x-ray-visualization-intraductal-ethanol-based-ablative-treatment-for

X-Ray Visualization of Intraductal Ethanol-Based Ablative Treatment for Prevention of Breast Cancer in Rat Models

There are still a limited number of primary interventions for prevention of breast cancer. For women at a high risk of developing breast cancer, the most ...

intraductal-delivery-x-ray-visualization-ethanol-based-ablative

Intraductal Delivery and X-ray Visualization of Ethanol-Based Ablative Solution for Prevention and Local Treatment of Breast Cancer in Mouse Models

Breast cancer is the most prevalent cancer and the second-leading cause of cancer-related death for women in the USA. For high-risk women, prophylactic ...

Michigan State University

In 1993, the Ambros lab reported the cloning and developmental function of lin-4, the first microRNA [...].

Celebrating 25 Years of MicroRNA Research: From Discovery to Clinical Application.

microRNAs are short noncoding RNAs that regulate protein expression posttranscriptionally. We previously showed that miR-155 promotes effector CD8 T-cell responses. However, little is known about the regulation of miR-155 expression. Here, we report that antigen affinity and dose determine miR-155 expression in CD8 T cells. In B16 tumors expressing a low-affinity antigen ligand, tumor-specific infiltrating CD8 T cells showed variable miR-155 expression, whereby high miR-155 expression was associated with more cytokine-producing cells and tumor control. Moreover, anti-PD-1 treatment led to both increased miR-155 expression and tumor control by specific CD8 T cells. In addition, miR-155 overexpression enhanced exhausted CD8 T-cell persistence in the LCMV cl13 chronic viral infection model. In agreement with these observations in mouse models, miR-155 expression in human effector memory CD8 T cells positively correlated with their frequencies in tumor-infiltrated lymph nodes of melanoma patients. Low miR-155 target gene signature in tumors was associated with prolonged overall survival in melanoma patients. Altogether, these results raise the possibility that high miR-155 expression in CD8 tumor-infiltrating T cells may be a surrogate marker of the relative potency of  antigen-specific CD8 T-cell responses.

MicroRNA-155 Expression Is Enhanced by T-cell Receptor Stimulation Strength and Correlates with Improved Tumor Control in Melanoma.

Prophylactic mastectomy is the most effective intervention to prevent breast cancer. However, this major surgery has life-changing consequences at the physical, emotional, psychological, and social levels. Therefore, only high-risk individuals consider this aggressive procedure, which completely removes the mammary epithelial cells from which breast cancer arises along with surrounding tissue. Here, we seek to develop a minimally invasive procedure as an alternative to prophylactic mastectomy by intraductal (ID) delivery of a cell-killing solution that locally ablates the mammary epithelial cells before they become malignant.

Ductal tree ablation by local delivery of ethanol prevents tumor formation in an aggressive mouse model of breast cancer.

Here, we describe the synthesis, characterization and in vitro and in vivo performance of a series of tantalum oxide (TaO) based nanoparticles (NPs) for computed tomography (CT). Five distinct versions of 9-12 nm diameter silane coated TaO nanocrystals (NCs) were fabricated by a sol-gel method with varying degrees of hydrophilicity and with or without fluorescence, with the highest reported Ta content to date (78%). Highly hydrophilic NCs were left bare and were evaluated in vivo in mice for micro-CT of full body vasculature, where following intravenous injection, TaO NCs demonstrate high vascular CT contrast, circulation in blood for ∼3 h, and eventual accumulation in RES organs; and following injection locally in the mammary gland, where the full ductal tree structure can be clearly delineated. Partially hydrophilic NCs were encapsulated within mesoporous silica nanoparticles (MSNPs; TaO@MSNPs) and hydrophobic NCs were encapsulated within poly(lactic-co-glycolic acid) (PLGA; TaO@PLGA) NPs, serving as potential CT-imagable drug delivery vehicles. Bolus intramuscular injections of TaO@PLGA NPs and TaO@MSNPs to mimic the accumulation of NPs at a tumor site produce high signal enhancement in mice. In vitro studies on bare NCs and formulated NPs demonstrate high cytocompatibility and low dissolution of TaO. This work solidifies that TaO-based NPs are versatile contrast agents for CT.

Tantalum oxide nanoparticles as versatile contrast agents for X-ray computed tomography.

