heparan sulfate ( glucosamine ) 3-o - sulfotransferase 4 hypoxia - inducible factor 1  subunit lung endothelial cells platelet - derived growth factor receptor  telomeric repeat - binding factor 2 tumor endothelial cell vascular endothelial growth factor wilms tumor suppressor 1 inhibition of tumor angiogenesis is widely accepted as a valuable therapeutic option for cancer treatment and a large number of cancer patients benefit from treatment with inhibitors of the angiogenic vascular endothelial growth factor ( vegf ) . however , different tumor types show unique features in their vasculature depending on tissue specificity and the expression pattern of pro- and anti - angiogenic molecules and their cognate receptors . thus , it is not surprising that , in addition to positive antitumor effects , increased invasion and metastasis have also been noted in divergent experimental models targeting vegf . these observations support the notion that other proangiogenic factors play a role in sustained tumor angiogenesis and progression . we previously found that the wilms tumor suppressor wt1 is highly expressed in vessels of human tumors but not in healthy adjacent tissues , and is required for angiogenesis . furthermore , wt1 is implicated in vessel formation during development and in pathophysiological conditions such as myocardial ischemia as a transcriptional target of hypoxia - inducible factor 1  ( hif1a ) . wt1 encodes a zinc - finger transcription factor with crucial functions in development and was originally identified as a tumor suppressor based on its mutational inactivation in wilms tumor . however , because of its overexpression in a variety of human cancers , it is now considered a potential oncogene . like wt1 , expression of the telomeric repeat - binding factor 2 ( trf2 , also known as terf2 ) , which plays a central role in telomere capping , is frequently increased in human tumors . consistent with a potent oncogenic role of a high level of trf2 , its downregulation in cancer cells reduces tumorigenicity whereas its overexpression favors oncogenesis . we showed that the high level of trf2 found in cancer cells positively regulates the expression of hs3st4 encoding heparan sulfate ( glucosamine ) 3-o - sulphotransferase 4 , which is involved in the recruitment of nk - cells , thus revealing that trf2 upregulation can have oncogenic properties through cell non - autonomous mechanisms . in our recent work 1 ) . we found that trf2 was highly expressed in the tumor vasculature of different human cancer types , but not in the vessels of healthy tissues . using ex vivo approaches , we demonstrated that tumor - derived endothelial cells ( tecs ) expressed higher levels of trf2 than endothelial cells from healthy lung tissues ( lecs ) and exhibited a higher angiogenic potential . we further showed that upregulation of trf2 in the tumor endothelium is the result of its transcriptional activation by wt1 . in agreement with an important angiogenic role of trf2 overexpression in tecs , depletion of trf2 in these cells led to loss of their angiogenic properties , and overexpression of trf2 in lecs conferred on them the high angiogenic potential of tecs . overall , these findings suggest that trf2 might play a role in vascular development and in cases of ischemia , as has been shown for wt1 . 
 figure 1.telomeric repeat - binding factor 2 ( trf2 ) regulates angiogenesis by acting as a transcription factor independent of its function in telomere protection . furthermore , trf2 expression is upregulated in tumor - derived endothelial cells , most likely because trf2 is a transcriptional target of the wilms tumor suppressor 1 ( wt1 ) , which is highly expressed in the tumor vasculature . in tumor endothelial cells , trf2 binds and transactivates the platelet - derived growth factor receptor  ( pdgfr ) promoter , which stimulates angiogenesis . overall , by activating tumor angiogenesis and cancer cell proliferation , trf2 emerges as a valuable multi - hit target for cancer therapy . telomeric repeat - binding factor 2 ( trf2 ) regulates angiogenesis by acting as a transcription factor independent of its function in telomere protection . , trf2 expression is upregulated in tumor - derived endothelial cells , most likely because trf2 is a transcriptional target of the wilms tumor suppressor 1 ( wt1 ) , which is highly expressed in the tumor vasculature . in tumor endothelial cells , trf2 binds and transactivates the platelet - derived growth factor receptor  ( pdgfr ) promoter , which stimulates angiogenesis . overall , by activating tumor angiogenesis and cancer cell proliferation , trf2 emerges as a valuable multi - hit target for cancer therapy . next , we investigated how a high trf2 level boosted the angiogenic properties of tecs . first , we did not observe telomere uncapping and initiation of the dna damage response ( ddr ) upon modulation of trf2 levels , indicating that the angiogenic function of trf2 in endothelial cells is uncoupled from its role in telomere capping . second , by screening for angiogenic targets of trf2 , we found that trf2 increases the expression of platelet - derived growth factor receptor  ( pdgfrb ) . autocrine growth stimulation of tumor endothelial cells through pdgfrb that is evoked by interaction with cancer cells has been postulated , underlining the diversity of proangiogenic mechanisms in tumor angiogenesis and the resulting difficulties in establishing adequate antiangiogenic therapies for cancer treatment . third , using different approaches we demonstrated that trf2 is a direct transcriptional activator of pdgfrb that is capable of binding and activating the pdgfrb promoter . overexpression of pdgfrb could rescue the inhibition of endothelial cell proliferation caused by depletion of trf2 , but only partially rescued the effects on the migratory potential of these cells . this indicates that trf2 might also activate factors other than pdgfrb that are implicated in endothelial cell migration . the fact that telomere factors such as trf2 bind extra - telomeric sites to regulate transcription is not unprecedented ( reviewed in ) . our finding that trf2 binds and activates the pdgfrb promoter should facilitate dissection of the mechanism by which trf2 acts as a transcriptional regulator and consequently will have strong implications for basic and biomedical research . taken together , these findings reveal a novel mechanism by which trf2 transcriptionally controls tumor angiogenesis independent of its role in telomere protection . they further suggest that pathways controlling replicative potential ( telomere ) and those controlling energy supply ( angiogenesis ) co - evolved for a better control of tissue homeostasis and renewal . they also point to trf2 as a novel multi - hit target in cancer therapy , as it is implicated in both the proliferation of cancer cells through cell autonomous and non - autonomous mechanisms and in the angiogenic properties of tecs . thus , compared to classic antiangiogenic therapies , the identification of molecules that target trf2 might be a major advance for cancer treatment through hitting 2 birds with one stone . the study was supported by the ligue nationale contre le cancer ( equipe lablise , eg ) , the institut national du cancer ( inca ) program telochrom , the anr ( national research agency ) programs innatelo and the investments for the future labex signalife ( reference anr-11-labx-002801 ) , the fondation arc ( association pour la recherche sur le cancer ) , and fondation de france ( kdw ) . m el ma is supported by a fellowship from the ligue nationale contre le cancer and the fondation arc pour la recherche sur le cancer .