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The Journal of Clinical Investigation Oct 2023Lung cancer progression relies on angiogenesis, which is a response to hypoxia typically coordinated by hypoxia-inducible transcription factors (HIFs), but growing...
Lung cancer progression relies on angiogenesis, which is a response to hypoxia typically coordinated by hypoxia-inducible transcription factors (HIFs), but growing evidence indicates that transcriptional programs beyond HIFs control tumor angiogenesis. Here, we show that the redox-sensitive transcription factor BTB and CNC homology 1 (BACH1) controls the transcription of a broad range of angiogenesis genes. BACH1 is stabilized by lowering ROS levels; consequently, angiogenesis gene expression in lung cancer cells, tumor organoids, and xenograft tumors increased substantially following administration of vitamins C and E and N-acetylcysteine in a BACH1-dependent fashion under normoxia. Moreover, angiogenesis gene expression increased in endogenous BACH1-overexpressing cells and decreased in BACH1-knockout cells in the absence of antioxidants. BACH1 levels also increased upon hypoxia and following administration of prolyl hydroxylase inhibitors in both HIF1A-knockout and WT cells. BACH1 was found to be a transcriptional target of HIF1α, but BACH1's ability to stimulate angiogenesis gene expression was HIF1α independent. Antioxidants increased tumor vascularity in vivo in a BACH1-dependent fashion, and overexpressing BACH1 rendered tumors sensitive to antiangiogenesis therapy. BACH1 expression in tumor sections from patients with lung cancer correlated with angiogenesis gene and protein expression. We conclude that BACH1 is an oxygen- and redox-sensitive angiogenesis transcription factor.
Topics: Humans; Antioxidants; Basic-Leucine Zipper Transcription Factors; Hypoxia; Lung Neoplasms; Neovascularization, Pathologic; Animals; Mice
PubMed: 37651203
DOI: 10.1172/JCI169671 -
Molecular Cancer Oct 2023Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population that plays a crucial role in remodeling the tumor microenvironment (TME). Here, through the...
Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population that plays a crucial role in remodeling the tumor microenvironment (TME). Here, through the integrated analysis of spatial and single-cell transcriptomics data across six common cancer types, we identified four distinct functional subgroups of CAFs and described their spatial distribution characteristics. Additionally, the analysis of single-cell RNA sequencing (scRNA-seq) data from three additional common cancer types and two newly generated scRNA-seq datasets of rare cancer types, namely epithelial-myoepithelial carcinoma (EMC) and mucoepidermoid carcinoma (MEC), expanded our understanding of CAF heterogeneity. Cell-cell interaction analysis conducted within the spatial context highlighted the pivotal roles of matrix CAFs (mCAFs) in tumor angiogenesis and inflammatory CAFs (iCAFs) in shaping the immunosuppressive microenvironment. In patients with breast cancer (BRCA) undergoing anti-PD-1 immunotherapy, iCAFs demonstrated heightened capacity in facilitating cancer cell proliferation, promoting epithelial-mesenchymal transition (EMT), and contributing to the establishment of an immunosuppressive microenvironment. Furthermore, a scoring system based on iCAFs showed a significant correlation with immune therapy response in melanoma patients. Lastly, we provided a web interface ( https://chenxisd.shinyapps.io/pancaf/ ) for the research community to investigate CAFs in the context of pan-cancer.
Topics: Humans; Cancer-Associated Fibroblasts; Tumor Microenvironment; Carcinoma; Epithelial-Mesenchymal Transition; Single-Cell Analysis; Fibroblasts
PubMed: 37833788
DOI: 10.1186/s12943-023-01876-x -
Journal of Hematology & Oncology Jun 2023Exosomal circRNA serves a novel genetic information molecule, facilitating communication between tumor cells and microenvironmental cells, such as immune cells,... (Review)
Review
Exosomal circRNA serves a novel genetic information molecule, facilitating communication between tumor cells and microenvironmental cells, such as immune cells, fibroblasts, and other components, thereby regulating critical aspects of cancer progression including immune escape, tumor angiogenesis, metabolism, drug resistance, proliferation and metastasis. Interestingly, microenvironment cells have new findings in influencing tumor progression and immune escape mediated by the release of exosomal circRNA. Given the intrinsic stability, abundance, and broad distribution of exosomal circRNAs, they represent excellent diagnostic and prognostic biomarkers for liquid biopsy. Moreover, artificially synthesized circRNAs may open up new possibilities for cancer therapy, potentially bolstered by nanoparticles or plant exosome delivery strategies. In this review, we summarize the functions and underlying mechanisms of tumor cell and non-tumor cell-derived exosomal circRNAs in cancer progression, with a special focus on their roles in tumor immunity and metabolism. Finally, we examine the potential application of exosomal circRNAs as diagnostic biomarkers and therapeutic targets, highlighting their promise for clinical use.
