed gene expression patterns in transgenic mouse models that develop lymphoma, as well as mice implanted with lymphoma cancer cells.

To their surprise, they team found that the usual culprits implicated in angiogenesis – inflammation, low oxygen levels, and Notch signalling – did not show up in their results.

They also looked at the role of vascular endothelial growth factor (VEGF) family of proteins, which are primary drivers of normal blood vessel development, as well as angiogenesis in tumours. VEGF-A is the family member mediating the process in most solid tumours, in conjunction with the receptor VEGFR-2.

The research team discovered that in the early stages of lymphoma, VEGF-C is the most active protein. However, nothing changed when they tried to block VEGFR-2 to inhibit VEGF-C activity.

But when they blocked a different receptor, VEGFR-3, blood vessel growth significantly slowed. They also found that when they inhibited the receptor for lymphotoxin, which is needed for normal lymph node development, it also helped to slow down angiogenesis.

Timing was crucial, they said: the team were studying angiogenesis during the first 12 days after cancer cells invaded lymph nodes. This enabled them to observe the early interactions between tumour cells and lymph node environment, well before any overt symptoms of lymphoma would normally occur.

They showed that the lymph node was being restructured even when only 5 to 10% of lymph node cells were cancerous. “The changes we saw occur very early and with a very low tumour burden,” said Dr Höpken.

Finally, the team used two drugs that are already approved for clinical use in autoimmune disorders to successfully inhibit the pathways. They confirmed the treatment also worked on human blood vessel cells in the lab. The researchers hope the treatment can be taken up for clinical trials to investigate its effectiveness in lymphoma patients.

Source: Gloger M, Menzel L, Grau M, Vion AC, Anagnostopoulos I, Zapukhlyak M, Gerlach K, Kammertöns T, Hehlgans T, Zschummel M, Lenz G, Gerhardt H, Höpken UE, Rehm A (2020) “Lymphoma Angiogenesis Is Orchestrated by Noncanonical Signaling Pathways”, Cancer Research, doi: 10.1158/0008-5472.CAN-19-1493


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