VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis

Tam, Betty; Wei, Kevin; Rudge, John S.; Hoffman, Jana; Holash, Joceyln; Park, Sang-ki; Yuan, Jing; Hefner, Colleen; Chartier, Cécile; Lee, Jeng-Shin; Jiang, Shelly; Nayak, Nihar R.; Kuypers, Frans A.; Ma, Lisa; Sundram, Uma; Wu, Gloria; Garcia, Joseph A.; Schrier, Stanley L.; Maher, Jacquelyn J.; Johnson, Randall S.; Yancopouloš, George D.; Mulligan, Richard C.; Kuo, Calvin J.

doi:10.1038/nm1428

Cited by 153 publications

(111 citation statements)

References 43 publications

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“…However, the unexpectedly high rates of VEGF production in non-tumor-bearing adult mice and humans is consistent with the recent realization that VEGF likely plays an ongoing role in the ''quiescent'' vasculature of normal adults (23). For example, treating normal adult mice and monkeys with VEGF antagonists can increase hematocrit (a measure of the proportion of the blood volume occupied by red blood cells) (24). Similarly, VEGF antagonists can also increase blood pressure (25), indicating that VEGF is involved in regulating VEGF Trap Complex provides guidance on when optimal VEGF blockade is achieved for antitumor purposes.…”

Section: Discussionsupporting

confidence: 75%

VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade

Rudge

Holash

Hylton

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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191

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VEGF is the best characterized mediator of tumor angiogenesis. Anti-VEGF agents have recently demonstrated impressive efficacy in human cancer trials, but the optimal dosing of such agents must still be determined empirically, because biomarkers to guide dosing have yet to be established. The widely accepted (but unverified) assumption that VEGF production is quite low in normal adults led to the notion that increased systemic VEGF levels might quantitatively reflect tumor mass and angiogenic activity. We describe an approach to determine host and tumor production of VEGF, using a high-affinity and long-lived VEGF antagonist now in clinical trials, the VEGF Trap. Unlike antibody complexes that are usually rapidly cleared, the VEGF Trap forms inert complexes with tissue- and tumor-derived VEGF that remain stably in the systemic circulation, where they are readily assayable, providing unprecedented capability to accurately measure VEGF production. We report that VEGF production is surprisingly high in non-tumor-bearing rodents and humans, challenging the notion that systemic VEGF levels can serve as a sensitive surrogate for tumor load; tumor VEGF contribution becomes significant only with very large tumor loads. These findings have the important corollary that anti-VEGF therapies must be sufficiently dosed to avoid diversion by host-derived VEGF. We further show that our assay can indicate when VEGF is optimally blocked; such biomarkers to guide dosing do not exist for other anti-VEGF agents. Based on this assay, VEGF Trap doses currently being assessed in clinical trials are in the efficacious range.

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Section: Discussionsupporting

confidence: 75%

VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade

Rudge

Holash

Hylton

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

191

150

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“…[32][33][34] Regulation of EPO through an HIF-1a-independent mechanism also has been recently reported. 35 In our study, we determined that treatment with EPO reduced the number of activated lung endothelial cells 6-fold in animals treated with bleomycin, as evidenced by changes in morphology. When activation of the endothelial cells occurs, these cells frequently assume a more round shape, cell-tocell junctions are destroyed and the endothelium becomes interrupted and leaky.…”

Section: Discussionmentioning

confidence: 77%

Erythropoietin ameliorates chemotherapy‐induced fibrosis of the lungs in a preclinical murine model

Sigounas

Salleng

Mehlhop

et al. 2008

Intl Journal of Cancer

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Organ toxicity induced by chemotherapeutic drugs is a serious obstacle in the effective treatment of patients suffering from cancer and autoimmune disease. A strong association exists between pulmonary toxicity, particularly fibrosis, and chemotherapeutic drugs. Attempts have been made to identify compounds capable of suppressing fibrosis. In addition to its erythropoietic activity, erythropoietin (EPO) has been shown to have effects on nonhemopoietic cells. Therefore, we postulated that EPO may exert beneficial effects on lung tissue during chemotherapy. To test our hypothesis, we investigated pulmonary changes caused by bleomycin, a fibrosis‐inducing agent, in animals treated with the drug alone and in combination with EPO. Fibrosis, cellular alterations and structural changes were assayed by blind analysis of the lung sections. A 6‐fold decrease in the number of prominent endothelial cells—suspected to be indicative of cellular activation and inflammatory response—was observed in lung sections derived from mice treated with bleomycin and EPO compared to animals injected with bleomycin alone (p < 0.008). Additionally, there was twice the number of ICAM1‐positive endothelial cells in animals treated with bleomycin alone compared with the number in the bleomycin and EPO‐treated group (p < 0.05). Alveolar mononuclear phagocytic hyperplasia was reduced by as much as 100% in animals treated with bleomycin and EPO compared to animals treated with bleomycin alone (p < 0.03). Finally, a 5‐fold decrease in interstitial fibrosis was observed in lung sections obtained from animals treated with bleomycin and EPO (p < 0.02). We conclude that EPO can ameliorate drug‐induced fibrosis and endothelial damage caused by chemotherapeutic agents. © 2008 Wiley‐Liss, Inc.

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“…VEGF inhibition may also increase risk of thrombosis by increasing haematocrit and blood viscosity via overproduction of erythropoietin. 47,48 Moreover, VEGFR-TKIs may increase the release of procoagulant from the tumor into the blood stream due to an enhanced cytotoxic effect. VEGF inhibition may also increase expression of proinflammatory cytokines causing damage and in situ thrombus formation.…”

Section: Discussionmentioning

confidence: 99%

Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

Min

Shen

et al. 2012

Intl Journal of Cancer

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Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have been widely used in advanced cancers. Concerns have arisen regarding the risk of venous thromboembolism with the use of these drugs. Currently, the contribution of VEGFR-TKIs to venous thromboembolism is still unknown. We performed a meta-analysis to determine the incidence and relative risk (RR) of venous thromboembolism events (VTEs) associated with these agents. Eligible studies included phase II and III prospective trials evaluating US Food and Drug Administration approved VEGFR-TKIs (pazopanib, sunitinib, sorafenib and vandetanib), and data on VTEs were available. Overall incidence rates, RR and 95% confidence intervals (CI) were calculated employing fixed-or random-effects models depending on the heterogeneity of included trials. A total of 14 studies (4,430 patients) were selected for this meta-analysis. The incidence of VTEs related to VEGFR-TKIs was 3% (95%CI: 1.7-5.1%), and there was no statistically significant increase in the risk of VTEs for VEGFR-TKIs versus controls in overall population (RR0.912, 95%CI: 0.617-1.348, p 5 0.643). On subgroup analysis, no significant increase in the risk of VTEs was found among different VEGFR-TKIs or tumor types. No evidence of publication bias was observed. The use of VEGFRTKIs does not significantly increase the risk of VTEs, the risk of VTEs in patients with cancer is driven predominantly by tumor types, host factors and concomitant usage of anticancer agents. These results would provide important information for clinicians who use VEGFR-TKIs to treat patients with solid cancer.

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VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis

Cited by 153 publications

References 43 publications

VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade

VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade

Erythropoietin ameliorates chemotherapy‐induced fibrosis of the lungs in a preclinical murine model

Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

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