Topics: Humans; RNA, Circular; Exosomes; Fibroblasts; Neoplasms; Biomarkers; Tumor Microenvironment
PubMed: 37365670
DOI: 10.1186/s13045-023-01452-2 -
Signal Transduction and Targeted Therapy Jul 2023VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can...
VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner. Mechanistically, as an RNA binding protein, BICC1 bounds to the 3'UTR of Lipocalin-2 (LCN2) mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells. When its level is elevated, LCN2 binds to its receptor 24p3R, which directly phosphorylates JAK2 and activates JAK2/STAT3 signal, leading to increased production of an angiogenic factor CXCL1. Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice, and increased the tumor suppressive effect of gemcitabine. In conclusion, BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer, leading to resistance to VEGF inhibitors. BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.
Topics: Humans; Animals; Mice; Pancreatic Neoplasms; Vascular Endothelial Growth Factor A; Adenocarcinoma; RNA-Binding Proteins
PubMed: 37443111
DOI: 10.1038/s41392-023-01478-5 -
European Journal of Pharmacology Jun 2023Angiogenesis is a double-edged sword; it is a mechanism that defines the boundary between health and disease. In spite of its central role in physiological homeostasis,... (Review)
Review
Angiogenesis is a double-edged sword; it is a mechanism that defines the boundary between health and disease. In spite of its central role in physiological homeostasis, it provides the oxygen and nutrition needed by tumor cells to proceed from dormancy if pro-angiogenic factors tip the balance in favor of tumor angiogenesis. Among pro-angiogenic factors, vascular endothelial growth factor (VEGF) is a prominent target in therapeutic methods due to its strategic involvement in the formation of anomalous tumor vasculature. In addition, VEGF exhibits immune-regulatory properties which suppress immune cell antitumor activity. VEGF signaling through its receptors is an integral part of tumoral angiogenic approaches. A wide variety of medicines have been designed to target the ligands and receptors of this pro-angiogenic superfamily. Herein, we summarize the direct and indirect molecular mechanisms of VEGF to demonstrate its versatile role in the context of cancer angiogenesis and current transformative VEGF-targeted strategies interfering with tumor growth.
Topics: Humans; Angiogenesis Inhibitors; Neoplasms; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 36906141
DOI: 10.1016/j.ejphar.2023.175586 -
Cell Reports Dec 2023CD276/B7-H3 represents a promising target for cancer therapy based on widespread overexpression in both cancer cells and tumor-associated stroma. In previous preclinical...
CD276/B7-H3 represents a promising target for cancer therapy based on widespread overexpression in both cancer cells and tumor-associated stroma. In previous preclinical studies, CD276 antibody-drug conjugates (ADCs) exploiting a talirine-type pyrrolobenzodiazepine (PBD) payload showed potent activity against various solid tumors but with a narrow therapeutic index and dosing regimen higher than that tolerated in clinical trials using other antibody-talirine conjugates. Here, we describe the development of a modified talirine PBD-based fully human CD276 ADC, called m276-SL-PBD, that is cross-species (human/mouse) reactive and can eradicate large 500-1,000-mm triple-negative breast cancer xenografts at doses 10- to 40-fold lower than the maximum tolerated dose. By combining CD276 targeting with judicious genetic and chemical ADC engineering, improved ADC purification, and payload sensitivity screening, these studies demonstrate that the therapeutic index of ADCs can be substantially increased, providing an advanced ADC development platform for potent and selective targeting of multiple solid tumor types.
