Bone Marrow Mesenchymal Stem Cells Derived Discoidin Domain-Containing Receptor 2 (DDR2) as a Communication Mediator to Strengthen the Invasiveness and Metastasis of Papillary Thyroid Carcinoma

Our current study plans to dissect the impacts and its underlying mechanisms of bone marrow mesenchymal stem cells (BMSCs) on the invasive and metastatic features of PTC. Clinical specimens from distantly metastatic PTC were collected to measure DRR2 level. After being identified via tri-lineage differentiation and flow cytometry, BMSCs were co-cultured with PTC cells followed by analysis of cell proliferation and migration by CCK-8 and Transwell assays, expression of DDR2 and EMT-associated proteins by Western blot. Eventually, shDDR2-transfected BMSCs were infused with PTC cells into the abdominal cavity of mice to establish a mouse model assess their effect on tumor growth and distant metastasis. DDR2 was upregulated in BMSCs and malignant cells located in the metastatic sites. Co-culture with BMSCs enhanced DRR2 expression in PTC cells, which was simultaneously accompanied by the escalated mesenchymalization process. In vivo experiments exhibited that co-injection with BMSCs facilitated disease progression and distant metastasis of malignancies. Instead, DDR2 knockdown significantly impeded BMSCs-triggered migrative and proliferative behaviors of malignant cells. In conclusion, DDR2 derived from BMSCs can function as a communication mediator to strengthen the invasiveness and metastasis of PTC.

Hydroxycamptothecin Impedes the Mesenchymal Stem Cells (MSCs)-Triggered Migrative Features of Breast Cancer Cells via Suppressing the Protein Kinase B/Mitogen-Activated Protein Kinase (AKT/MAPK) Activation in Bone Marrowmesenchymal Stem Cells

The current study aimed to dissect the impacts and mechanisms of hydroxycamptothecin on breast cancer. Collect conditioned medium from MSCs cells to apply it into the co-culture system of breast cancer cells, which were pre-treated with hydroxycamptothecin. The cell counting kit was employed to measure the proliferation potential of cells, while the phosphorylation degrees of AKT/MAPKrelated proteins were examined via Western blotting. Then the cellular migration was test by transwell. Finally, the transcriptional and translational levels of IL-6 and RANTES in cells were detected by real-time PCR and enzyme-linked immunosorbent assay. HC could remarkably influence the interplay between MSC and breast malignant cells, reduce the MSC-activated migrative behavior of breast malignant cells and impede the capability of MSC to maintain the migration of cancer cells. RANTES and IL-6 exerted a synergistic induction in the migrative feature of breast cancer cells. HC could retard the migrating activities of breast cancer cells via diminishing the RANTES and IL-6 levels. Hydroxycamptothecin could impede the proliferative and migrative activities of MSC, of which the impediment was accompanied by an inhibitory impact on the secretory production of two growth factors IL-6 and RANTES from MSC, thereby enhancing the migration of breast malignant cells.

The Crosstalk Between Malignant Cells and Tumor-Promoting Immune Cells Relevant to Immunotherapy in Pancreatic Ductal Adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is dominated by an immunosuppressive microenvironment, which makes immune checkpoint blockade (ICB) often non-responsive. Understanding the mechanisms by which PDAC forms an immunosuppressive microenvironment is important for the development of new effective immunotherapy strategies.Methods: This study comprehensively evaluated the cell-cell communications between malignant cells and immune cells by integrative analyses of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC. A Malignant-Immune cell crosstalk (MIT) score was constructed to predict survival and therapy response in PDAC patients. Immunological characteristics, enriched pathways, and mutations were evaluated in high- and low MIT groups.Results: We found that PDAC had high level of immune cell infiltrations, mainly were tumor-promoting immune cells. Frequent communication between malignant cells and tumor-promoting immune cells were observed. 15 ligand-receptor pairs between malignant cells and tumor-promoting immune cells were identified. We selected genes highly expressed on malignant cells to construct a Malignant-Immune Crosstalk (MIT) score. MIT score was positively correlated with tumor-promoting immune infiltrations. PDAC patients with high MIT score usually had a worse response to immune checkpoint blockade (ICB) immunotherapy.Conclusion: The ligand-receptor pairs identified in this study may provide potential targets for the development of new immunotherapy strategy. MIT score was established to measure tumor-promoting immunocyte infiltration. It can serve as a prognostic indicator for long-term survival of PDAC, and a predictor to ICB immunotherapy response.

