Strategies for Remodeling the Tumor Microenvironment Using Active Ingredients of Ginseng—A Promising Approach for Cancer Therapy

The tumor microenvironment (TME) plays a key role in promoting the initiation and progression of tumors, leading to chemoradiotherapy resistance and immunotherapy failure. Targeting of the TME is a novel anti-tumor therapeutic approach and is currently a focus of anti-tumor research. Panax ginseng C. A. Meyer (ginseng), an ingredient of well-known traditional Asia medicines, exerts beneficial anti-tumor effects and can regulate the TME. Here, we present a systematic review that describes the current status of research efforts to elucidate the functions and mechanisms of ginseng active components (including ginsenosides and ginseng polysaccharides) for achieving TME regulation. Ginsenosides have variety effects on TME, such as Rg3, Rd and Rk3 can inhibit tumor angiogenesis; Rg3, Rh2 and M4 can regulate the function of immune cells; Rg3, Rd and Rg5 can restrain the stemness of cancer stem cells. Ginseng polysaccharides (such as red ginseng acidic polysaccharides and polysaccharides extracted from ginseng berry and ginseng leaves) can regulate TME mainly by stimulating immune cells. In addition, we propose a potential mechanistic link between ginseng-associated restoration of gut microbiota and the tumor immune microenvironment. Finally, we describe recent advances for improving ginseng efficacy, including the development of a nano-drug delivery system. Taken together, this review provides novel perspectives on potential applications for ginseng active ingredients as anti-cancer adjuvants that achieve anti-cancer effects by reshaping the tumor microenvironment.

RTID-06. TRENDS IN INTERNATIONAL INVESTMENT IN CHILDHOOD, ADOLESCENT AND YOUNG ADULT (CYA) BRAIN TUMOR RESEARCH 2006-2018, WITH A FOCUS ON DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Organizations funding brain tumor research want to identify gap areas for funding individually or in collaboration and want to better understand existing project focus to maximize new project investments. The International Cancer Research Partnership and the US Coalition Against Childhood Cancer used international research portfolio data to assess the landscape of CYA brain tumor research. From 2006-2018, investment for brain tumor research increased from $13m to $73m, and as a percentage of the CYA portfolio, brain tumor research received the highest percent investment (30%) in 2018. Research into treatment had risen (from $6m to $38m) as had research into biology (from $3m to $19m) - an essential foundation for more future personalized treatments. Given the lifelong impact on survivors it was encouraging that survivorship research investment had also started to increase. While 5-year survival for CYA cancers is now over 80%, survival for Diffuse Intrinsic Pontine Glioma (DIPG) remains very low. To assess capacity for future progress, several indicators were considered. The number of new DIPG projects per year increased from an average of 3 per year (2006-2012) to 11 (2013-2018) and funding increased from $0.5m (2006) to $10m (2018). Also, by 2018, 9 projects included a training component to build future research capacity. The number of laboratories researching DIPG increased from 2 in the US (2006) to 53 institutions in 6 countries (2018). Recent years had seen increased funding for pre-clinical models essential for identifying new targets. Collaborative initiatives such as DIPG-Open and DIPG-All had been funded to collect biological samples and accelerate translation of therapeutics to the clinic. Despite evidence that 5-year survival had improved from 1% to 2%, clearly major advances need to be made in new treatments, and monitoring the funding landscape carefully to make strategic investments will be essential.

circSLC30A7 Inhibits Hepatocellular Carcinoma Cell Proliferation via the miR-767-5p/FBXW7/NOTCH1 Axis

Circular RNAs, noncoding RNAs, have attracted much attention in various human tumor research fields. They regulate the development of various human cancers via microRNA sponges. This study aimed to assess the molecular mechanism of circSLC30A7 in hepatocellular carcinoma (HCC). In our study, we identified that circSLC30A7 was significantly downregulated in HCC cell lines and tissues. Furthermore, gain and loss function experiments were conducted to elucidate the biological functions of circSLC30A7 in HCC cell lines. Mechanistically, circSLC30A7 sponged miR-767-5p, inhibiting the expression of its downstream protein, FBXW7. In summary, this study revealed that circSLC30A7 is an essential tumor suppressor that inhibits HCC tumorigenesis through the miR-767-5p/FBXW7/NOTCH1 axis. Taken together, circSLC30A7 reduces HCC malignancy and can be a biomarker for HCC management.

