Stem cell membrane, stem cell-derived exosomes and hybrid stem cell camouflaged nanoparticles: A promising biomimetic nanoplatforms for cancer theranostics.

Nanomedicine research has advanced dramatically in recent decades. Nonetheless, traditional nanomedicine faces significant obstacles such as the low concentration of the drug at target sites and accelerated removal of the drug from blood circulation. Various techniques of nanotechnology, including cell membrane coating, have been developed to address these challenges and to improve targeted distribution and redcue cell membrane-mediated immunogenicity. Recently, stem cell (SC) membranes, owing to their immunosuppressive and regenerative properties, have grabbed attention as attractive therapeutic carriers for targeting specific tissues or organs. Bioengineering strategies that combine synthetic nanoparticles (NPs) with SC membranes, because of their homing potential and tumor tropism, have recently received a lot of publicity. Several laboratory experiments and clinical trials have indicated that the benefits of SC-based technologies are mostly related to the effects of SC-derived exosomes (SC-Exos). Exosomes are known as nano-sized extracellular vehicles (EVs) that deliver particular bioactive molecules for cell-to-cell communication. In this regard, SC-derived exosome membranes have recently been employed to improve the therapeutic capability of engineered drug delivery vehicles. Most recently, for further enhancing NPs' functionality, a new coating approach has been offered that combines membranes from two separate cells. These hybrid membrane delivery vehicles have paved the way for the development of biocompatible, high-efficiency, biomimetic NPs with varying hybrid capabilities that can overcome the drawbacks of present NP-based treatment techniques. This review explores stem cell membranes, SC-Exos, and hybrid SC-camouflaged NPs preparation methods and their importance in cancer therapy.

The cross-talk between tumor-associated macrophages and tumor endothelium: Recent advances in macrophage-based cancer immunotherapy.

Tumor-associated macrophages (TAMs) are among the abundant cell populations of the tumor microenvironment (TME), which have pivotal roles in tumor development, chemoresistance, immune evasion, and metastasis. Growing evidence indicates that TAMs and the cross-talk between TAMs and tumoral endothelial cells can substantially contribute to tumor angiogenesis, which is considered a vital process for cancer development. Besides, tumoral endothelial cells can regulate the leukocyte infiltration to the TME in solid cancers and contribute to immune evasion. Therefore, targeting the immunosuppressive TAMs and the cross-talk between them can be a promising strategy for improving anti-tumoral immune responses. This review aims to summarize the biology of TAMs, their recently identified roles in tumor development/angiogenesis, and recent advances in macrophage-based cancer immunotherapy approaches for treating cancers.

Silencing ZEB2 Induces Apoptosis and Reduces Viability in Glioblastoma Cell Lines.

BACKGROUND: Glioma is an aggressive type of brain tumor that originated from neuroglia cells, accounts for about 80% of all malignant brain tumors. Glioma aggressiveness has been associated with extreme cell proliferation, invasion of malignant cells, and resistance to chemotherapies. Due to resistance to common therapies, glioma affected patients' survival has not been remarkably improved. ZEB2 (SIP1) is a critical transcriptional regulator with various functions during embryonic development and wound healing that has abnormal expression in different malignancies, including brain tumors. ZEB2 overexpression in brain tumors is attributed to an unfavorable state of the malignancy. Therefore, we aimed to investigate some functions of ZEB2 in two different glioblastoma U87 and U373 cell lines. METHODS: In this study, we investigated the effect of ZEB2 knocking down on the apoptosis, cell cycle, cytotoxicity, scratch test of the two malignant brain tumor cell lines U87 and U373. Besides, we investigated possible proteins and microRNA, SMAD2, SMAD5, and miR-214, which interact with ZEB2 via in situ analysis. Then we evaluated candidate gene expression after ZEB2-specific knocking down. RESULTS: We found that ZEB2 suppression induced apoptosis in U87 and U373 cell lines. Besides, it had cytotoxic effects on both cell lines and reduced cell migration. Cell cycle analysis showed cell cycle arrest in G0/G1 and apoptosis induction in U87 and U373 cell lines receptively. Also, we have found that SAMAD2/5 expression was reduced after ZEB2-siRNA transfection and miR-214 upregulated after transfection. CONCLUSIONS: In line with previous investigations, our results indicated a critical oncogenic role for ZEB2 overexpression in brain glioma tumors. These properties make ZEB2 an essential molecule for further studies in the treatment of glioma cancer.

Suppression of Nanog inhibited cell migration and increased the sensitivity of colorectal cancer cells to 5-fluorouracil.

Nanog is a major transcription factor related to cellular multipotency that plays important roles in the development of tumor cells, drug resistance, migration, and stemness; indicating its great potential as a therapeutic target for various malignancies including colorectal cancer (CRC). Therefore, this study was aimed to evaluate the Nanog suppression effect using small interference RNA (siRNA) combined with 5-fluorouracil (5-FU) on CRC cells. Nanog-overexpressing SW-480 cells were transfected with Nanog si-RNA and treated with 5-FU, in combination or separately. Subsequently, it was observed that Nanog expression was significantly reduced after transfection of SW-480 cells using Nanog siRNA in mRNA and protein levels. Furthermore, Nanog knockdown significantly increased CRC cell sensitivity to 5-FU drug via modulating Bax and Bcl-2 mRNA expression. Also, Nanog knockdown and 5-FU treatment cooperatively decreased the migration and self-renewal ability of SW-480 cells by regulating the expression of relevant genes. Moreover, combination therapy led to cell cycle arrest at the sub-G1 phase in CRC cells. In conclusion, our results indicated that Nanog may play an important role in the drug sensitivity, migration, and self-renewal of CRC cells; suggesting Nanog as a promising target in combination with 5-FU for the development of new therapeutic approaches for CRC.

