Shivam Pancholy

Background: Secondary lymphedema is a chronic and progressive complication commonly associated with cancer treatment, particularly following lymphadenectomy and radiation therapy.^2-4 The disease is characterized by impaired lymphatic drainage, persistent inflammation, extracellular matrix (ECM) deposition, and progressive fibrosis, all of which contribute to significant morbidity and decreased quality of life in 1 of every 3 patients undergoing axillary lymph node dissection.^3-4 Breast cancer-related lymphedema (BCRL) arises from iatrogenic disturbance of axillary lymphatic networks following axillary lymph node dissection, radiation therapy, or sentinel lymph node biopsy (correlated to lower risk for BCRL; 3-5% of patients) in breast cancer patients. ^2-4 Current therapies remain largely supportive, including palliative care and carefully scheduled compression techniques, and fail to directly target the molecular mechanisms underlying disease progression. Novel evidence suggests activation of the renin-angiotensin-aldosterone system (RAAS) and transforming growth factor-beta (TGF-β) signaling pathways play a central role in lymphatic dysfunction and fibrotic remodeling following BCRL.^1,3

Objective: In this narrative review, we explored the mechanistic relationship between renin-angiotensin-aldosterone system (RAAS) activation and transforming growth factor-beta (TGF-β)-mediated fibrosis in secondary lymphedema, with emphasis on the clinical potential of angiotensin-converting enzyme (ACE) inhibition as a translational therapeutic strategy for breast cancer-related lymphedema (BCRL).

Search Methods: An online literature search was conducted using PubMed and Google Scholar databases for primary research articles published from 2018 to 2023. Search terms included: “secondary lymphedema,” “breast cancer-related lymphedema,” “RAAS,” “renin-angiotensin system,” “TGF-beta,” “fibrosis,” “angiotensin II,” “ACE inhibitors,” “lymphangiogenesis,” and “topical captopril.” Only recent primary mechanistic studies and translational animal-model investigations relevant to fibrosis and lymphatic dysfunction were included.

Results: Recent mechanistic studies have demonstrated that angiotensin II stimulates lymphatic endothelial cell proliferation and migration through angiotensin type 1 receptor signaling, linking RAAS activation to lymphatic remodeling.⁵ Additional experimental models of secondary lymphedema identified TGF-β1/Smad signaling as a major driver of fibroblast activation, myofibroblast differentiation, collagen deposition, and chronic tissue fibrosis.⁶ Pharmacologic inhibition of TGF-β signaling reduced fibrosis and improved lymphangiogenesis in murine lymphedema models, further supporting the pathogenic significance.⁷ Studies investigating angiotensin-converting enzyme (ACE) inhibition revealed suppression of fibrotic signaling pathways, resulting in decreased fibroblast proliferation and improved tissue remodeling.⁸ Translational investigations using topical captopril demonstrated reduced fibrosis, improved lymphatic vessel function, and decreased inflammatory infiltration without systemic adverse effects. In addition to a significant 2.3-fold increase in lymphangiogenesis markers, the side effects of oral ACE inhibition were mitigated via topical and local application of captopril, identifying an optimal route of administration for ACE inhibitors in future clinical trials for the greatest outcomes and minimal risk for the patient.¹ These findings identify local RAAS signaling as a modifiable driver of fibrosis and major lymphatic dysfunction, providing a translational rationale for topical ACE inhibition.

Conclusion: Collectively, these findings establish a mechanistic relationship between RAAS activation and TGF-β-mediated fibrosis in secondary lymphedema and support localized ACE inhibition as a promising disease-modifying therapeutic strategy. Future research should focus on clinical translation of topical RAAS inhibition and the long-term therapeutic implications for patients with breast cancer-related lymphedema.

Works Cited:

1. Brown S, Nores GDG, Sarker A, et al. Topical captopril: a promising treatment for secondary lymphedema. Transl Res. 2023;257:43-53. doi:10.1016/j.trsl.2023.01.005
2. Brown S, Campbell AC, Kuonqui K, et al. The Future of Lymphedema: Potential Therapeutic Targets for Treatment. Curr Breast Cancer Rep. Published online June 1, 2023. doi:10.1007/s12609-023-00491-5
3. Dayan JH, Ly CL, Kataru RP, Mehrara BJ. Lymphedema: Pathogenesis and Novel Therapies. Annu Rev Med. 2018;69:263-276. doi:10.1146/annurev-med-060116-022900
4. Rockson SG. Lymphedema after Breast Cancer Treatment. N Engl J Med. 2018;379(20):1937-1944. doi:10.1056/NEJMcp1803290
5. Lin QY, Bai J, Liu JQ, Li HH. Angiotensin II stimulates the proliferation and migration of lymphatic endothelial cells through angiotensin type 1 receptors. Front Physiol. 2020;11:560170. doi:10.3389/fphys.2020.560170
6. Sano M, Hirakawa S, Suzuki M, et al. Potential role of transforming growth factor-beta 1/Smad signaling in secondary lymphedema after cancer surgery. Cancer Sci. 2020;111(7):2620-2634. doi:10.1111/cas.14457
7. Baik JE, Park HJ, Kataru RP, et al. TGF-β1 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation. Clin Transl Med. 2022;12(6):e758. doi:10.1002/ctm2.758
8. Fang QQ, Wang XF, Zhao WY, et al. Angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical TGF-β1 pathways. Sci Rep. 2018;8(1):3332. doi:10.1038/s41598-018-21600-w