Pharmacological Treatment of Secondary Lymphedema

Brown, Stav; Dayan, Joseph H.; Coriddi, Michelle; Campbell, Adana; Kuonqui, Kevin; Shin, Jinyeon; Park, Hyeung Ju; Mehrara, Babak J.; Kataru, Raghu P.

doi:10.3389/fphar.2022.828513

Cited by 23 publications

(17 citation statements)

References 162 publications

(168 reference statements)

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“…26,27 However, the application of VEGF-C therapy in the clinical setting has yet to be realized because VEGF-C acts as a key regulator of the tumor microenvironment, potentially increasing the risk of recurrence and metastasis. 25,28 Previous studies have reported that Roxadustat is noncarcinogenic 29 and it was found not to promote the initiation, progression, or metastasis of tumors in a VEGF-sensitive spontaneous breast cancer model. 30 Meanwhile, a phase 2 study is being conducted to evaluate roxadustat for the treatment of anemia in patients receiving chemotherapy for nonmyeloid malignancies (NCT04076943).…”

Section: Hif-1α Promotes Lymphangiogenesis By Inducing Vegfr-3 and Ve...mentioning

confidence: 99%

Therapeutic Potential of the Prolyl Hydroxylase Inhibitor Roxadustat in a Mouse Hindlimb Lymphedema Model

Hoshino

Osawa

Funayama

et al. 2023

Lymphatic Research and Biology

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Background: Lymphedema is an intractable disease with no curative treatment available.Conservative treatment is the mainstay, and new drug treatment options are strongly needed.The purpose of this study was to investigate the effect of roxadustat, a prolyl-4-hydroxylase inhibitor, on lymphangiogenesis and its therapeutic effect on lymphedema in a radiation-free mouse hindlimb lymphedema model. 2 Methods and Results: Male C57BL/6N mice (8-10 weeks old) were used for the lymphedema model. Mice were randomized to an experimental group receiving roxadustat or a control group. The circumferential ratio of the hindlimbs was evaluated and lymphatic flow of the hindlimbs was compared by fluorescent lymphography up to 28 days postoperatively. The roxadustat group showed an early improvement in hindlimb circumference and stasis of lymphatic flow. The number and area of lymphatic vessels on postoperative day 7 were significantly larger and smaller, respectively, in the roxadustat group compared with the control group. Skin thickness and macrophage infiltration on postoperative day 7 were significantly reduced in the roxadustat group compared with the control group. The relative mRNA expression of hypoxia-inducible factor-1α (Hif-1α), vascular endothelial growth factor receptor-3 (VEGFR-3), vascular endothelial growth factor-C (VEGF-C), and Prospero homeobox 1 (Prox1) on postoperative day 4 were significantly higher in the roxadustat group compared with the control group. Conclusions: Roxadustat demonstrated a therapeutic effect in a murine model of hindlimb lymphedema via promotion of lymphangiogenesis through the activation of HIF-1α, VEGF-C, VEGFR-3, and Prox1, suggesting the potential of roxadustat as a therapeutic option in lymphedema.

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Section: Hif-1α Promotes Lymphangiogenesis By Inducing Vegfr-3 and Ve...mentioning

confidence: 99%

Therapeutic Potential of the Prolyl Hydroxylase Inhibitor Roxadustat in a Mouse Hindlimb Lymphedema Model

Hoshino

Osawa

Funayama

et al. 2023

Lymphatic Research and Biology

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“…Lymphedema is caused by a dysfunction of the lymphatic system, resulting in localized interstitial fluid retention and tissue swelling; it is classified as primary or secondary. Primary lymphedema develops due to inherited hypoplasia/dysplasia or dysfunction of lymphatic vessels because of some intrinsic factors such as genetic mutations in the signaling pathway for vascular endothelial growth factor C (VEGF-C), while secondary lymphedema is caused by a dysfunction of the lymphatic vascular system due to trauma or parasitic infection [ 1 , 2 , 3 ]. Although the incidence of secondary lymphedema has been declining due to advances in surgery, this iatrogenic disorder has a strong negative impact on physical and mental quality of life (QOL) [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, radiation therapy (RT) increases the risk of lymphedema in the upper and lower limbs; for instance, in breast cancer patients, the risk of lymphedema is five times higher with postoperative RT than with axillary lymph node dissection alone [ 5 ]. Patients with lymphedema typically present with symptoms such as altered mechanical properties and sensitivity of the skin, increased susceptibility to systemic and local infections, decreased function of the affected upper or lower limb, and chronic pain and discomfort [ 3 , 6 ]. In addition, patients may have problems with body image and social acceptability and exhibit low self-esteem [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema

Ogino

Yokooji

Hayashida

et al. 2022

IJMS

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Secondary lymphedema is a common complication of lymph node dissection or radiation therapy for cancer treatment. Conventional therapies such as compression sleeve therapy, complete decongestive physiotherapy, and surgical therapies decrease edema; however, they are not curative because they cannot modulate the pathophysiology of lymphedema. Recent advances reveal that the activation and accumulation of CD4+ T cells are key in the development of lymphedema. Based on this pathophysiology, the efficacy of pharmacotherapy (tacrolimus, anti-IL-4/IL-13 antibody, or fingolimod) and cell-based therapy for lymphedema has been demonstrated in animal models and pilot studies. In addition, mesenchymal stem/stromal cells (MSCs) have attracted attention as candidates for cell-based lymphedema therapy because they improve symptoms and decrease edema volume in the long term with no serious adverse effects in pilot studies. Furthermore, MSC transplantation promotes functional lymphatic regeneration and improves the microenvironment in animal models. In this review, we focus on inflammatory cells involved in the pathogenesis of lymphedema and discuss the efficacy and challenges of pharmacotherapy and cell-based therapies for lymphedema.

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“…Excessive growth of lymphatic vessels (lymphangiogenesis) is associated with transplant rejection and cancer ( Vaahtomeri et al, 2017 ; Morfoisse and Noel, 2019 ). Failure of the lymphatic system leads to an impaired drainage capacity resulting in fluid accumulation and tissue swelling called lymphedema (LD) ( Grada and Phillips, 2017 ; Dayan et al, 2018 ; Azhar et al, 2020 ; Brown et al, 2022 ). LD is a chronic, multifactorial disease affecting approximately 250 million people worldwide ( Oliver et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…This lifelong and unpredictable condition often develops in a delayed manner, months or even years after surgery. Current treatments are poorly effective, mainly palliative and include compression massage, extensive decongestive therapy by physiotherapists, restrictive diets or surgery to transfer vascularized lymph nodes ( Carl et al, 2017 ; Borman, 2018 ; Chang et al, 2021 ; Brown et al, 2022 ). Pharmacological treatments based on pro-lymphangiogenic factors (VEGF-C) are promising, but are not sufficient to restore functional lymphatic vessels with efficient valves ( Szoke et al, 2021 ; Brown et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Single and combined impacts of irradiation and surgery on lymphatic vasculature and fibrosis associated to secondary lymphedema

Buntinx

Lebeau²,

Gillot³

et al. 2022

Front. Pharmacol.

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Lymphedema (LD) refers to a condition of lymphatic dysfunction associated with excessive fluid accumulation, fibroadipose tissue deposition and swelling. In industrialized countries, LD development mainly results from a local disruption of the lymphatic network by an infection or cancer-related surgery (secondary LD). In the absence of efficient therapy, animal models are needed to decipher the cellular and molecular mechanisms underlying LD and test putative drugs. In this study, we optimized and characterized a murine model of LD that combines an irradiation of the mice hind limb and a radical surgery (lymph node resection associated to lymphatic vessel ligation). We investigated the respective roles of irradiation and surgery in LD formation by comparing their impacts, alone or in combination (with different intervention sequences), on eight different features of the pathology: swelling (paw thickness), indocyanine green (ICG) clearance, lymphatic vasculature remodeling, epidermal and dermal thickening, adipocyte accumulation, inflammatory cell infiltration and collagen deposition. This study supports the importance of radiation prior to surgery to experimentally induce a rapid, severe and sustained tissue remodeling harboring the different hallmarks of LD. We provide the first experimental evidence for an excessive deposition of periostin (POSTN) and tenascin-C (TNC) in LD. Through a computerized method of digital image quantification, we established the spatial map of lymphatic expansion, as well as collagen, POSTN and TNC deposition in papillary and reticular dermis of lymphedematous skins. This mouse model is available to study the patho-physiology of LD and test potential therapeutic targets.

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Pharmacological Treatment of Secondary Lymphedema

Cited by 23 publications

References 162 publications

Therapeutic Potential of the Prolyl Hydroxylase Inhibitor Roxadustat in a Mouse Hindlimb Lymphedema Model

Therapeutic Potential of the Prolyl Hydroxylase Inhibitor Roxadustat in a Mouse Hindlimb Lymphedema Model

Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema

Single and combined impacts of irradiation and surgery on lymphatic vasculature and fibrosis associated to secondary lymphedema

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