Cancer-Associated Fibroblasts in Intrahepatic Cholangiocarcinoma: Insights into Origins, Heterogeneity, Lymphangiogenesis, and Peritoneal Metastasis.

Intrahepatic cholangiocarcinoma (iCCA) denotes a rare, highly malignant, and heterogeneous class of primary liver adenocarcinomas exhibiting phenotypic characteristics of cholangiocyte differentiation. Among the distinctive pathological features of iCCA, one that differentiates the most common macroscopic subtype (eg, mass-forming type) of this hepatic tumor from conventional hepatocellular carcinoma, is a prominent desmoplastic reaction manifested as a dense fibro-collagenous-enriched tumor stroma. Cancer-associated fibroblasts (CAFs) represent the most abundant mesenchymal cell type in the desmoplastic reaction.

A microfluidic co-culture model for investigating colonocytes-microbiota interactions in colorectal cancer.

Changes in the abundance of certain bacterial species within the colorectal microbiota correlate with colorectal cancer (CRC) development. While carcinogenic mechanisms of single pathogenic bacteria have been characterized , limited tools are available to investigate interactions between pathogenic bacteria and both commensal microbiota and colonocytes in a physiologically relevant tumor microenvironment. To address this, we developed a microfluidic device that can be used to co-culture colonocyte spheroids and colorectal microbiota.

Single-Cell RNA Sequencing Identifies Response of Renal Lymphatic Endothelial Cells to Acute Kidney Injury.

Significance Statement: The renal lymphatic vasculature and the lymphatic endothelial cells that make up this network play important immunomodulatory roles during inflammation. How lymphatics respond to AKI may affect AKI outcomes. The authors used single-cell RNA sequencing to characterize mouse renal lymphatic endothelial cells in quiescent and cisplatin-injured kidneys.

Identification of New Markers of Angiogenic Sprouting Using Transcriptomics: New Role for RND3.

Background: New blood vessel formation requires endothelial cells to transition from a quiescent to an invasive phenotype. Transcriptional changes are vital for this switch, but a comprehensive genome-wide approach focused exclusively on endothelial cell sprout initiation has not been reported.

Methods: Using a model of human endothelial cell sprout initiation, we developed a protocol to physically separate cells that initiate the process of new blood vessel formation (invading cells) from noninvading cells.

Emerging Therapeutic Strategies in The Fight Against Primary Biliary Cholangitis.

The liver has a vital role in many metabolic and regulatory processes in the body. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a chronic cholestatic autoimmune disease of the intrahepatic bile ducts associated with loss of tolerance to mitochondrial antigens. At this time there is no definitive cure for PBC; however, ursodeoxycholic acid (UDCA) has been shown to reduce injury when administered as the first line of treatment.

Oxidative Stress-Induced Liver Damage and Remodeling of the Liver Vasculature.

As an organ critically important for targeting and clearing viruses, bacteria, and other foreign material, the liver operates via immune-tolerant, anti-inflammatory mechanisms indispensable to the immune response. Stress and stress-induced factors disrupt the homeostatic balance in the liver, inflicting tissue damage, injury, and remodeling. These factors include oxidative stress (OS) induced by viral infections, environmental toxins, drugs, alcohol, and diet.

Single-cell RNA sequencing identifies response of renal lymphatic endothelial cells to acute kidney injury.

The inflammatory response to acute kidney injury (AKI) likely dictates future renal health. Lymphatic vessels are responsible for maintaining tissue homeostasis through transport and immunomodulatory roles. Due to the relative sparsity of lymphatic endothelial cells (LECs) in the kidney, past sequencing efforts have not characterized these cells and their response to AKI.

Conjugated Bile Acids Promote Lymphangiogenesis by Modulation of the Reactive Oxygen Species-p90RSK-Vascular Endothelial Growth Factor Receptor 3 Pathway.

Conjugated bile acids (BA) are significantly elevated in several liver pathologies and in the metastatic lymph node (LN). However, the effects of BAs on pathological lymphangiogenesis remains unknown. The current study explores the effects of BAs on lymphangiogenesis.

Cellular Senescence as a Brake or Accelerator for Oncogenic Transformation and Role in Lymphatic Metastasis.

Cellular senescence-the irreversible cell cycle arrest driven by a variety of mechanisms and, more specifically, the senescence-associated secretory phenotype (SASP)-is an important area of research in the context of different age-related diseases, such as cardiovascular disease and cancer. SASP factors play both beneficial and detrimental roles in age-related disease progression depending on the source of the SASPs, the target cells, and the microenvironment. The impact of senescence and the SASP on different cell types, the immune system, and the vascular system has been widely discussed.

Epigenetic-Metabolic Interplay in the DNA Damage Response and Therapeutic Resistance of Breast Cancer.

Therapy resistance is imposing a daunting challenge on effective clinical management of breast cancer. Although the development of resistance to drugs is multifaceted, reprogramming of energy metabolism pathways is emerging as a central but heterogenous regulator of this therapeutic challenge. Metabolic heterogeneity in cancer cells is intricately associated with alterations of different signaling networks and activation of DNA damage response pathways.

Knockout of secretin ameliorates biliary and liver phenotypes during alcohol-induced hepatotoxicity.

Background: Alcohol-related liver disease (ALD) is characterized by ductular reaction (DR), liver inflammation, steatosis, fibrosis, and cirrhosis. The secretin (Sct)/secretin receptor (SR) axis (expressed only by cholangiocytes) regulates liver phenotypes in cholestasis. We evaluated the role of Sct signaling on ALD phenotypes.

Recent Advances in Intrahepatic Biliary Epithelial Heterogeneity.