Co-Expression of CD34, CD90, OV-6 and Cell-Surface Vimentin Defines Cancer Stem Cells of Hepatoblastoma, Which Are Affected by Hsp90 Inhibitor 17-AAG

Cancer stem cells (CSCs) are nowadays one of the major focuses in tumor research since this subpopulation was revealed to be a great obstacle for successful treatment. The identification of CSCs in pediatric solid tumors harbors major challenges because of the immature character of these tumors. Here, we present CD34, CD90, OV-6 and cell-surface vimentin (csVimentin) as reliable markers to identify CSCs in hepatoblastoma cell lines. We were able to identify CSC characteristics for the subset of CD34+CD90+OV-6+csVimentin+-co-expressing cells, such as pluripotency, self-renewal, increased expression of EMT markers and migration. Treatment with Cisplatin as the standard chemotherapeutic drug in hepatoblastoma therapy further revealed the chemo-resistance of this subset, which is a main characteristic of CSCs. When we treated the cells with the Hsp90 inhibitor 17-AAG, we observed a significant reduction in the CSC subset. With our study, we identified CSCs of hepatoblastoma using CD34, CD90, OV-6 and csVimentin. This set of markers could be helpful to estimate the success of novel therapeutic approaches, as resistant CSCs are responsible for tumor relapses.

Systematic tissue collection during clinical breast biopsy is feasible, safe and enables high-content translational analyses

Systematic collection of fresh tissues for research at the time of diagnostic image-guided breast biopsy has the potential to fuel a wide variety of innovative studies. Here we report the initial experience, including safety, feasibility, and laboratory proof-of-principle, with the collection and analysis of research specimens obtained via breast core needle biopsy immediately following routine clinical biopsy at a single institution over a 14-month period. Patients underwent one or two additional core biopsies following collection of all necessary clinical specimens. In total, 395 patients were approached and 270 consented to the research study, yielding a 68.4% consent rate. Among consenting patients, 238 lesions were biopsied for research, resulting in 446 research specimens collected. No immediate complications were observed. Representative research core specimens showed high diagnostic concordance with clinical core biopsies. Flow cytometry demonstrated consistent recovery of hundreds to thousands of viable cells per research core. Among a group of HER2 + tumor research specimens, HER2 assessment by flow cytometry correlated highly with immunohistochemistry (IHC) staining, and in addition revealed extensive inter- and intra-tumoral variation in HER2 levels of potential clinical relevance. Suitability for single-cell transcriptomic analysis was demonstrated for a triple-negative tumor core biopsy, revealing substantial cellular diversity in the tumor immune microenvironment, including a prognostically relevant T cell subpopulation. Thus, collection of fresh tissues for research purposes at the time of diagnostic breast biopsy is safe, feasible and efficient, and may provide a high-yield mechanism to generate a rich tissue repository for a wide variety of cross-disciplinary research.

Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response

Tumors are not only aggregates of malignant cells but also well-organized complex ecosystems. The immunological components within tumors, termed the tumor immune microenvironment (TIME), have long been shown to be strongly related to tumor development, recurrence and metastasis. However, conventional studies that underestimate the potential value of the spatial architecture of the TIME are unable to completely elucidate its complexity. As innovative high-flux and high-dimensional technologies emerge, researchers can more feasibly and accurately detect and depict the spatial architecture of the TIME. These findings have improved our understanding of the complexity and role of the TIME in tumor biology. In this review, we first epitomized some representative emerging technologies in the study of the spatial architecture of the TIME and categorized the description methods used to characterize these structures. Then, we determined the functions of the spatial architecture of the TIME in tumor biology and the effects of the gradient of extracellular nonspecific chemicals (ENSCs) on the TIME. We also discussed the potential clinical value of our understanding of the spatial architectures of the TIME, as well as current limitations and future prospects in this novel field. This review will bring spatial architectures of the TIME, an emerging dimension of tumor ecosystem research, to the attention of more researchers and promote its application in tumor research and clinical practice.

Immunotherapy in endometrial cancer: rationale, practice and perspectives

Tumor immunotherapy has attracted more and more attention nowadays, and multiple clinical trials have confirmed its effect in a variety of solid tumors. Immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell transfer (ACT), and lymphocyte-promoting cytokines are the main immunotherapy methods. Endometrial cancer (EC) is one of the most frequent tumors in women and the prognosis of recurrent or metastatic EC is poor. Since molecular classification has been applied to EC, immunotherapy for different EC subtypes (especially POLE and MSI-H) has gradually attracted attention. In this review, we focus on the expression and molecular basis of the main biomarkers in the immunotherapy of EC firstly, as well as their clinical application significance and limitations. Blocking tumor immune checkpoints is one of the most effective strategies for cancer treatment in recent years, and has now become the focus in the field of tumor research and treatment. We summarized clinical date of planned and ongoing clinical trials and introduced other common immunotherapy methods in EC, such as cancer vaccine and ACT. Hormone aberrations, metabolic syndrome (MetS) and p53 mutant and that affect the immunotherapy of endometrial cancer will also be discussed in this review.