Immune checkpoints in tumor microenvironment and their relevance to the development of cancer stem cells.

Cancer is the second cause of mortality in the world after cardiovascular disease. Various studies attribute the emergence of therapeutic resistance in tumors to the presence of cancer stem cells or cancer-initiating cells (CSC/CIC). These relatively rare cells because of their typical stemness features, are responsible for tumor cell progression and recurrence. Moreover, CSCs have immunomodulatory capabilities and through orchestrating, some immunological profiles can stay safe from host anticancer immunity, and provide immunotherapy resistance in cancer patients. Many studies have shown that CSCs by producing immune system inhibitory factors and interacting with immune checkpoint molecules like CD47, PDL-1, CTLA4, Tim3, and LAG3, are able to communicate with tumor microenvironment (TME) components and protect cancer cells from immune clearance. In this review, we summarize the CSCs immunological mechanisms and comprehensively discuss interactions between these cells and factors that are present in the TME to repress immune system responses and enhance tumor survival. Therefore, it seems that further studies on this topic will open new doors to improve the therapeutic approaches of malignant cancers.

Tumor Cell Death via Apoptosis and Improvement of Activated Lymphocyte Cytokine Secretion by Extracts from Euphorbia Hebecarpa and Euphorbia Petiolata.

Background: Immunomodulatory materials from natural herbs and the characterization of their immune enhancement effects may have tremendous potential as cancer treatment. The aim of the present study was to investigate the apoptosis-inducing activities of Euphorbia hebecarpa Boiss and Euphorbia petiolata Banks & Sol. plant extracts and their effects on cytokine secretion by lymphocytes. Materials and Methods: We assessed the apoptosis-inducing effect of the plants' hexane extracts on previously determined sensitive cell lines (HeLa for E. hebecarpa and K562 for E. petiolata) by flow cytometry and measurement of caspase 3 activation. The apoptosis-related gene expressions were examined by real-time PCR. The effects of the extracts on lymphocyte proliferation and cytokine secretion were examined. Results: Flow cytometry analysis showed that the inhibitory effect of the extracts on tumor cell growth was due to cell apoptosis. The plant extracts at the 100 µg/ml dose induced apoptosis in HeLa (98.5 ± 0.1%) and K562 (57.7 ± 1.9%) cells. The extracts increased caspase 3 activation (≈2-fold>control). Real-time PCR showed Fas and Bax gene upregulation and Bcl-2 downregulation, which resulted in an increased Bax/Bcl-2 expression ratio. The extracts increased lymphocyte proliferation and increased levels of IFN-γ production in the presence and absence of mitogen (p < 0.05). They significantly increased IL-4 and decreased IL-10 secretion by mitogen-stimulated lymphocytes. E. hebecarpa also increased IL-17 release. Conclusion: These results have shown that both extracts possess antitumor activity by inducing apoptosis, possibly through both intrinsic and extrinsic pathways. In addition, they induced secretion of different T helper subset related cytokines that are effective in the immune response against cancer.

Augmentation of lymphocytes activation and T cell modulation by the extracts from some Euphorbia species.

CONTEXT: Euphorbia is an important Euphorbiaceae genus that is traditionally being used for various infections, inflammation, and cancer. OBJECTIVE: The present study investigated the possible in vitro immunomodulatory effect of three species of Euphorbia genus including Euphorbia microciadia Boiss, Euphorbia osyridea Boiss, and Euphorbia heteradenia Jaub. & Sp. on lymphocyte activation and cytokine secretion. MATERIALS AND METHODS: Human lymphocytes were cultured in the presence of various concentrations (0.1-200 µg/ml) of the butanol/hexane extracts of the plants in the presence or absence of phytohemmagglutinin (PHA). The activation of lymphocytes after 48 h was determined by a proliferation assay. The release of T cell cytokines was studied to determine the dominant T cell subsets involved in the immune response. RESULTS: All three plant extracts increased the proliferation of PHA-treated lymphocytes (maximum; 132% of control). Extract treatment of lymphocytes in the absence of PHA resulted in an increased proliferation of the cells indicating their lymphocyte mitogenic activity (maximum at 10 µg/ml E. microciadia extract; 494.5 ± 42.2% of control, p < 0.01). The extracts of E. microciadia and E. osyridea could increase IL-4 and IL-10 secretion but not IFN-γ production showing their capacity to deviate immune response toward a Th2 pattern. Euphorbia heteradenia did not change the release of IL-4 and IFN-γ cytokines but increased IL-10 production. The three extracts stimulated lymphocytes to produce IL-17 which showed their possible effects on Th17 cells activation. CONCLUSION: The studied extracts had the ability to modulate T cell responses suggesting their possible beneficial effects on immune host defense.