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Circulation Research Jan 2023Giant cell arteritis is an autoimmune disease of medium and large arteries, characterized by granulomatous inflammation of the three-layered vessel wall that results in... (Review)
Review
Giant cell arteritis is an autoimmune disease of medium and large arteries, characterized by granulomatous inflammation of the three-layered vessel wall that results in vaso-occlusion, wall dissection, and aneurysm formation. The immunopathogenesis of giant cell arteritis is an accumulative process in which a prolonged asymptomatic period is followed by uncontrolled innate immunity, a breakdown in self-tolerance, the transition of autoimmunity from the periphery into the vessel wall and, eventually, the progressive evolution of vessel wall inflammation. Each of the steps in pathogenesis corresponds to specific immuno-phenotypes that provide mechanistic insights into how the immune system attacks and damages blood vessels. Clinically evident disease begins with inappropriate activation of myeloid cells triggering the release of hepatic acute phase proteins and inducing extravascular manifestations, such as muscle pains and stiffness diagnosed as polymyalgia rheumatica. Loss of self-tolerance in the adaptive immune system is linked to aberrant signaling in the NOTCH pathway, leading to expansion of NOTCH1CD4 T cells and the functional decline of NOTCH4 T regulatory cells (Checkpoint 1). A defect in the endothelial cell barrier of adventitial vasa vasorum networks marks Checkpoint 2; the invasion of monocytes, macrophages and T cells into the arterial wall. Due to the failure of the immuno-inhibitory PD-1 (programmed cell death protein 1)/PD-L1 (programmed cell death ligand 1) pathway, wall-infiltrating immune cells arrive in a permissive tissues microenvironment, where multiple T cell effector lineages thrive, shift toward high glycolytic activity, and support the development of tissue-damaging macrophages, including multinucleated giant cells (Checkpoint 3). Eventually, the vascular lesions are occupied by self-renewing T cells that provide autonomy to the disease process and limit the therapeutic effectiveness of currently used immunosuppressants. The multi-step process deviating protective to pathogenic immunity offers an array of interception points that provide opportunities for the prevention and therapeutic management of this devastating autoimmune disease.
Topics: Humans; Giant Cell Arteritis; Inflammation; Arteries; Immunity, Innate; Giant Cells
PubMed: 36656970
DOI: 10.1161/CIRCRESAHA.122.322128 -
Molecular Cancer Jun 2022Undifferentiated carcinoma with osteoclast-like giant cells (OGCs) of pancreas (UCOGCP) is a rare subtype of pancreatic ductal adenocarcinoma (PDAC), which had poorly...
BACKGROUND
Undifferentiated carcinoma with osteoclast-like giant cells (OGCs) of pancreas (UCOGCP) is a rare subtype of pancreatic ductal adenocarcinoma (PDAC), which had poorly described histopathological and clinical features.
METHODS
In this study, single-cell RNA sequencing (scRNA-seq) was used to profile the distinct tumor microenvironment of UCOGCP using samples obtained from one UCOGCP patient and three PDAC patients. Bioinformatic analysis was carried out and immunohistochemical (IHC) staining was used to support the findings of bioinformatic analysis. After quality control of the raw data, a total of 18,376 cells were obtained from these four samples for subsequent analysis. These cells were divided into ten main cell types following the Seurat analysis pipeline. Among them, the UCOGCP sample displayed distinct distribution patterns from the rest samples in the epithelial cell, myeloid cell, fibroblast, and endothelial cell clusters. Further analysis supported that the OGCs were generated from stem-cell-like mesenchymal epithelial cells (SMECs).
RESULTS
Functional analysis showed that the OGCs cluster was enriched in antigen presentation, immune response, and stem cell differentiation. Gene markers such as LOX, SPERINE1, CD44, and TGFBI were highly expressed in this SMECs cluster which signified poor prognosis. Interestingly, in myeloid cell, fibroblasts, and endothelial cell clusters, UCOGCP contained higher percentage of these cells and unique subclusters, compared with the rest of PDAC samples.
