Sanguinarine Regulates Tumor-Associated Macrophages to Prevent Lung Cancer Angiogenesis Through the WNT/β-Catenin Pathway

Abstract

Tumor-associated macrophage (TAM)-mediated angiogenesis in the tumor microenvironment is a prerequisite for lung cancer growth and metastasis. Therefore, targeting TAMs, which block angiogenesis, is expected to be a breakthrough in controlling the growth and metastasis of lung cancer. In this study, we found that Sanguinarine (Sang) inhibits tumor growth and tumor angiogenesis of subcutaneously transplanted tumors in Lewis lung cancer mice. Furthermore, Sanguinarine inhibited the proliferation, migration, and lumen formation of HUVECs and the expression of CD31 and VEGF by regulating the polarization of M2 macrophages in vitro. However, the inhibitory effect of Sanguinarine on angiogenesis remained in vivo despite the clearance of macrophages using small molecule drugs. Further high-throughput sequencing suggested that WNT/β-Catenin signaling might represent the underlying mechanism of the beneficial effects of Sanguinarine. Finally, the β-Catenin activator SKL2001 antagonized the effect of Sanguinarine, indicating that Sanguinarine can regulate M2-mediated angiogenesis through the WNT/β-Catenin pathway. In conclusion, this study presents the first findings that Sanguinarine can function as a novel regulator of the WNT/β-Catenin pathway to modulate the M2 macrophage polarization and inhibit angiogenesis, which has potential application value in immunotherapy and antiangiogenic therapy for lung cancer.

The response prediction and prognostic values of systemic inflammation response index in patients with advanced lung adenocarcinoma

“…[25][26][27] Monocytes were found to differentiate into tumor-associated macrophages, which could secrete tumor necrosis factor alpha and vascular endothelial growth factor to facilitate tumor angiogenesis, inflammatory response, and metastases. 28,29 Lymphocytes are crucial components of anticancer immunity and immune surveillance. 30 Downregulation of peripheral lymphocytes impairs the host's anticancer immunity and correlates with poor survival in cancer patients.…”

“…Neutrophils could influence tumor development and progression via promoting tumor angiogenesis, aiding tumor cells to evade immune surveillance, and secreting large amounts of reactive oxygen species and nitric oxide 25–27 . Monocytes were found to differentiate into tumor‐associated macrophages, which could secrete tumor necrosis factor alpha and vascular endothelial growth factor to facilitate tumor angiogenesis, inflammatory response, and metastases 28,29 . Lymphocytes are crucial components of anticancer immunity and immune surveillance 30 .…”

Sanguinarine induces apoptosis in osteosarcoma by attenuating the binding of STAT3 to the single‐stranded DNA‐binding protein 1 (SSBP1) promoter region

“…Subsequent in‐depth research has revealed the expanding pharmacological repertoire of SNG, encompassing its antimicrobial, anti‐inflammatory and antihypertensive effects (Ma, Sun, et al, 2017). In recent years, a substantial body of research has demonstrated that SNG is an effective anticancer drug, exhibiting significant antitumour effects through various targets and pathways in multiple cancer types, including gastric cancer (Pallichankandy et al, 2015), prostate cancer (Rahman et al, 2019), lung cancer (Cui et al, 2022), colorectal cancer (Malla & Bhamidipati, 2022), bladder cancer (Han et al, 2013), breast cancer (Su et al, 2021), pancreatic cancer (Ma, Yu, et al, 2017) and human leukaemia (Kuttikrishnan et al, 2019). However, the precise anticancer mechanism of SNG in osteosarcoma remains incompletely understood.…”

“…In addition, SNG has been found to induce autophagy by impeding lysosome formation and inhibiting autophagosome degradation, thereby impeding the progression of various cancers (Su et al, 2020; J. Wang, Su, et al, 2021). Moreover, SNG exhibits a pivotal role in inhibiting angiogenesis and regulating cellular migration and invasion, which are critical processes in cancer progression (Cui et al, 2022; Su et al, 2019). Despite its well‐established efficacy in numerous cancer types, there remains a scarcity of studies investigating the potential of SNG in osteosarcoma.…”

A review of natural products targeting tumor immune microenvironments for the treatment of lung cancer

“…Sanguinarine reduces the MDSC accumulation, weakens the immunosuppressive ability of MDSCs, promotes the differentiation of MDSCs (differentiated into macrophages and DC), and increases the anti-lung-cancer immune response ( 133 ). In addition, sanguinarine has the potential to act as a novel regulator of the Wnt/β-catenin signaling pathway, modulating M2 macrophage polarization and inhibiting angiogenesis, both of which have potential application values in LC immunotherapy therapy ( 134 ).…”