Role of Silymarin in Cancer Treatment: Facts, Hypotheses, and Questions

The flavonoid silymarin extracted from the seeds of Sylibum marianum is a mixture of 6 flavolignan isomers. The 3 more important isomers are silybin (or silibinin), silydianin, and silychristin. Silybin is functionally the most active of these compounds. This group of flavonoids has been extensively studied and they have been used as hepato-protective substances for the mushroom Amanita phalloides intoxication and mainly chronic liver diseases such as alcoholic cirrhosis and nonalcoholic fatty liver. Hepatitis C progression is not, or slightly, modified by silymarin. Recently, it has also been proposed for SARS COVID-19 infection therapy. The biochemical and molecular mechanisms of action of these substances in cancer are subjects of ongoing research. Paradoxically, many of its identified actions such as antioxidant, promoter of ribosomal synthesis, and mitochondrial membrane stabilization, may seem protumoral at first sight, however, silymarin compounds have clear anticancer effects. Some of them are: decreasing migration through multiple targeting, decreasing hypoxia inducible factor-1α expression, inducing apoptosis in some malignant cells, and inhibiting promitotic signaling among others. Interestingly, the antitumoral activity of silymarin compounds is limited to malignant cells while the nonmalignant cells seem not to be affected. Furthermore, there is a long history of silymarin use in human diseases without toxicity after prolonged administration. The ample distribution and easy accessibility to milk thistle—the source of silymarin compounds, its over the counter availability, the fact that it is a weed, some controversial issues regarding bioavailability, and being a nutraceutical rather than a drug, has somehow led medical professionals to view its anticancer effects with skepticism. This is a fundamental reason why it never achieved bedside status in cancer treatment. However, in spite of all the antitumoral effects, silymarin actually has dual effects and in some cases such as pancreatic cancer it can promote stemness. This review deals with recent investigations to elucidate the molecular actions of this flavonoid in cancer, and to consider the possibility of repurposing it. Particular attention is dedicated to silymarin's dual role in cancer and to some controversies of its real effectiveness.

Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1

STIP1 homology and U-Box containing protein 1 (STUB1) plays a key role in maintaining cell health during stress and aging. Recent evidence suggested STUB1 also helps regulate immunity with the potential of clearing malignant cells. Indeed, we and others have shown that STUB1 is a pivotal negative regulator of interferon gamma sensing – a process critical to the immunosurveillance of tumors and pathogens. Thus far, investigation of STUB1’s role relies mostly on genetic approaches as pharmacological inhibitors of this protein are lacking. Identification of a STUB1 tool compound is important as it would allow therapeutically relevant target validation in a broader sense. Accordingly, we leveraged phage display and computational modeling to identify and refine STUB1 binders. Screening of >10E9 macrocyclic peptides resulted in several conserved motifs as well as structurally diverse leads. Co-crystal structure of the peptide hit and STUB1 has enabled us to employ structure-based in silico design for further optimization. Of the modifications employed, replacing the hydrophilic solvent-exposed region of the macrocyclic peptides with a hydrophobic scaffold improved cellular permeability, while the binding conformation was maintained. Further substitution of the permeability-limiting terminal aspartic acid with a tetrazole bioisostere retained the binding to certain extent while improving permeability, suggesting a path forward. The current lead, although not optimal for cellular study, provides a valuable template for further development into selective tool compounds for STUB1 to enable target validation.

The transcriptional hallmarks of intra-tumor heterogeneity across a thousand tumors

Each tumor contains malignant cells that differ in genotype, phenotype, and in their interactions with the tumor micro-environment (TME). This results in distinct integrated cellular states that govern intra-tumor heterogeneity (ITH), a central challenge of cancer therapeutics. Dozens of recent studies have begun to describe ITH by single cell RNA-seq, but each study typically profiledonly a small number of tumors and provided a narrow view of transcriptional ITH. Here, we curate, annotate and integrate the data from 77 different studies to reveal the patterns of ITH across 1,163 tumor samples covering 24 tumor types. Focusing on the malignant cells, we find thousands of transcriptional ITH programs that can be described by 41 consensus meta-programs (MPs), each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many different tumors. The MPs cover diverse cellular processes and differ in their cancer-type distribution. General MPs associated with processes such as cell cycle and stress vary within most tumors, while context-specific MPs reflect the unique biology of particular cancer types, often resembling developmental cell types and suggesting the co-existence of variable differentiation states within tumors. Some of the MPs are further associated with overall tumor proliferation or immune state, highlighting their potential clinical significance. Based on functional similarities among MPs, we propose a set of 11 hallmarks that together account for the majority of observed ITH programs. Given the breadth and scope of the investigated cohort, the MPs and hallmarks described here reflect the first comprehensive pan-cancer description of transcriptional ITH.

Effect of Monoclonal Antibodies Conjugation With Gallium-Containing Solamargine: Warburg Effect- Based Cancer Therapeutic Strategy. Article Review

Therapy by Monoclonal antibodies is considered extremely hoping method for cancer therapy. But cancer cells have variable methods for resistance by multiple genetic mutations. The aim of that article to illustrate tagging monoclonal antibodies by gallium containing solamargine glycoside within the antibody by glycosylation the asparagine of its Fc portion. Malignant cells need to a big extent high carbohydrate content for aerobic glycolysis for cancer progression. Solamargine as a specific glycoside can be diffused easily and effectively into malignant cells with a high degree of specificity. Complexion gallium to solamargine then conjugation into monoclonal antibodies will increase Monoclonal antibody potency and affinity by Warburg effect based mechanism and gallium particles. Gallium can be retained for a long time inside malignant cells. By that method, the monoclonal antibody will be targeted to cancer cells by solamargine, retained gallium particles besides its functioning specific Fab region.

Molecular testing on serous effusion: An update

Cytological examination of the effusion fluid provides valuable information regarding the presence of malignancy. At times, it is challenging to diagnose malignant cells in serous effusion. The various ancillary techniques are available to solve the problem including immunocytochemistry, DNA ploidy, and multicolored flow cytometry. At present, the molecular tests on the effusion sample are of growing interest. The effusion sample is rich in cells and cell-free fluid that contains free DNA, cytokines, and extracellular vesicles. Molecular tests in effusion sample not only provide a diagnosis of malignancy but can also give valuable information that may be essential for the individualized therapy, management, and prognostic assessment. In this paper, we reviewed the application of the different molecular tests in the effusion sample.