The microenvironment of pancreatic cancer adenocarcinoma (PDAC) is highly desmoplastic with distinct tumor-restraining and tumor-promoting fibroblast subpopulations. Re-education rather than indiscriminate elimination of these fibroblasts has emerged as a new strategy for combination therapy. Here, we studied the effects of global loss of profibrotic noncoding regulatory microRNA-21 (miR-21) in K-Ras-driven p53-deleted genetically engineered mouse models of PDAC. Strikingly, loss of miR-21 accelerated tumor initiation via mucinous cystic neoplastic lesions and progression to locally advanced invasive carcinoma from which animals precipitously succumbed at an early age. The absence of tumor-restraining myofibroblasts and a massive infiltrate of immune cells were salient phenotypic features of global miR-21 loss. Stromal miR-21 activity was required for induction of tumor-restraining myofibroblasts in in vivo isograft transplantation experiments. Low miR-21 expression negatively correlated with a fibroblast gene expression signature and positively with an immune cell gene expression signature in The Cancer Genome Atlas PDAC data set (n = 156) mirroring findings in the mouse models. Our results exposed an overall tumor-suppressive function of miR-21 in in vivo PDAC models. These results have important clinical implications for anti-miR-21-based inhibitory therapeutic approaches under consideration for PDAC and other cancer types. Mechanistic dissection of the cell-intrinsic role of miR-21 in cancer-associated fibroblasts and other cell types will be needed to inform best strategies for pharmacological modulation of miR-21 activity to remodel the tumor microenvironment and enhance treatment response in PDAC.

Loss of microRNA-21 leads to profound stromal remodeling and short survival in K-Ras-driven mouse models of pancreatic cancer.

microRNAs are an important class of noncoding regulatory RNAs with functional roles in development, physiology, and disease. Visualization of microRNA expression at a single-cell level has contributed to a better understanding of their biological function in animal models and their etiological contribution to human diseases. In addition, several microRNAs have been highlighted as potential biomarkers carrying diagnostic and prognostic information. Co-detection of microRNA expression with that of cell-type-specific proteins can enhance the interpretative power of expression changes during development or altered expression in pathological conditions. Here, we describe an automated fluorescence-based five-color multiplex assay for co-detection of microRNA (e.g., miR-10b, miR-21, miR-205), noncoding RNA (e.g., snRNA U6, 18S rRNA), and protein expression (e.g., cytokeratin 19, vimentin, collagen I) in paraffin-embedded formalin-fixed tissue slides on a Leica Bond Rx staining station. While this protocol uses mainly mouse tissues to demonstrate multiplex detection, it can be generally applied to single-cell expression analysis of other animal models and clinical specimens.

Automated Five-Color Multiplex Co-detection of MicroRNA and Protein Expression in Fixed Tissue Specimens.

It has been almost two decades since the first link between microRNAs and cancer was established. In the ensuing years, this abundant class of short noncoding regulatory RNAs has been studied in virtually all cancer types. This tremendously large body of research has generated innovative technological advances for detection of microRNAs in tissue and bodily fluids, identified the diagnostic, prognostic, and/or predictive value of individual microRNAs or microRNA signatures as potential biomarkers for patient management, shed light on regulatory mechanisms of RNA-RNA interactions that modulate gene expression, uncovered cell-autonomous and cell-to-cell communication roles of specific microRNAs, and developed a battery of viral and nonviral delivery approaches for therapeutic intervention. Despite these intense and prolific research efforts in preclinical and clinical settings, there are a limited number of microRNA-based applications that have been incorporated into clinical practice. We review recent literature and ongoing clinical trials that highlight most promising approaches and standing challenges to translate these findings into viable microRNA-based clinical tools for cancer medicine. This article is categorized under: RNA in Disease and Development > RNA in Disease.

microRNA-based diagnostic and therapeutic applications in cancer medicine.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with an overall 5-year survival rate of less than 10%. The 1-year survival rate of patients with locally advanced or metastatic disease is abysmal. The aggressive nature of cancer cells, hypovascularization, extensive desmoplastic stroma, and immunosuppressive tumor microenvironment (TME) endows PDAC tumors with multiple mechanisms of drug resistance. With no obvious genetic mutation(s) driving tumor progression or metastatic transition, the challenges for understanding the biological mechanism(s) of these processes are paramount. A better understanding of the molecular and cellular mechanisms of these processes could lead to new diagnostic tools for patient management and new targets for therapeutic intervention. microRNAs (miRNAs) are an evolutionarily conserved gene class of short non-coding regulatory RNAs. miRNAs are an extensive regulatory layer that controls gene expression at the posttranscriptional level. This review focuses on preclinical models that functionally dissect miRNA activity in tumor progression or metastatic processes in PDAC. Collectively, these studies suggest an influence of miRNAs and RNA-RNA networks in the processes of epithelial to mesenchymal cell transition and cancer cell stemness. At a cell-type level, some miRNAs mainly influence cancer cell-intrinsic processes and pathways, whereas other miRNAs predominantly act in distinct cellular compartments of the TME to regulate fibroblast and immune cell functions and/or influence other cell types' function via cell-to-cell communications by transfer of extracellular vesicles. At a molecular level, the influence of miRNA-mediated regulation often converges in core signaling pathways, including TGF-β, JAK/STAT, PI3K/AKT, and NF-κB.

