Potential role of transforming growth factor‐beta 1/Smad signaling in secondary lymphedema after cancer surgery

Abstract

Secondary lymphedema often develops after cancer surgery, and over 250 million patients suffer from this complication. A major symptom of secondary lymphedema is swelling with fibrosis, which lowers the patient's quality of life, even if cancer does not recur. Nonetheless, the pathophysiology of secondary lymphedema remains unclear, with therapeutic approaches limited to physical or surgical therapy. There is no effective pharmacological therapy for secondary lymphedema. Notably, the lack of animal models that accurately mimic human secondary lymphedema has hindered pathophysiological investigations of the disease. Here, we developed a novel rat hindlimb model of secondary lymphedema and showed that our rat model mimics human secondary lymphedema from early to late stages in terms of cell proliferation, lymphatic fluid accumulation, and skin fibrosis. Using our animal model, we investigated the disease progression and found that transforming growth factor‐beta 1 (TGFB1) was produced by macrophages in the acute phase and by fibroblasts in the chronic phase of the disease. TGFB1 promoted the transition of fibroblasts into myofibroblasts and accelerated collagen synthesis, resulting in fibrosis, which further indicates that myofibroblasts and TGFB1/Smad signaling play key roles in fibrotic diseases. Furthermore, the presence of myofibroblasts in skin samples from lymphedema patients after cancer surgery emphasizes the role of these cells in promoting fibrosis. Suppression of myofibroblast‐dependent TGFB1 production may therefore represent an effective pharmacological treatment for inhibiting skin fibrosis in human secondary lymphedema after cancer surgery.

TGF‐β1 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation

“…Using immunohistochemistry, previous papers have shown that the expression of TGF-β1 was increased in tissue sections collected from a small number of patients with lymphedema. 13,33 To confirm these findings and study other TGF-β isoforms, we collected matched upper extremity biopsies from 18 patients with unilateral BCRL (Table 1). These patients were all female and ranged in age from 48 to 68 years.…”

Pharmacological Treatment of Secondary Lymphedema

“…(Avraham et al, 2010) Other studies have shown that inhibition of TGF-B1 using small molecule inhibitors or neutralizing antibodies decreases fibrosis and the severity of lymphedema in the mouse tail model. (Clavin et al, 2008;Sano et al, 2020;Yoon et al, 2020) Anti-TGF-B1 treatments also increased collateral lymphatic formation, a finding that is supported by the antilymphangiogenic activity of TGF-B1 in vitro and some physiologic settings. (Sano et al, 2020) Thus, there is significant potential for anti-fibrotic and anti-TGF-B1 therapies for lymphedema treatment.…”

“…(Clavin et al, 2008;Sano et al, 2020;Yoon et al, 2020) Anti-TGF-B1 treatments also increased collateral lymphatic formation, a finding that is supported by the antilymphangiogenic activity of TGF-B1 in vitro and some physiologic settings. (Sano et al, 2020) Thus, there is significant potential for anti-fibrotic and anti-TGF-B1 therapies for lymphedema treatment. However, effective means of chronically decreasing TGF-B1 activity without induction of autoimmune responses remains a challenge and will require additional investigation.…”

“…(Meng et al, 2016) The expression of TGF-B1 is increased in clinical lymphedema specimens and mouse models of the disease, suggesting that this growth factor also plays a role in regulating lymphedema-induced fibrosis. (Sano et al, 2020) Inhibition of TGF-B1 with a small molecule inhibitor decreases fibrosis and improves radiation-induced lymphatic dysfunction. (Avraham et al, 2010) Other studies have shown that inhibition of TGF-B1 using small molecule inhibitors or neutralizing antibodies decreases fibrosis and the severity of lymphedema in the mouse tail model.…”

Crosstalk Between microRNAs and the Pathological Features of Secondary Lymphedema

“…An in vivo study demonstrated that Smad-mediated activation of TGF-β1 from infiltrating macrophages leads to the transition of fibroblasts to myofibroblasts. This process occurs during the acute to subacute phase of lymphedema ( Sano et al, 2020 ). The crosstalk between miRNAs and TGF-β in endothelial-mesenchymal transformation (endMT) and EMT have been by reported in some studies.…”