Oncotarget最新文献

Matrix metalloproteinases (MMPs) are crucial in remodeling the extracellular matrix (ECM), modulating key processes involved in cancer progression, such as migration, invasion, angiogenesis, and metastasis. The overexpression of MMPs, particularly MMP-9, is markedly observed in glioblastoma multiforme (GBM), an aggressive primary brain tumor known for its diffuse and infiltrative nature. Tissue inhibitors of metalloproteinases (TIMPs), endogenous MMP inhibitors, offer significant therapeutic potential due to their wider interaction interfaces relative to small molecule inhibitors. Here, we studied the effect of wild-type human TIMP-1 and TIMP-3 and minimal TIMP variants (mTC1 and mTC3), previously engineered for MMP inhibition, on migration and invasion of GBM cells. Our study focused on minimal TIMP variants, due to their small molecular size and potential in higher cellular uptake and delivery, to assess their potential in cell-based assays. The results demonstrated that the minimal TIMP variants, mTC1, and mTC3, effectively inhibit MMP activity underscoring their potential to limit tumor invasion and progression. Given the lethal nature of GBM and the limited efficacy of current therapies, the application of TIMPs and their engineered minimal variants represents a novel and potentially transformative approach to regulating MMP activity in GBM.

Clinical parameters of leukogram and weight were analyzed in animal models before and after seven days of 5-FU infusions. A comparison of leukograms before and after 5-FU administrations was analyzed. The results showed a significant difference (p = 0,004), confirming immunosuppression. There was a decrease in the weight of the animals after 7 days of 5-FU infusions (p = 0.02). After immunosuppression occurred, oral mucositis (OM) ulcerative lesions were observed. Two of the animals were selected to receive PLGA dressings. Then, electrospun PLGA membranes, with or without autologous cells, were applied to the ulcerative lesions, aiming to accelerate the regeneration process. Although this therapeutic innovation for OM lesions was still not tested in the bioengineering area, morphological analysis presented promising results. Lesions covered by cell-free PLGA, exhibited areas of inflammation persistence and angiogenesis. The cell-seeded cell-seeded PLGA membrane exhibited complete reepithelialization after 6 days, with minor inflammatory infiltrate. Interestingly, the present work showed preclinical parameters of cachexia induced by chemotherapy for cancer treatment. Moreover, it showed an innovative approach by applying dressings consisting of electrospun PLGA with the addition of autologous mesenchymal cells for OM ulcerative lesions. This promising innovation will pave the way for future applications in oral mucosa lesions.

Cancers that retain wild type TP53 presumably harbor other clonal alterations that permitted their precursors to bypass p53-mediated growth suppression. Consequently, studies that employ TP53-wild type cancer cells and their isogenic derivatives may systematically fail to appreciate the full scope of p53 functionality. Several TP53 phenotypes are known to be absent in the widely used isogenic HCT116 colorectal cancer (CRC) model, which originated from a tumor that had retained wild type TP53. In contrast, we show that restoration of p53 in the TP53-mutant CRC cell line DLD-1 impeded cell proliferation, increased levels of senescence and sensitized cells to ionizing radiation (IR). To study p53 in a non-cancer context, we disrupted TP53 in hTERT-RPE1 cells. Derived from primary cells that were immortalized in vitro, hTERT-RPE1 expressed striking p53-dependent phenotypes and appeared to select for p53 loss during routine culture. hTERT-RPE1 expressed a p53-responsive transcriptome that was highly representative of diverse experimental systems. We discovered several novel downstream p53 targets of potential clinical relevance including ALDH3A1, which is involved in the detoxification of aldehydes and the metabolism of reactive oxygen species, and nectin cell adhesion molecule 4 (NECTIN4) which encodes a secreted surface protein that is overexpressed in many tumors.