Abstract
Chemotherapy remains a mainstay of cancer treatment but its use is often limited by the development of adverse reactions. Severe loss of body weight (cachexia) is a frequent cause of death in cancer patients and is exacerbated by chemotherapy. We show that genetic inactivation of vascular endothelial growth factor (VEGF)-A in myeloid cells prevents chemotherapy-induced cachexia by inhibiting skeletal muscle loss and the lipolysis of white adipose tissue. It also improves clearance of senescent tumour cells by natural killer cells and inhibits tumour regrowth after chemotherapy. The effects depend on the chemoattractant chemerin, which is released by the tumour endothelium in response to chemotherapy. The findings define chemerin as a critical mediator of the immune response, as well as an important inhibitor of cancer cachexia. Targeting myeloid cell-derived VEGF signalling should impede the lipolysis and weight loss that is frequently associated with chemotherapy, thereby substantially improving the therapeutic outcome.
Highlights
Chemotherapy remains a mainstay of cancer treatment but its use is often limited by the development of adverse reactions
We have shown that specific deletion of vascular endothelial growth factor (VEGF) in tumour-infiltrating myeloid cells leads to normalized tumour blood vessels and increased tumour cell apoptosis[3]
The VEGF-A gene is deleted in the myeloid cells of the resulting mutant (Mut, LysMCre/VEGFf/f) mice and the animals’ response to chemotherapy is improved: the mice show vascular normalization and an increase in tumour cell apoptosis[3]
Summary
Chemotherapy remains a mainstay of cancer treatment but its use is often limited by the development of adverse reactions. Severe loss of body weight (cachexia) is a frequent cause of death in cancer patients and is exacerbated by chemotherapy. We show that genetic inactivation of vascular endothelial growth factor (VEGF)-A in myeloid cells prevents chemotherapy-induced cachexia by inhibiting skeletal muscle loss and the lipolysis of white adipose tissue. It improves clearance of senescent tumour cells by natural killer cells and inhibits tumour regrowth after chemotherapy. Targeting myeloid cell-derived VEGF signalling should impede the lipolysis and weight loss that is frequently associated with chemotherapy, thereby substantially improving the therapeutic outcome. We demonstrate further that endothelial release of chemerin on chemotherapy can be enhanced by targeting VEGF-A in myeloid cells, leading to improved chemotherapeutic success
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