Platelet-derived microparticles adoptively transfer integrin ß3 to promote antitumor effect of tumor-infiltrating T cells.

Approximately two-thirds of hepatocellular carcinoma (HCC) is considered a "cold tumor" characterized by few tumor-infiltrating T cells and an abundance of immunosuppressive cells. Cilengitide, an integrin αvß3 inhibitor, has failed in clinical trials as a potential anticancer drug. This failure implies that integrin αvß3 may play an important role in immune cells. However, the expression and potential role of integrin αvß3 in T cells of HCC patients remain unknown. Here, we established two HCC models and found that cilengitide had a dual effect on the HCC microenvironment by exerting both antitumor effect and immunosuppressive effect on T cells. This may partly explain the failure of cilengitide in clinical trials. In clinical specimens, HCC-infiltrating T cells exhibited deficient expression and activation of integrin ß3, which was associated with poor T-cell infiltration into tumors. Additionally, integrin ß3 functioned as a positive immunomodulatory molecule to facilitate T-cell infiltration and T helper 1-type immune response in vitro. Furthermore, T cells and platelet-derived microparticles (PMPs) co-culture assay revealed that PMPs adoptively transferred integrin ß3 to T cells and positively regulated T cell immune response. This process was mediated by clathrin-dependent endocytosis and macropinocytosis. Our data demonstrate that integrin ß3 deficiency on HCC-infiltrating T cells may be involved in shaping the immunosuppressive tumor microenvironment. PMPs transfer integrin ß3 to T cells and positively regulate T cell immune response, which may provide a new insight into immune therapy of HCC.

TGFß1/integrin ß3 positive feedback loop contributes to acquired EGFR TKI resistance in EGFR-mutant lung cancer.

Inevitable emergence of acquired resistance to EGFR TKIs including third-generation TKI osimertinib limits their long-term efficacy in treating EGFR-mutant lung cancer. A fuller investigation of novel molecular mechanisms underlying acquired resistance is essential to develop efficacious therapeutic strategies. Consequently, we have identified a novel TGFß1/integrin ß3 loop that contributes to the occurrence of EGFR TKI-acquired resistance. EGFR TKIs dramatically and sustainably increased the expression of both TGFß1 and integrin ß3 in in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to EGFR TKIs. Previously, we reported that integrin ß3 expression was partially induced by TGFß1 in these models. Moreover, elevated TGFß1 in these models was secreted mostly from lung cancer cells. Mechanistically, TGFß1 was induced and activated by overexpressed integrin ß3, forming a positive feedback loop. More importantly, the interruption of TGFß1/integrin ß3 positive feedback loop was shown to dramatically delay the occurrence of acquired resistance and greatly improve the efficacy of EGFR TKI in treating EGFR-mutant lung cancer. Taken together, our study first demonstrated the TGFß1/integrin ß3 loop a new mechanism and target for acquired EGFR TKI resistance in EGFR-mutant lung cancer.

Ameliorating the antitumor activity of gemcitabine against breast tumor using αvß3 integrin-targeting lipid nanoparticles.

OBJECTIVE: The main objective is to formulate solid lipid nanoparticles conjugated with cyclic RGDfk peptide encapsulated with gemcitabine hydrochloride drug for targeting breast cancer. SIGNIFICANCE: The hydrophilic nature of gemcitabine hampers passive transport by cell membrane permeation that may lead to drug resistance as it has to enter the cells via nucleoside transporters. The art of encapsulating the drug in a nanovesicle and then anchoring it with a targeting ligand is one of the present areas of research in cancer chemotherapy. METHODS: In this study, solid lipid nanoparticles were prepared by double emulsification and solvent evaporation method. Cyclic RGDfk and gemcitabine hydrochloride were used as targeting ligands and chemotherapeutic drugs, respectively, for targeting breast cancer. The prepared nanoparticles were evaluated for in vitro and in vivo performance to showcase the targeting efficiency and therapeutic benefits of the gemcitabine-loaded ligand conjugated nanoparticles. RESULTS: When compared with gemcitabine (GEM) and GEM loaded nanoparticles (GSLN), the ligand conjugated GEM nanoparticles (cGSLN) showed superior cytotoxicity, apoptosis, and inhibition of 3D multicellular spheroids in human breast cancer cells (MDA MB 231). The in vivo tumor regression studies in orthotopic breast cancer induced Balb/C mice showed that cGSLN displayed superior tumor suppression and also the targeting potential of the cGSLN toward induced breast cancer. CONCLUSION: Prepared nanoformulations showed enhanced anticancer activity in both 2D and 3D cell culture models along with antitumor efficacy in orthotopic breast cancer mouse models.

Precisely Targeted Nano-Controller of PD-L1 Level for Non-Small Cell Lung Cancer Spinal Metastasis Immunotherapy.