Role of non-coding RNAs in tumor progression and metastasis in pancreatic cancer.

Acinar Cell-Enriched-MicroRNA-802 Connects the Dots Between Kras Signaling, Acinar Ductal Metaplasia, and Pancreatic Cancer.

Traditional targeted therapeutic agents have relied on small synthetic molecules or large proteins, such as monoclonal antibodies. These agents leave a lot of therapeutic targets undruggable because of the lack or inaccessibility of active sites and/or pockets in their three-dimensional structure that can be chemically engaged. RNA presents an attractive, transformative opportunity to reach any genetic target with therapeutic intent. RNA therapeutic design is amenable to modularity and tunability and is based on a computational blueprint presented by the genetic code. Here, we will focus on short non-coding RNAs (sncRNAs) as a promising therapeutic modality because of their potency and versatility. We review recent progress towards clinical application of small interfering RNAs (siRNAs) for single-target therapy and microRNA (miRNA) activity modulators for multi-target therapy. siRNAs derive their potency from the fact that the underlying RNA interference (RNAi) mechanism is catalytic and reliant on post-transcriptional mRNA degradation. Therapeutic siRNAs can be designed against virtually any mRNA sequence in the transcriptome and specifically target a disease-causing mRNA variant. Two main classes of microRNA activity modulators exist to increase (miRNA mimics) or decrease (anti-miRNA inhibitors) the function of a specific microRNA. Since a single microRNA regulates the expression of multiple target genes, a miRNA activity modulator can have a more profound effect on global gene expression and protein output than siRNAs do. Both types of sncRNA-based drugs have been investigated in clinical trials and some siRNAs have already been granted FDA approval for the treatment of genetic, cardiometabolic, and infectious diseases. Here, we detail clinical results using siRNA and miRNA therapeutics and present an outlook for the potential of these sncRNAs in medicine.

Article Total : 2	Year
Publication title	2022
Publication title	2022

Article	Year
Celebrating 25 Years of MicroRNA Research: From Discovery to Clinical Application. International journal of molecular sciences\| PubMed ID: 31018550	2019
MicroRNA-155 Expression Is Enhanced by T-cell Receptor Stimulation Strength and Correlates with Improved Tumor Control in Melanoma. Cancer immunology research\| PubMed ID: 31043416	2019
Ductal tree ablation by local delivery of ethanol prevents tumor formation in an aggressive mouse model of breast cancer. Breast cancer research : BCR\| PubMed ID: 31779648	2019
Tantalum oxide nanoparticles as versatile contrast agents for X-ray computed tomography. Nanoscale\| PubMed ID: 32211669	2020
Loss of microRNA-21 leads to profound stromal remodeling and short survival in K-Ras-driven mouse models of pancreatic cancer. International journal of cancer\| PubMed ID: 32388866	2020
Automated Five-Color Multiplex Co-detection of MicroRNA and Protein Expression in Fixed Tissue Specimens. Methods in molecular biology (Clifton, N.J.)\| PubMed ID: 32394388	2020
microRNA-based diagnostic and therapeutic applications in cancer medicine. Wiley interdisciplinary reviews. RNA\| PubMed ID: 33998154	2021
Role of non-coding RNAs in tumor progression and metastasis in pancreatic cancer. Cancer metastasis reviews\| PubMed ID: 34591242	2021
Acinar Cell-Enriched-MicroRNA-802 Connects the Dots Between Kras Signaling, Acinar Ductal Metaplasia, and Pancreatic Cancer. Gastroenterology\| PubMed ID: 34662582	2022
Clinical Applications of Short Non-Coding RNA-Based Therapies in the Era of Precision Medicine. Cancers\| PubMed ID: 35326738	2022

Lorenzo F. Sempere

Biography

JoVE Journal Publications

Other Publications