CONCLUSIONS
Analysis of cell communication depicted that CD74 plays important roles in the formation of the microenvironment of UCOGCP. Our findings illustrated the genesis and function of OGCs, and the tumor microenvironment (TME) of UCOGCP, providing insights for prognosis and treatment strategy for this rare type of pancreatic cancer.
Topics: Adenocarcinoma; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Giant Cells; Humans; Osteoclasts; Pancreatic Neoplasms; RNA-Seq; Tumor Microenvironment
PubMed: 35733218
DOI: 10.1186/s12943-022-01596-8 -
International Journal of Molecular... Jun 2022Cell fusion (fusogenesis) occurs in natural and pathological conditions in prokaryotes and eukaryotes. Cells of monocyte-macrophage lineage are highly fusogenic. They... (Review)
Review
Cell fusion (fusogenesis) occurs in natural and pathological conditions in prokaryotes and eukaryotes. Cells of monocyte-macrophage lineage are highly fusogenic. They create syncytial multinucleated giant cells (MGCs) such as osteoclasts (OCs), MGCs associated with the areas of infection/inflammation, and foreign body-induced giant cells (FBGCs). The fusion of monocytes/macrophages with tumor cells may promote cancer metastasis. We describe types and examples of monocyte-macrophage lineage cell fusion and the role of actin-based structures in cell fusion.
Topics: Cell Differentiation; Cell Fusion; Giant Cells; Giant Cells, Foreign-Body; Monocytes; Osteoclasts
PubMed: 35742997
DOI: 10.3390/ijms23126553 -
Cells Oct 2020Filamentous fungi typically grow as interconnected multinucleate syncytia that can be microscopic to many hectares in size. Mechanistic details and rules that govern the... (Review)
Review
Filamentous fungi typically grow as interconnected multinucleate syncytia that can be microscopic to many hectares in size. Mechanistic details and rules that govern the formation and function of these multinucleate syncytia are largely unexplored, including details on syncytial morphology and the regulatory controls of cellular and molecular processes. Recent discoveries have revealed various adaptations that enable fungal syncytia to accomplish coordinated behaviors, including cell growth, nuclear division, secretion, communication, and adaptation of the hyphal network for mixing nuclear and cytoplasmic organelles. In this review, we highlight recent studies using advanced technologies to define rules that govern organizing principles of hyphal and colony differentiation, including various aspects of nuclear and mitochondrial cooperation versus competition. We place these findings into context with previous foundational literature and present still unanswered questions on mechanistic aspects, function, and morphological diversity of fungal syncytia across the fungal kingdom.
Topics: Cell Nucleus; Cytoplasm; Fungi; Giant Cells; Mitochondria
PubMed: 33050028
DOI: 10.3390/cells9102255 -
Biology of Reproduction Aug 2021Current first-line treatment of patients with high-grade serous ovarian cancer (HGSOC) involves the use of cytotoxic drugs that frequently lead to recurrent tumors... (Review)
Review
Current first-line treatment of patients with high-grade serous ovarian cancer (HGSOC) involves the use of cytotoxic drugs that frequently lead to recurrent tumors exhibiting increased resistance to the drugs and poor patient survival. Strong evidence is accumulating to show that HGSOC tumors and cell lines contain a subset of cells called polyploidy giant cancer cells (PGCCs) that act as stem-like, self-renewing cells. These PGCCs appear to play a key role in tumor progression by generating drug-resistant progeny produced, in part, as a consequence of utilizing a modified form of mitosis known as endoreplication. Thus, developing drugs to target PGCCs and endoreplication may be an important approach for reducing the appearance of drug-resistant progeny. In the review, we discuss newly identified regulatory factors that impact mitosis and which may be altered or repurposed during endoreplication in PGCCs. We also review recent papers showing that a single PGCC can give rise to tumors in vivo and spheroids in culture. To illustrate some of the specific features of PGCCs and factors that may impact their function and endoreplication compared to mitosis, we have included immunofluorescent images co-localizing p53 and specific mitotic regulatory, phosphoproteins in xenografts derived from commonly used HGSOC cell lines.
