Abstract
Triple-negative breast cancer (TNBC), a specific subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor ...2 (HER-2), has clinical features that include high invasiveness, high metastatic potential, proneness to relapse, and poor prognosis. Because TNBC tumors lack ER, PR, and HER2 expression, they are not sensitive to endocrine therapy or HER2 treatment, and standardized TNBC treatment regimens are still lacking. Therefore, development of new TNBC treatment strategies has become an urgent clinical need. By summarizing existing treatment regimens, therapeutic drugs, and their efficacy for different TNBC subtypes and reviewing some new preclinical studies and targeted treatment regimens for TNBC, this paper aims to provide new ideas for TNBC treatment.
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•This review summarized the recent progress in metal-organic frameworks (MOFs)-based nanozymes for cancer combination therapy.•The fundamental catalysis mechanisms and general ...synthetic strategies for MOFs-based nanozymes were discussed.•The progress was described with four new categories based on the characteristic factors in tumor microenvironment.•The current challenges and perspectives of these smart nanoplatforms on the future research directions were proposed.
Nanomaterials with enzyme-like catalytic activity, named as nanozymes, have aroused wide research interest owing to their striking merits bridging nanotechnology and biology. Metal-organic frameworks (MOFs) are a novel class of porous inorganic-organic hybrid materials made from metal ions/clusters and organic ligands, and have shown great prospect in the construction of novel nanozymes, making the as-emerged MOFs-based nanozymes promising candidates for biosensing, biocatalysis, biomedical imaging, and therapeutic applications. In this feature article, we tend to systematically summarize the recent process concerning MOFs-based nanozymes for combined cancer therapy, which emerged as a new trend in clinical oncology in view of the synergistic therapeutic efficacy and reduced side effects originating from different treatments. Firstly, classic kinds of MOFs-based nanozymes are briefly described with representatives for catalysis mechanism analysis. Secondly, general strategies for construction of MOFs-based nanozymes are discussed. Thirdly, recent advances in the application of MOFs-based nanozymes for dual or triple combination of therapeutic modalities have been reviewed in detail with a particular emphasis focusing upon underlying synergistic mechanisms involved in each combination formulation. Finally, current challenges and future perspectives of MOFs-based nanozymes with a view to maximizing their great potential in the research of translational medicine are also discussed. It is highly expected that our demonstration on this evolving area will play a more important role in the field of the personalized nanomedicine in combating cancer.
Glioblastoma is the most lethal brain tumor and harbors glioma stem cells (GSCs) with potent tumorigenic capacity. The function of GSCs in tumor propagation is maintained by several core ...transcriptional regulators including c-Myc. c-Myc protein is tightly regulated by posttranslational modification. However, the posttranslational regulatory mechanisms for c-Myc in GSCs have not been defined. In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation. In contrast, overexpression of the ubiquitin E3 ligase FBXL14 induced c-Myc degradation, promoted GSC differentiation, and inhibited tumor growth. Ectopic expression of the ubiquitin-insensitive mutant T58A-c-Myc rescued the effects caused by FBXL14 overexpression or USP13 disruption. These data suggest that USP13 and FBXL14 play opposing roles in the regulation of GSCs through reversible ubiquitination of c-Myc.
Hepatocellular carcinoma (HCC) exhibits cellular heterogeneity and embryonic stem‐cell–related genes are preferentially overexpressed in a fraction of cancer cells of poorly differentiated tumors. ...However, it is not known whether or how these cancer cells contribute to tumor initiation and progression. Here, our data showed that increased expression of pluripotency transcription factor Nanog in cancer cells correlates with a worse clinical outcome in HCC. Using the Nanog promoter as a reporter system, we could successfully isolate a small subpopulation of Nanog‐positive cells. We demonstrate that Nanog‐positive cells exhibited enhanced ability of self‐renewal, clonogenicity, and initiation of tumors, which are consistent with crucial hallmarks in the definition of cancer stem cells (CSCs). NanogPos CSCs could differentiate into mature cancer cells in in vitro and in vivo conditions. In addition, we found that NanogPos CSCs exhibited resistance to therapeutic agents (e.g., sorafenib and cisplatin) and have a high capacity for tumor invasion and metastasis. Knock‐down expression of Nanog in NanogPos CSCs could decrease self‐renewal accompanied with decreased expression of stem‐cell–related genes and increased expression of mature hepatocyte‐related genes. Overexpression of Nanog in NanogNeg cells could restore self‐renewal. Furthermore, we found that insulin‐like growth factor (IGF)2 and IGF receptor (IGF1R) were up‐regulated in NanogPos CSCs. Knock‐down expression of Nanog in NanogPos CSCs inhibited the expression of IGF1R, and overexpression of Nanog in NanogNeg cells increased the expression of IGF1R. A specific inhibitor of IGF1R signaling could significantly inhibit self‐renewal and Nanog expression, indicating that IGF1R signaling participated in Nanog‐mediated self‐renewal. Conclusion: These data indicate that Nanog could be a novel biomarker for CSCs in HCC, and that Nanog could play a crucial role in maintaining the self‐renewal of CSCs through the IGF1R‐signaling pathway. (HEPATOLOGY 2012;56:1004–1014)