Topics: Humans; Mice; Animals; Immunoconjugates; Cell Line, Tumor; Xenograft Model Antitumor Assays; Antibodies, Monoclonal, Humanized; Transcription Factors; Neoplasms; B7 Antigens
PubMed: 38019654
DOI: 10.1016/j.celrep.2023.113503 -
Frontiers in Oncology 2023The onset, development, diagnosis, and treatment of cancer involve intricate interactions among various factors, spanning the realms of mechanics, physics, chemistry,... (Review)
Review
The onset, development, diagnosis, and treatment of cancer involve intricate interactions among various factors, spanning the realms of mechanics, physics, chemistry, and biology. Within our bodies, cells are subject to a variety of forces such as gravity, magnetism, tension, compression, shear stress, and biological static force/hydrostatic pressure. These forces are perceived by mechanoreceptors as mechanical signals, which are then transmitted to cells through a process known as mechanical transduction. During tumor development, invasion and metastasis, there are significant biomechanical influences on various aspects such as tumor angiogenesis, interactions between tumor cells and the extracellular matrix (ECM), interactions between tumor cells and other cells, and interactions between tumor cells and the circulatory system and vasculature. The tumor microenvironment comprises a complex interplay of cells, ECM and vasculature, with the ECM, comprising collagen, fibronectins, integrins, laminins and matrix metalloproteinases, acting as a critical mediator of mechanical properties and a key component within the mechanical signaling pathway. The vasculature exerts appropriate shear forces on tumor cells, enabling their escape from immune surveillance, facilitating their dissemination in the bloodstream, dictating the trajectory of circulating tumor cells (CTCs) and playing a pivotal role in regulating adhesion to the vessel wall. Tumor biomechanics plays a critical role in tumor progression and metastasis, as alterations in biomechanical properties throughout the malignant transformation process trigger a cascade of changes in cellular behavior and the tumor microenvironment, ultimately culminating in the malignant biological behavior of the tumor.
PubMed: 37901315
DOI: 10.3389/fonc.2023.1273154 -
Biochimica Et Biophysica Acta.... Feb 2024Water is essential for all life because it is required for the proper functioning of the cells and tissues of all organisms. It crosses biological membranes down osmotic...
Water is essential for all life because it is required for the proper functioning of the cells and tissues of all organisms. It crosses biological membranes down osmotic gradients through the pores of aquaporin membrane channels at rates of up to 3 billion molecules per second. In the twenty years since Peter Agre was awarded the 2003 Nobel Prize in Chemistry for the discovery of the aquaporin family, aquaporin structure and function have become established in the literature. As a consequence, we understand in fine detail the mechanism by which aquaporins facilitate membrane water flow while excluding protons. We also know that some aquaporins facilitate the permeation of other small neutral solutes, ions or even unexpected substrates across biological membranes. The thirteen aquaporins in the human body have been implicated in pathologies including oedema, epilepsy, cancer cell migration, tumour angiogenesis, metabolic disorders and inflammation. Surprisingly, however, there is no aquaporin-targeted drug in the clinic. Some scientists have therefore concluded that aquaporins are intrinsically non-druggable targets. Discovering medicines to treat disorders of water homeostasis is thus an enduring challenge for the aquaporin field. Success in this endeavour will meet the urgent clinical need of millions of patients suffering from a range of life-threatening conditions and for whom no pharmacological interventions are currently available.
Topics: Humans; Aquaporins; Cell Membrane; Homeostasis; Water
PubMed: 37146744
DOI: 10.1016/j.bbamem.2023.184164 -
Human Vaccines & Immunotherapeutics Dec 2023For decades, immunotherapies have offered hope for patients with advanced cancer. However, they show distinct benefits and limited clinical effects. Tumor vaccines have... (Review)
Review
For decades, immunotherapies have offered hope for patients with advanced cancer. However, they show distinct benefits and limited clinical effects. Tumor vaccines have the potential to prime tumor-antigen-specific T cells and induce broad subsets of immune responses, ultimately eradicating tumor cells. Here, we classify tumor vaccines by their anti-tumor mechanisms, which include boosting the immune system, overcoming tumor immunosuppression, and modulating tumor angiogenesis. We focus on multidimensional tumor vaccine strategies using combinations of two or three of the above mechanisms, as these are superior to single-dimensional treatments. This review offers a perspective on tumor vaccine strategies and the future role of vaccine therapies in cancer treatment.
Topics: Humans; Cancer Vaccines; Neoplasms; Immunotherapy; Antigens, Neoplasm; T-Lymphocytes
PubMed: 37905395
DOI: 10.1080/21645515.2023.2271334