Topics: Animals; Female; Giant Cells; Humans; Mice; Mitosis; Ovarian Neoplasms; Polyploidy
PubMed: 34037700
DOI: 10.1093/biolre/ioab102 -
Seminars in Cancer Biology Jun 2022Therapeutic resistance represents a major cause of death for most lethal cancers. However, the underlying mechanisms of such resistance have remained unclear. The... (Review)
Review
Therapeutic resistance represents a major cause of death for most lethal cancers. However, the underlying mechanisms of such resistance have remained unclear. The polyploid cells are due to an increase in DNA content, commonly associated with cell enlargement. In human, they play a variety of roles in physiology and pathologic conditions and perform the specialized functions during development, inflammation, and cancer. Recent work shows that cancer cells can be induced into polyploid giant cancer cells (PGCCs) that leads to reprogramming of surviving cancer cells to acquire resistance. In this article, we will review the polyploidy involved in development and inflammation, and the process of PGCCs formation and propagation that benefits to cell survival. We will discuss the potential opportunities in fighting resistant cancers. The increased knowledge of PGCCs will offer a completely new paradigm to explore the therapeutic intervention for lethal cancers.
Topics: Giant Cells; Humans; Inflammation; Neoplasms; Polyploidy
PubMed: 33839294
DOI: 10.1016/j.semcancer.2021.04.005 -
Clinical and Translational Medicine Feb 2024Tumour cell dormancy is critical for metastasis and resistance to chemoradiotherapy. Polyploid giant cancer cells (PGCCs) with giant or multiple nuclei and high DNA... (Review)
Review
Tumour cell dormancy is critical for metastasis and resistance to chemoradiotherapy. Polyploid giant cancer cells (PGCCs) with giant or multiple nuclei and high DNA content have the properties of cancer stem cell and single PGCCs can individually generate tumours in immunodeficient mice. PGCCs represent a dormant form of cancer cells that survive harsh tumour conditions and contribute to tumour recurrence. Hypoxic mimics, chemotherapeutics, radiation and cytotoxic traditional Chinese medicines can induce PGCCs formation through endoreduplication and/or cell fusion. After incubation, dormant PGCCs can recover from the treatment and produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric cell division. Additionally, PGCCs can resist hypoxia or chemical stress and have a distinct protein signature that involves chromatin remodelling and cell cycle regulation. Dormant PGCCs form the cellular basis for therapeutic resistance, metastatic cascade and disease recurrence. This review summarises regulatory mechanisms governing dormant cancer cells entry and exit of dormancy, which may be used by PGCCs, and potential therapeutic strategies for targeting PGCCs.
Topics: Animals; Mice; Cell Line, Tumor; Giant Cells; Antineoplastic Agents; Polyploidy; Neoplasms
PubMed: 38362620
DOI: 10.1002/ctm2.1567 -
Seminars in Cancer Biology Jun 2022Recent data suggest that most genotoxic agents in cancer therapy can lead to shock of genome and increase in cell size, which leads whole genome duplication or... (Review)
Review
Recent data suggest that most genotoxic agents in cancer therapy can lead to shock of genome and increase in cell size, which leads whole genome duplication or multiplication, formation of polyploid giant cancer cells, activation of an early embryonic program, and dedifferentiation of somatic cells. This process is achieved via the giant cell life cycle, a recently proposed mechanism for malignant transformation of somatic cells. Increase in both cell size and ploidy allows cells to completely or partially restructures the genome and develop into a blastocyst-like structure, similar to that observed in blastomere-stage embryogenesis. Although blastocyst-like structures with reprogrammed genome can generate resistant or metastatic daughter cells or benign cells of different lineages, they also acquired ability to undergo embryonic diapause, a reversible state of suspended embryonic development in which cells enter dormancy for survival in response to environmental stress. Therapeutic agents can activate this evolutionarily conserved developmental program, and when cells awaken from embryonic diapause, this leads to recurrence or metastasis. Understanding of the key mechanisms that regulate the different stages of the giant cell life cycle offers new opportunities for therapeutic intervention.