Although immune checkpoint inhibitors (ICIs) have been widely applied to treat non-small cell lung cancer (NSCLC), a significant proportion of patients, especially those with spinal metastasis (NSCLC-SM), are insensitive to anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) ICIs. A drug delivery nano-controller of PD-L1 that targets NSCLC-SM can solve this problem, however, none have been developed to date. In this study, it is shown that integrin ß3 (ß3-int) is strongly upregulated in NSCLC-SM. Its inhibitor RGDyK promotes PD-L1 ubiquitination, indicating the potential application of RGDyK as a new PD-L1 inhibitor in nano-controller and a targeting peptide for NSCLC-SM treatment. According to the synergistic effect of photodynamic therapy and ICIs on T-cell activation through the release of tumor antigens, RGDyK-modified and zinc protoporphyrin (ZnPP)-loaded mesoporous silicon nanoparticles (ZnPP@MSN-RGDyK) are fabricated. The ZnPP@MSN-RGDyK nanoparticles precisely target ß3-int to inhibit PD-L1, exhibiting high photodynamic therapy efficiency, and excellent immunotherapeutic effects in an NSCLC-SM mouse model. Collectively, the findings indicate that ZnPP@MSN-RGDyK is a promising immunotherapeutic agent for treating NSCLC-SM.

Pristimerin exerts antitumor activity against MDA-MB-231 triple-negative breast cancer cells by reversing of epithelial-mesenchymal transition via downregulation of integrin ß3.

BACKGROUND: Pristimerin, a natural flavonoid compound, has potential anti-tumor activities. These activities have been illustrated in various cancer cell lines, including MDA-MB-231 cells. MDA-MB-231 cells are a representative mesenchymal subtype of triple negative breast cancer (MES-TNBC) cell line. Currently, the main treatment for patients with advanced MES-TNBC is cytotoxic chemotherapy. We tried to examine the role and effect of pristimerin on epithelial-mesenchymal transition (EMT) in MDA-MB-231 cells. METHODS: The effects of pristimerin on the proliferation of MDA-MB-231 cells were investigated by cloning formation growth assay. In vitro transwell and adhesion assays were performed for cell invasion and adhesion. The expression levels of EMT markers in E-cadherin and N-cadherin were examined by western blotting. We also established overexpressed- and silenced-integrin ß3 cell lines to evaluate the role of integrin ß3 in mediating the EMT reversion events in MDA-MB-231 cells. RESULTS: Pristimerin inhibited cell proliferation, and its inhibitory effect was dose-dependent. We demonstrated that pristimerin reserved EMT by upregulating E-cadherin and downregulating N-cadherin expression. Meanwhile, we revealed that pristimerin inhibited mRNA and protein expression of integrin ß3, which is a key heterodimeric transmembrane receptor associated with EMT. These inhibitory effects and reversion of EMT were enhanced when integrin ß3 was knockdown in MDA-MB-231 cells, while the overexpression of integrin ß3 attenuated these effects. In vivo studies using xenograft mouse model demonstrated that pristimerin inhibited tumor growth. CONCLUSIONS: Our findings provide important insights into the effects of pristimerin on inhibiting cancer progression and EMT reversion by suppression of integrin ß3.

Function and antagonism of beta3 integrins in the development of cancer therapy.

The integrin family of cell surface receptors integrates cell-extracellular matrix interactions with the cell cytoskeleton and signalling across the cell membrane, resulting in an important role in cell adhesion, mobility and migration, proliferation, and survival. Changes in the number and identity of integrin receptors are common in cancer cells resulting in alteration of the ability of malignant cells to interact with the extracellular matrix, and promoting migration as well as facilitating survival outside the tumour normal environment. beta(3) integrins are potentially involved in every step of the metastatic process and expression of both alpha(IIb)beta(3) and alpha(n)beta(3) is correlated with metastatic ability of tumour cells. The recognition of the RGD binding motif common to the disintegrins and natural integrin ligands such as fibrinogen allowed the development of small molecule beta(3) integrin antagonists, progressing from linear peptides containing the RGD sequence to cyclic peptides with well-defined conformation, and hence to small molecule peptidomimetics with improved pharmacological properties. In this review, we summarize the role of the beta(3)-subfamily of integrins when expressed in normal and tumour tissue, the development of small-molecule antagonists of beta(3) integrins and their potential anti-cancer applications.

The role of low-molecular-weight heparin in cardiovascular diseases.

Unfractionated heparin continues to have important limitations in clinical practice. It has an inconsistent anticoagulant effect, needs frequent monitoring, and is inactivated by several plasma proteins. Low-molecular-weight heparins have a more predictable anticoagulant effect than unfractionated heparin, are easier to administer, and may not require monitoring. The anticoagulation effect of low-molecular-weight heparins is caused by a combination of inhibition of thrombin generation and inhibition of thrombin activity. Low-molecular-weight heparins have now been evaluated for a number of cardiovascular conditions and have been found to be safe and effective. We review and summarize the existing data regarding the use of low-molecular-weight heparins in cardiovascular diseases, including venous thromboembolism, percutaneous coronary interventions, and acute coronary syndromes such as ST-segment elevation myocardial infarction.