
Potential role of transforming growth factor‐beta 1/Smad signaling in secondary lymphedema after cancer surgery
Author(s) -
Sano Masaki,
Hirakawa Satoshi,
Suzuki Minoru,
Sakabe Junichi,
Ogawa Mikako,
Yamamoto Seiji,
Hiraide Takanori,
Sasaki Takeshi,
Yamamoto Naoto,
Inuzuka Kazunori,
Tanaka Hiroki,
Saito Takaaki,
Sugisawa Ryota,
Katahashi Kazuto,
Yata Tatsuro,
Kayama Takafumi,
Urano Tetsumei,
Tokura Yoshiki,
Sato Kohji,
Setou Mitsutoshi,
Takeuchi Hiroya,
Konno Hiroyuki,
Unno Naoki
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14457
Subject(s) - lymphedema , secondary lymphedema , medicine , myofibroblast , fibrosis , smad , transforming growth factor , transforming growth factor beta , pathology , wound healing , cancer , cancer research , pathophysiology , oncology , immunology , breast cancer
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.