Zeroing in on two targets at the same time may be the key to stopping the spread of aggressive cancers, according to new research from the University of East Anglia and the Quadram Institute. Scientists found that tumor growth in mice could be stopped by simultaneously targeting two signaling switches that trigger growth of new blood vessels.

Their study “Endothelial VEGFR co-receptors neuropilin-1 and neuropilin-2 are essential for tumor angiogenesis”, published in Cancer Research Communications, points to new approaches for treating cancer in humans.

“Neuropilin (NRP) expression is highly correlated with poor outcome in multiple cancer subtypes. As known co-receptors for vascular endothelial growth factor receptors (VEGFRs), core drivers of angiogenesis, past investigations have alluded to their functional roles in facilitating tumorigenesis by promoting invasive vessel growth. Despite this, it remains unclear as to whether NRP1 and NRP2 act in a synergistic manner to enhance pathological angiogenesis,” the investigators wrote.

“Here we demonstrate, using NRP1ECKO, NRP2ECKO, and NRP1/NRP2ECKO mouse models, that maximum inhibition of primary tumor development and angiogenesis is achieved when both endothelial NRP1 and NRP2 are targeted simultaneously. Metastasis and secondary site angiogenesis was also significantly inhibited in NRP1/NRP2ECKO animals. Mechanistic studies revealed that co-depleting NRP1 and NRP2 in mouse-microvascular endothelial cells (ECs) stimulates rapid shuttling of VEGFR-2 to Rab7+ endosomes for proteosomal degradation.

“Our results highlight the importance of targeting both NRP1 and NRP2 to modulate tumor angiogenesis.”

Without a blood supply to provide oxygen and nutrients, tumors fail to develop larger than a few millimeters. To grow they release signaling proteins that trigger cells to form blood vessels, a process known as angiogenesis.

Disrupting the signaling proteins

Disrupting these signaling proteins and the receptors on the cell surface that recognize them has been identified previously as a potential strategy to slow tumor growth, but currently, the clinical benefits of such interventions have shown limited success unless supplemented by chemotherapy. In part, this is because researchers are still unsure of the exact mechanisms by which angiogenesis is controlled, either in a healthy state or in cancer.

Neuropilin-1 and -2 bind to VEGFs, in addition to a plethora of other proteins, triggering a cascade of signals within the cell to activate angiogenesis. Stopping this process in cancer could therefore prevent tumors from developing the complex organization of blood vessels they need to grow.

Researchers have been trying to do just that, using cell and animal models of cancer to identify compounds that block neuropilin-interactions with VEGF. Promising candidates targeting neuropilin-1 have already been demonstrated to slow breast cancer progression in mice.

However, to date, there have been limited studies targeting both neuropilin-1 and -2 simultaneously. Christopher Benwell, PhD, a postdoctoral researcher working with the team of Stephen Robinson, PhD, in the Quadram Institute, sought to address this gap in understanding, by studying mice in which the genes for either neuropilin-1 and -2, or both in combination, had been deleted.

They found that in multiple models of cancer, targeting both neuropilin-1 and -2 severely inhibited tumor angiogenesis, cancer growth, and metastasis. The extent of the effect was much greater than when either one of the receptors was targeted individually.

“We are really excited by these results and have started to delve deeper into the ways these receptors can be manipulated to control angiogenesis in different disease states,” said Benwell.

Further studies in cultured cells suggested how this protection works. When both neuropilin receptors are targeted, the VEGF receptor is rapidly destroyed by the cell, which cuts off the angiogenic response at its source.

“We are hoping this piece of research will inspire others to consider the impact of targeting multiple proteins to achieve a synergistic anticancer response. By doing so, we aim to restrict a cancer’s ability to escape therapy,” said Robinson.



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