Time to revisit antiangiogenic treatment of cancer Targeting tumour blood vessel network is a well-established anti-cancer strategy. However, European scientists showed that antiangiogenic treatments may prompt metastatases and have continued research into this important area. Fundamental Research Health © sruilk, Shutterstock Renal cell carcinoma (RCC) is the main type of kidney cancer that has consistently increased in incidence. Metastatic RCC has a poor outcome due to resistance to standard chemotherapy and prominent vascularisation pattern. Moreover, RCC represents a paradigm for anti-angiogenic treatment but this often leads to the recurrence of metastases and even the development of new metastatic niches. Researchers with the EU-funded VELYMPH (Investigation of VEGF-C involvement in acquired metastatic properties of renal cell carcinoma following anti-angiogenesis treatments) project hypothesised that antiangiogenic therapy might be triggering tumour cells to escape via the lymphatic system, causing metastases. They therefore set out to investigate the association between antiangiogenic treatment and vascular endothelial growth factor-C (VEGF-C), a growth factor for vascular and lymphatic endothelial cells. Sunitinib – mechanism of action VELYMPH work focused on sunitinib, a tyrosine kinase inhibitor of several VEGF receptors and a first line antiangiogenic drug administered in patients with RCC. The scientists used a mouse RCC model and showed that sunitinib induced stress that led to higher VEG-C expression in treated tumours. Strikingly, these high VEGF-C levels correlated with shorter survival and increased metastasis. Underlying mechanisms indicated a stimulation of vegfc gene transcription and an increase in the VEGF-C mRNA half-life. Ultimately this led to the development of lymphatic vessels that facilitated metastatic dissemination. ‘The receptors targeted by the current anti-angiogenic drugs are also expressed on tumour cells that finally adapt to the pressure of selection exerted by the treatments,’Dr Pages explains. ‘Finally tumours relapse after treatment because of such genomic plasticity of tumour cells.’ ‘The challenge was to prove that this mechanism operated in sunitinib-treated patients as well,’ Dr Pages continues. For this purpose, researchers collaborated with different hospitals to obtain samples from RCC patients treated with sunitinib in a neo-adjuvant setting. Analysis of these retrospective samples alongside primary cells from operated tumours indicated an increase in lymphatic vessel formation and lymph node invasion. The next generation of antiangiogenic drugs The VEGFC-dependent development of lymphatic vessels in RCC clearly demonstrated the capacity of cancer cells to evade antiangiogenic treatment and emphasised the need for a new approach. VELYMPH data strongly suggest that a combination of antiangiogenic and anti-VEGFC treatments may improve the chances of long-term survival for patients with metastatic RCC. ‘It is important our results are communicated to inform clinicians that antiangiogenic treatment must not be used in a neo-adjuvant setting.’ note VELYMPH researchers. Overall, the VELYMPH study demonstrated that although sunitinib and radiotherapy have revolutionised the care of RCC patients, their efficiency may be improved by targeting key molecules involved in the development of the lymphatic network. VEGF-C constitutes such a therapeutic target as well as a predictive marker of escape to antiangiogenic therapies. Improved treatment approaches for RCC and other cancers will lead to better clinical outcomes and reduced healthcare costs. Keywords Antiangiogenic treatment, renal cell carcinoma, VELYMPH, VEGFC, sunitinib
