Growth Factor Therapy and Autologous Lymph Node Transfer in Lymphedema

Abstract

Background— Lymphedema after surgery, infection, or radiation therapy is a common and often incurable problem. Application of lymphangiogenic growth factors has been shown to induce lymphangiogenesis and to reduce tissue edema. The therapeutic effect of autologous lymph node transfer combined with adenoviral growth factor expression was evaluated in a newly established porcine model of limb lymphedema. Methods and Results— The lymphatic vasculature was destroyed within a 3-cm radius around an inguinal lymph node. Lymph node grafts and adenovirally (Ad) delivered vascular endothelial growth factor (VEGF)-C (n=5) or VEGF-D (n=9) were used to reconstruct the lymphatic network in the inguinal area; AdLacZ (β-galactosidase; n=5) served as a control. Both growth factors induced robust growth of new lymphatic vessels in the defect area, and postoperative lymphatic drainage was significantly improved in the VEGF-C/D–treated pigs compared with controls. The structure of the transferred lymph nodes was best preserved in the VEGF-C–treated pigs. Interestingly, VEGF-D transiently increased accumulation of seroma fluid in the operated inguinal region postoperatively, whereas VEGF-C did not have this side effect. Conclusions— These results show that growth factor gene therapy coupled with lymph node transfer can be used to repair damaged lymphatic networks in a large animal model and provide a basis for future clinical trials of the treatment of lymphedema.

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…To date, several factors have been reported to stimulate lymphangiogenesis of both cultured LECs and animals, including VEGF-A, VEGF-C, VEGF-D, FGF-2, PDGF, IGF-1, IGF-2, Angiopoietin-1, and HGF (Adams and Alitalo 2007;Karpanen and Alitalo 2008;Tammela and Alitalo 2010;Lahteenvuo et al 2011;Norrmen et al 2011), and the list is growing rapidly. Among them, VEGF-C has been best characterized and is considered to be the most promising therapeutic agent to treat human lymphedema (Norrmen et al 2011).…”

“…Adenoviral delivery of VEGF-C or VEGF-D into lymph-node-excised mice resulted in robust proliferation of lymphatic capillaries, followed by remodeling, differentiation, and maturation to establish functional collecting lymphatic vessels that are equipped with uniform endothelial cell -cell junctions and intraluminal valves, as well as mural cell investment (Tammela et al 2007). Moreover, this experimental paradigm has been further extended to a non-rodent model: Lahteenvuo et al (2011) evaluated the therapeutic effect of autologous lymph node transfer combined with adenoviral expression of VEGF-C or VEGF-D in a newly established porcine model of lymphedema in the inguinal area. Consistent with the data from the rodent model, both growth factors stimulated robust lymphangiogenesis in the defect area, and postoperative lymphatic drainage was dramatically improved, with the structure of the transferred lymph nodes best preserved in the VEGF-Ctreated pigs.…”

Diabetic foot ulcers in conjunction with lower limb lymphedema: pathophysiology and treatment procedures

“…74 Lahteenvuo et al and Honkonen et al showed that the transferred lymph nodes produce vascular endothelial growth factor-C, inducing lymphangiogenesis which may facilitate canalization of recipient lymphatic vessels to the lymph node. 75,76 Lin et al and Cheng et al hypothesized that the transferred lymph nodes act as "lymph pumps", ejecting the absorbed lymph fluid from the surrounding interstitial tissue into the venous circulation via the lymphovenous communication. 77,78 Despite the encouraging results in treating lymphedema, the reported clinical studies involve only patients with chronic lymphedema secondary to iatrogenic injury, which does not reflect the exact pathophysiology of lymphedema associated with a DFU.…”

Strategies in Modulating Lymphedema

“…Furthermore, survival and functionality of the transferred lymph nodes was markedly improved in the injected animals as compared to the controls. Lymph node transfer has been used in humans with limited success (22-31%), but in this model, the presence of VEGF-C resulted in better lymphatic vessel function, collecting vessel formation, and lymph node histology compared to controls (Lahteenvuo et al, 2011). Similar studies have also been performed on other large animals such as sheep.…”