Ziheng Guo

COVID-19 has been associated with high prevalences of retinal diseases in humans. However, cellular and molecular mechanisms that underlie the COVID-19-associated retinopathy remains unknown. Here, we deployed a mouse COVID-19 model to investigate the causative link between SARS-CoV-2 infection and retinopathy development. Our data showed that COVID-19-induced pulmonary hypoxia triggered systemic hypoxia and markedly augmented VEGF expression levels in the retina and plasma. High VEGF levels altered vascular structures and functions in the retina, resulting in neovascularization, vascular disorganization, and increased leakiness. We deployed a terminology of coviretinopathy to accurately describe these COVID-19-induced pathological changes in the retina. Consequently, blocking VEGF by a specific neutralizing antibody (VEGF blockade) completely ablated the COVID-19-associated vascular changes in the retina. Together, these findings provide mechanistic insights into the COVID-19-associated retinopathy and propose a therapeutic paradigm for effective treatment of coviretinopathy.

Anti-angiogenic drugs (AADs), which mainly target the vascular endothelial growth factor-A signaling pathway, have become a therapeutic option for cancer patients for two decades. During this period, tremendous clinical experience of anti-angiogenic therapy has been acquired, new AADs have been developed, and the clinical indications for AAD treatment of various cancers have been expanded using monotherapy and combination therapy. However, improvements in the therapeutic outcomes of clinically available AADs and the development of more effective next-generation AADs are still urgently required. This review aims to provide historical and perspective views on tumor angiogenesis to allow readers to gain mechanistic insights and learn new therapeutic development. We revisit the history of concept initiation and AAD discovery, and summarize the up-to-date clinical translation of anti-angiogenic cancer therapy in this field.

Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues^1–6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis^2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes^4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1—the key mediator for BAT-thermogenesis—ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.