Nanomedicine‐based synergy of chemodynamic therapy (CDT) and radiotherapy (RT) modulated by tumor microenvironment enables rapid tumor ablation, which holds great hope for the refractory and ...recurrent cancers, such as triple negative breast cancer (TNBC). The clinical translation of hafnium oxide (HfO2), commercially named as NBTXR3, has aroused new research focus on single‐component inorganic nanomedicines as clinical candidates. Herein, the single‐component MnWO4 is first reported as a new kind of Fenton‐like agent yet radiosensitizer for TNBC treatment undergoing the synergistic CDT/RT mechanism. MnWO4 nanorods are synthesized via a simple one‐pot hydrothermal method and then undergo a layer‐by‐layer PEGylation to obtain bioavailable MnWO4‐PEG (MWP). MWP‐based Fenton‐like reaction efficacy depends on reaction time, temperatures, pH values, and MWP concentrations. Mn‐triggered chemodynamic effect delays RT‐induced DNA damage repair and sorts cell cycles distribution toward radiosensitive phases, while W‐mediated radiosensitization improves the tumoral H2O2 overexpression to enhance CDT, remarkably amplifying of the intracellular oxidative stress to boost 4T1 cell apoptosis. In vitro and in vivo evaluations further demonstrate the effectiveness and biosafety of MWP‐based synergistic therapy. Considering the potential magnetic resonance and computed tomography imaging capabilities, MWP can be expected as an intelligent cancer theranostics for imaging‐guided cancer therapy in clinic in the future.
A single‐component MnWO4 is first reported as a new kind of catalytic nanoradiosensitizer enabling synergy of chemodynamic therapy (CDT) and radiotherapy (RT) for efficient treatment of triple negative breast cancer. This study is a step forward toward the design and promotion of single‐component based inorganic multifunctional nanomaterials as potential clinical candidates.
E‐cadherin (E‐cad) plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. This protein exists in two forms: a membrane‐tethered form and a soluble form. ...Full‐length E‐cad is membrane tethered. As a type I transmembrane glycoprotein, E‐cad mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. Soluble E‐cad (sE‐cad) is the extracellular fragment of the protein that is cleaved from the membrane after proteolysis of full‐length E‐cad. The production of sE‐cad undermines adherens junctions, causing a reduction in cell aggregation capacity; furthermore, sE‐cad can diffuse into the extracellular environment and the blood. As a paracrine/autocrine signaling molecule, sE‐cad activates or inhibits multiple signaling pathways and participates in the progression of various types of cancer, such as breast cancer, ovarian cancer, and lung cancer, by promoting invasion and metastasis. This article briefly reviews the role of sE‐cad in tumorigenesis and tumor progression and its significance in clinical therapeutics.
Metabolism reprogramming has been linked with the initiation, metastasis, and recurrence of cancer. The aldehyde dehydrogenase (ALDH) family is the most important enzyme system for aldehyde ...metabolism. The human ALDH family is composed of 19 members. ALDH1A3 participates in various physiological processes in human cells by oxidizing all‐trans‐retinal to retinoic acid. ALDH1A3 expression is regulated by many factors, and it is associated with the development, progression, and prognosis of cancers. In addition, ALDH1A3 influences a diverse range of biological characteristics within cancer stem cells and can act as a marker for these cells. Thus, growing evidence indicates that ALDH1A3 has the potential to be used as a target for cancer diagnosis and therapy.
Tumor-associated macrophages (TAMs) constitute a large population of glioblastoma and facilitate tumor growth and invasion of tumor cells, but the underlying mechanism remains undefined. In this ...study, we demonstrate that chemokine (C-C motif) ligand 8 (CCL8) is highly expressed by TAMs and contributes to pseudopodia formation by GBM cells. The presence of CCL8 in the glioma microenvironment promotes progression of tumor cells. Moreover, CCL8 induces invasion and stem-like traits of GBM cells, and CCR1 and CCR5 are the main receptors that mediate CCL8-induced biological behavior. Finally, CCL8 dramatically activates ERK1/2 phosphorylation in GBM cells, and blocking TAM-secreted CCL8 by neutralized antibody significantly decreases invasion of glioma cells. Taken together, our data reveal that CCL8 is a TAM-associated factor to mediate invasion and stemness of GBM, and targeting CCL8 may provide an insight strategy for GBM treatment.
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