Biliary epithelium (i.e., cholangiocytes) is a heterogeneous population of epithelial cells in the liver, which line small and large bile ducts and have individual responses and functions dependent on size and location in the biliary tract.

Recent advancement of imaging strategies of the lymphatic system: Answer to the decades old questions.

The role of the lymphatic system in maintaining tissue homeostasis and a number of different pathophysiological conditions has been well established. The complex and delicate structure of the lymphatics along with the limitations of conventional imaging techniques make lymphatic imaging particularly difficult. Thus, in-depth high-resolution imaging of lymphatic system is key to understanding the progression of lymphatic diseases and cancer metastases and would greatly benefit clinical decisions.

Hypertensive Stimuli Indirectly Stimulate Lymphangiogenesis through Immune Cell Secreted Factors.

(1) Background: Renal immune cells and lymphatic vessel (LV) density have been reported previously to be increased in multiple mouse models of hypertension (HTN). However, whether interstitial levels of HTN stimuli such as angiotensin II, salt, or asymmetric dimethylarginine have a direct or indirect effect on lymphangiogenesis is unknown. We hypothesized that these 3 HTN stimuli directly increase lymphatic endothelial cell (LEC) proliferation, LEC 3-D matrix invasion and vessel formation, and sprouting of mouse mesometrial LVs.

Intracellular calcium dynamics of lymphatic endothelial and muscle cells co-cultured in a Lymphangion-Chip under pulsatile flow.

The lymphatic vascular function is regulated by pulsatile shear stresses through signaling mediated by intracellular calcium [Ca]. Further, the intracellular calcium dynamics mediates signaling between lymphatic endothelial cells (LECs) and muscle cells (LMCs), including the lymphatic tone and contractility. Although calcium signaling has been characterized on LEC monolayers under uniform or step changes in shear stress, these dynamics have not been revealed in LMCs under physiologically-relevant co-culture conditions with LECs or under pulsatile flow.

Development and Characterization of Human Primary Cholangiocarcinoma Cell Lines.

Cholangiocarcinoma (CCA) is the second most common primary liver tumor and is associated with late diagnosis, limited treatment options, and a 5-year survival rate of around 30%. CCA cell lines were first established in 1971, and since then, only 70 to 80 CCA cell lines have been established. These cell lines have been essential in basic and translational research to understand and identify novel mechanistic pathways, biomarkers, and disease-specific genes.

The Effects of Taurocholic Acid on Biliary Damage and Liver Fibrosis Are Mediated by Calcitonin-Gene-Related Peptide Signaling.

Background & Aims: Cholangiocytes are the target cells of liver diseases that are characterized by biliary senescence (evidenced by enhanced levels of senescence-associated secretory phenotype, SASP, e.g., TGF-β1), and liver inflammation and fibrosis accompanied by altered bile acid (BA) homeostasis.

The Functional Roles of Immune Cells in Primary Liver Cancer.

Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Incidence of liver cancer has been increasing in recent years, and the 5-year survival is <20%. HCC and CCA are often accompanied with a dense stroma coupled with infiltrated immune cells, which is referred to as the tumor microenvironment.

Molecular Mechanisms Linking Risk Factors to Cholangiocarcinoma Development.

The poor prognosis of cholangiocarcinoma in humans is related to several factors, such as (i) the heterogeneity of the disease, (ii) the late onset of symptoms and (iii) the limited comprehension of the carcinogenic pathways determining neoplastic changes, which all limit the pursuit of appropriate treatment. Several risk factors have been recognized, including different infective, immune-mediated, and dysmorphogenic disorders of the biliary tree. In this review, we report the details of possible mechanisms that lead a specific premalignant pathological condition to become cholangiocarcinoma.

FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2 Mouse Model of Primary Sclerosing Cholangitis.

Fibroblast growth factor 1 (FGF1) belongs to a family of growth factors involved in cellular growth and division. MicroRNA 16 (miR-16) is a regulator of gene expression, which is dysregulated during liver injury and insult. However, the role of FGF1 in the progression of biliary proliferation, senescence, fibrosis, inflammation, angiogenesis, and its potential interaction with miR-16, are unknown.

Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies.

B-cell non-Hodgkin lymphomas (B-NHLs) are highly heterogenous by genetic, phenotypic, and clinical appearance. Next-generation sequencing technologies and multi-dimensional data analyses have further refined the way these diseases can be more precisely classified by specific genomic, epigenomic, and transcriptomic characteristics. The molecular and genetic heterogeneity of B-NHLs may contribute to the poor outcome of some of these diseases, suggesting that more personalized precision-medicine approaches are needed for improved therapeutic efficacy.

Biliary Epithelial Senescence in Liver Disease: There Will Be SASP.

Cellular senescence is a pathophysiological phenomenon in which proliferative cells enter cell cycle arrest following DNA damage and other stress signals. Natural, permanent DNA damage can occur after repetitive cell division; however, acute stress or other injuries can push cells into premature senescence and eventually a senescence-associated secretory phenotype (SASP). In recent years, there has been increased evidence for the role of premature senescence in disease progression including diabetes, cardiac diseases, and end-stage liver diseases including cholestasis.

Disruption of Cell-Cell Communication in Anaplastic Thyroid Cancer as an Immunotherapeutic Opportunity.

Thyroid cancer incidence is increasing at an alarming rate, almost tripling every decade. About 44,280 new cases of thyroid cancer (12,150 in men and 32,130 in women) are estimated to be diagnosed in 2021, with an estimated death toll of around 2200. Although most thyroid tumors are treatable and associated with a favorable outcome, anaplastic thyroid cancer (ATC) is extremely aggressive with a grim prognosis of 6-9 months post-diagnosis.