Increasing significance of tumor–stromal interaction in development and progression of cancer implies that signaling molecules in the tumor microenvironment (TME) might be the effective therapeutic targets for hepatocellular carcinoma (HCC). Here, the role of microRNA miR-199a-3p in the regulation of TME and development of HCC has been investigated by several in vitro and in vivo assays. Expression of miR-199a-3p was observed significantly low in HCC tissues and its overexpression remarkably inhibited in vivo tumor growth and metastasis to lung in NOD-SCID mice. In vitro restoration of miR-199a-3p expression either in endothelial cells (ECs) or in cancer cells (CACs) significantly diminished migration of ECs in co-culture assay. Again incubation of miR-199a-3p transfected ECs with either conditioned media (CM) of CACs or recombinant VEGF has reduced tube formation, in ECs and it was also dropped upon growth in CM of either anti-VEGF antibody-treated or miR-199a-3p-transfected CACs. In addition, bioinformatics and luciferase-reporter assays revealed that miR-199a-3p inhibited VEGF secretion from CACs and VEGFR1 and VEGFR2 expression on ECs and thus restricted cross talk between CACs and ECs. Again, restoration of miR-199a-3p in hepatic stellate cells (HSCs) reduced migration and invasion of CACs in co-culture assay, while it was enhanced by the overexpression of HGF suggesting miR-199a-3p has hindered HSC-CACs cross talk probably by inhibiting HGF and regulating matrix metalloproteinase MMP2, which were found as targets of miR-199a-3p subsequently by luciferase-reporter assay and gelatin zymography, respectively. Thus, these findings collectively highlight that miR-199a-3p restricts metastasis, invasion and angiogenesis in HCC and hence it may be considered as one of the powerful effective therapeutics for management of HCC patients.
Bidirectional cell-cell communication involving exosome-borne cargo such as miRNA, has emerged as a critical mechanism for wound healing. Unlike other shedding vesicles, exosomes selectively package miRNA by SUMOylation of heterogeneous nuclear ribonucleoproteinA2B1 (hnRNPA2B1). In this work, we elucidate the significance of exosome in keratinocyte-macrophage crosstalk following injury. Keratinocyte-derived exosomes were genetically labeled with GFP reporter (Exo κ-GFP ) using tissue nanotransfection and were isolated from dorsal murine skin and wound-edge tissue by affinity selection using magnetic beads. Surface N-glycans of Exo κ-GFP were also characterized. Unlike skin exosome, wound-edge Exo κ-GFP demonstrated characteristic N-glycan ions with abundance of low base pair RNA and were selectively engulfed by woundmacrophages (ωmϕ) in granulation tissue. In vitro addition of wound-edge Exo κ-GFP to proinflammatory ωmϕ resulted in conversion to a proresolution phenotype. To selectively inhibit miRNA packaging within Exo κ-GFP in vivo, pH-responsive keratinocyte-targeted siRNA-hnRNPA2B1 functionalized lipid nanoparticles (TLNP κ ) were designed with 94.3% encapsulation *
This review focuses on new possibilities to exploit OPN as a tumor and stroma-derived therapeutic target to combat cancer.
The aim of this study was to synthesize selenium nanoparticles (SeNPs) using cell suspension and total cell protein of Acinetobacter sp. SW30 and optimize its synthesis by studying the influence of physiological and physicochemical parameters. Also, we aimed to compare its anticancer activity with that of chemically synthesized SeNPs in breast cancer cells. Cell suspension of Acinetobacter sp. SW30 was exposed to various physiological and physicochemical conditions in the presence of sodium selenite to study their effects on the synthesis and morphology of SeNPs. Breast cancer cells (4T1, MCF-7) and noncancer cells (NIH/3T3, HEK293) were exposed to different concentrations of SeNPs. The 18 h grown culture with 2.7×10 9 cfu/mL could synthesize amorphous nanospheres of size 78 nm at 1.5 mM and crystalline nanorods at above 2.0 mM Na 2 SeO 3 concentration. Polygonal-shaped SeNPs of average size 79 nm were obtained in the supernatant of 4 mg/mL of total cell protein of Acinetobacter sp. SW30. Chemical SeNPs showed more anticancer activity than SeNPs synthesized by Acinetobacter sp. SW30 (BSeNPs), but they were found to be toxic to noncancer cells also. However, BSeNPs were selective against breast cancer cells than chemical ones. Results suggest that BSeNPs are a good choice of selection as anticancer agents.