Topics: Animals; Blastomeres; Female; Giant Cells; Humans; Life Cycle Stages; Neoplasms; Polyploidy; Pregnancy
PubMed: 34670140
DOI: 10.1016/j.semcancer.2021.10.005 -
Romanian Journal of Morphology and... 2011Sarcoidosis is an inflammatory granulomatous disease affecting multiple organ systems. Neurosarcoidosis (central nervous system involvement) is seen in approximately 25%...
Sarcoidosis is an inflammatory granulomatous disease affecting multiple organ systems. Neurosarcoidosis (central nervous system involvement) is seen in approximately 25% of patients with systemic sarcoidosis, although it is subclinical in most of these cases. Clinical presentations and imaging findings in nervous system were varied. Cranial nerve abnormalities were the most common clinical presentation and involvement of the optic nerve in particular was associated with a poor prognosis for visual recovery. A patient is described who presented with decreased visual acuity, hypoesthesia of the face and multiple tumors of the eyelids on both eyes. Initial biopsy of one of the tumor of the eyelids revealed a non-caseating granulomatous inflammatory process with nodular infiltrates made up of epithelioid cells, Langhans-type giant multinucleated cells and mononuclear cells; the diagnosis of sarcoidosis was suspected. After two years of clinical and MRI (Magnetic Resonance Imaging) follow up, the diagnosis of isolated neurosarcoidosis was confirmed by histology. In this study, we analyzed clinical and radiologic records of this patient with biopsy proven and clinically diagnosed neurosarcoidosis for the following reasons: (1) to assess the concordance between abnormalities noted on MRI with neurologic symptoms at presentation; (2) to correlate changes in imaging findings during follow-up with clinical worsening; and (3) to show up the characteristic feature of this case with no general sign/symptoms of sarcoidosis.
Topics: Aged; Central Nervous System Diseases; Contrast Media; Female; Giant Cells; Granuloma; Humans; Magnetic Resonance Imaging; Ophthalmoscopy; Sarcoidosis
PubMed: 22119838
DOI: No ID Found -
The Prostate Sep 2019Cancer led to the deaths of more than 9 million people worldwide in 2018, and most of these deaths were due to metastatic tumor burden. While in most cases, we still do... (Review)
Review
Cancer led to the deaths of more than 9 million people worldwide in 2018, and most of these deaths were due to metastatic tumor burden. While in most cases, we still do not know why cancer is lethal, we know that a total tumor burden of 1 kg-equivalent to one trillion cells-is not compatible with life. While localized disease is curable through surgical removal or radiation, once cancer has spread, it is largely incurable. The inability to cure metastatic cancer lies, at least in part, to the fact that cancer is resistant to all known compounds and anticancer drugs. The source of this resistance remains undefined. In fact, the vast majority of metastatic cancers are resistant to all currently available anticancer therapies, including chemotherapy, hormone therapy, immunotherapy, and systemic radiation. Thus, despite decades-even centuries-of research, metastatic cancer remains lethal and incurable. We present historical and contemporary evidence that the key actuators of this process-of tumorigenesis, metastasis, and therapy resistance-are polyploid giant cancer cells.
Topics: Animals; Carcinogenesis; Drug Resistance, Neoplasm; Giant Cells; Humans; Male; Neoplasm Metastasis; Polyploidy; Prostatic Neoplasms
PubMed: 31376205
DOI: 10.1002/pros.23877