Objective To evaluate the efficacy and security of metformin in the treatment of endocrine resistance and postmenopausal hormone receptor positive advanced breast cancer. Methods 60 cases of postmenopausal HR+advanced breast cancer whose first-line or second-line endocrine therapy failed were randomly divided into study group(n=30),treated with metformin combined with AI and control group(n=30),treated with placebo combined with AI. Standard RECIST guidelines were used to evaluate the clinical response. The objective response rate(ORR),clinical benefit rate(CBR),progression-free survival,and adverse reactions of two groups were compared. Results The ORR of two groups were 16.7%and 10%respectively and the difference was not statistically significant(P > 0.05). But CBR in study group was significantly higher than that in control group (63.3%vs 36.7%),and the difference was statistically significant(P<0.05). The median PFS in study group was slightly longer than that in control group (3.7 m vs 4.2 m),but there was no statistical difference. Multivariate regression analysis showed that PFS was only associated with the previous endocrine therapy. No serious adverse reactions occurred in two groups. Conclusion Metformin is expected to improve secondary endocrine resistance in breast cancer,but large prospective clinical studies are needed to confirm it.

Transporters are traditionally considered to transport small molecules rather than large-sized nanoparticles due to their small pores. In this study, we demonstrate that the upregulated intestinal transporter (PCFT), which reaches a maximum of 12.3-fold expression in the intestinal epithelial cells of diabetic rats, mediates the uptake of the folic acid-grafted nanoparticles (FNP). Specifically, the upregulated PCFT could exert its function to mediate the endocytosis of FNP and efficiently stimulate the traverse of FNP across enterocytes by the lysosome-evading pathway, Golgi-targeting pathway and basolateral exocytosis, featuring a high oral insulin bioavailability of 14.4% in the diabetic rats. Conversely, in cells with relatively low PCFT expression, the positive surface charge contributes to the cellular uptake of FNP, and FNP are mainly degraded in the lysosomes. Overall, we emphasize that the upregulated intestinal transporters could direct the uptake of ligand-modified nanoparticles by mediating the endocytosis and intracellular trafficking of ligand-modified nanoparticles via the transporter-mediated pathway. This study may also theoretically provide insightful guidelines for the rational design of transporter-targeted nanoparticles to achieve efficient drug delivery in diverse diseases.

BACKGROUND: Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a micro-barrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells. METHODS: The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin β8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. RESULTS: Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts. CONCLUSIONS The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.
Animals ; Mice ; Humans ; Proto-Oncogene Proteins c-akt/metabolism* ; Actins/metabolism* ; Neoplasm Recurrence, Local ; TOR Serine-Threonine Kinases/metabolism* ; Urinary Bladder Neoplasms ; Glycolysis ; Cell Line, Tumor ; Cell Proliferation ; Mammals/metabolism* ; Tripartite Motif Proteins/metabolism* ; Intracellular Signaling Peptides and Proteins/metabolism* ; Integrin beta Chains