Functional characterization and understanding of the intricate signaling mechanisms in stem-like cells is crucial for the development of effective therapies in melanoma. We have studied whether melanoma cells are phenotypically distinct and hierarchically organized according to their tumorigenic nature. We report that melanoma-specific CD133 cancer stem cells exhibit increased tumor-initiating potential, tumor-endothelial cell interaction, and lung metastasis. These cells are able to transdifferentiate into an endothelial-like phenotype when cultured under endothelial differentiation-promoting conditions. Mechanistically, Notch1 upregulates mitogen-activated protein kinase activation through CD133, which ultimately controls vascular endothelial growth factor and matrix metalloproteinase expression in CD133 stem cells leading to melanoma growth, angiogenesis, and lung metastasis. Blockade or genetic ablation of Notch1 and mitogen-activated protein kinase pathways abolishes melanoma cell migration and angiogenesis. Chromatin immunoprecipitation and reporter assays revealed that Notch1 intracellular domain regulates CD133 expression at the transcriptional level. Andrographolide inhibits Notch1 intracellular domain expression, Notch1 intracellular domain-dependent CD133-mediated mitogen-activated protein kinase and activator protein-1 activation, and epithelial to mesenchymal-specific gene expression, ultimately attenuating melanoma growth and lung metastasis. Human malignant melanoma specimen analyses revealed a strong correlation between Notch1 intracellular domain, CD133, and p-p38 mitogen-activated protein kinase expression and malignant melanoma progression. Thus, targeting Notch1 and its regulated signaling network may have potential therapeutic implications for the management of cancer stem cell-mediated melanoma progression.
Melanoma is a form of cancer that initiates in melanocytes. Melanoma has multiple phenotypically distinct subpopulation of cells, some of them have embryonic like plasticity which are involved in self-renewal, tumor initiation, metastasis and progression and provide reservoir of therapeutically resistant cells. Cancer stem cells (CSCs) can be identified and characterized based on various unique cell surface and intracellular markers. CSCs exhibit different molecular pattern with respect to non-CSCs. They maintain their stemness and chemoresistant features through specific signaling cascades. CSCs are weak in immunogenicity and act as immunosupressor in the host system. Melanoma treatment becomes difficult and survival is greatly reduced when the patient develop metastasis. Standard conventional oncology treatments such as chemotherapy, radiotherapy and surgical resection are only responsible for shrinking the bulk of the tumor mass and tumor tends to relapse. Thus, targeting CSCs and their microenvironment niche addresses the alternative of traditional cancer therapy. Combined use of CSCs targeted and traditional therapies may kill the bulk tumor and CSCs and offer a promising therapeutic strategy for the management of melanoma.
A successful design of a novel red fluorescent carbon dots liposomal nanopitchers for deep tissue visualization and on demand phototriggered combined cancer therapy. The laser irradiation produces heat and reactive oxygen species that cause cancer cell death and tumor growth inhibition.
Developing a nanotheranostic agent with better image resolution and high accumulation into solid tumor microenvironment is a challenging task. Herein, we established a light mediated phototriggered strategy for enhanced tumor accumulation of nanohybrids. A multifunctional liposome based nanotheranostics loaded with gold nanoparticles (AuNPs) and emissive graphene quantum dots (GQDs) were engineered named as NFGL. Further, doxorubicin hydrochloride was encapsulated in NFGL to exhibit phototriggered chemotherapy and functionalized with folic acid targeting ligands. Encapsulated agents showed imaging bimodality for in vivo tumor diagnosis due to their high contrast and emissive nature. Targeted NFGL nanohybrids demonstrated near infrared light (NIR, 750 nm) mediated tumor reduction because of generated heat and Reactive Oxygen Species (ROS). Moreover, NFGL nanohybrids exhibited remarkable ROS scavenging ability as compared to GQDs loaded liposomes validated by antitumor study. Hence, this approach and engineered system could open new direction for targeted imaging and cancer therapy.
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