The Effect of Salvianolic Acid A on Tumor-Associated Macrophage Polarization and Its Mechanisms in the Tumor Microenvironment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with a high degree of malignancy and poor prognosis. Tumor-associated macrophages (TAMs) have been identified as significant contributors to the growth and metastasis of TNBC through the secretion of various growth factors and chemokines. Salvianolic acid A (SAA) has been shown to have anti-cancer activities. However, the potential activity of SAA on re-polarized TAMs remains unclear. As there is a correlation between the TAMs and TNBC, this study investigates the effect of SAA on TAMs in the TNBC microenvironment. For that purpose, M2 TAM polarization was induced by two kinds of TNBC-conditioned medium (TNBC-TCM) in the absence or presence of SAA. The gene and protein expression of TAM markers were analyzed by qPCR, FCM, IF, ELISA, and Western blot. The protein expression levels of ERK and p-ERK in M2-like TAMs were analyzed by Western blot. The migration and invasion properties of M2-like TAMs were analyzed by Transwell assays. Here, we demonstrated that SAA increased the expression levels of CD86, IL-1ß, and iNOS in M2-like TAMs and, conversely, decreased the expression levels of Arg-1 and CD206. Moreover, SAA inhibited the migration and invasion properties of M2-like TAMs effectively and decreased the protein expression of TGF-ß1 and p-ERK in a concentration-dependent manner, as well as TGF-ß1 gene expression and secretion. Our current findings for the first time demonstrated that SAA inhibits macrophage polarization to M2-like TAMs by inhibiting the ERK pathway and promotes M2-like TAM re-polarization to the M1 TAMs, which may exert its anti-tumor effect by regulating M1/M2 TAM polarization. These findings highlight SAA as a potential regulator of M2 TAMs and the possibility of utilizing SAA to reprogram M2 TAMs offers promising insights for the clinical management of TNBC.

Evaluation of therapeutic effectiveness of (131)I-antiEGFR-BSA-PCL in a mouse model of colorectal cancer.

AIM: To investigate the biological effects of internal irradiation, and the therapeutic effectiveness was assessed of (131)I-labeled anti-epidermal growth factor receptor (EGFR) liposomes, derived from cetuximab, when used as a tumor-targeting carrier in a colorectal cancer mouse model. METHODS: We described the liposomes and characterized their EGFR-targeted binding and cellular uptake in EGFR-overexpressing LS180 colorectal cancer cells. After intra-tumor injections of 74 MBq (740 MBq/mL) (131)I-antiEGFR-BSA-PCL, we investigated the biological effects of internal irradiation and the therapeutic efficacy of (131)I-antiEGFR-BSA-PCL on colorectal cancer in a male BALB/c mouse model. Tumor size, body weight, histopathology, and SPECT imaging were monitored for 33 d post-therapy. RESULTS: The rapid radioiodine uptake of (131)I-antiEGFR-BSA-PCL and (131)I-BSA-PCL reached maximum levels at 4 h after incubation, and the (131)I uptake of (131)I-antiEGFR-BSA-PCL was higher than that of (131)I-BSA-PCL in vitro. The (131)I tissue distribution assay revealed that (131)I-antiEGFR-BSA-PCL was markedly taken up by the tumor. Furthermore, a tissue distribution assay revealed that (131)I-antiEGFR-BSA-PCL was markedly taken up by the tumor and reached its maximal uptake value of 21.0 ± 1.01 %ID/g (%ID/g is the percentage injected dose per gram of tissue) at 72 h following therapy; the drug concentration in the tumor was higher than that in the liver, heart, colon, or spleen. Tumor size measurements showed that tumor development was significantly inhibited by treatments with (131)I-antiEGFR-BSA-PCL and (131)I-BSA-PCL. The volume of tumor increased, and treatment rate with (131)I-antiEGFR-BSA-PCL was 124% ± 7%, lower than that with (131)I-BSA-PCL (127% ± 9%), (131)I (143% ± 7%), and normal saline (146% ± 10%). The percentage losses in original body weights were 39% ± 3%, 41% ± 4%, 49% ± 5%, and 55% ± 13%, respectively. The best survival and cure rates were obtained in the group treated with (131)I-antiEGFR-BSA-PCL. The animals injected with (131)I-antiEGFR-BSA-PCL and (131)I-BSA-PCL showed more uniform focused liposome distribution within the tumor area. CONCLUSION: This study demonstrated the potential beneficial application of (131)I-antiEGFR-BSA-PCL for treating colorectal cancer. (131)I-antiEGFR-BSA-PCL suppressed the development of xenografted colorectal cancer in nude mice, thereby providing a novel candidate for receptor-mediated targeted radiotherapy.