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Endocrine Reviews Aug 2019Pelvic endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects primarily pelvic tissues, including the... (Review)
Review
Pelvic endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects primarily pelvic tissues, including the ovaries. It is caused when shed endometrial tissue travels retrograde into the lower abdominal cavity. Endometriosis is the most common cause of chronic pelvic pain in women and is associated with infertility. The underlying pathologic mechanisms in the intracavitary endometrium and extrauterine endometriotic tissue involve defectively programmed endometrial mesenchymal progenitor/stem cells. Although endometriotic stromal cells, which compose the bulk of endometriotic lesions, do not carry somatic mutations, they demonstrate specific epigenetic abnormalities that alter expression of key transcription factors. For example, GATA-binding factor-6 overexpression transforms an endometrial stromal cell to an endometriotic phenotype, and steroidogenic factor-1 overexpression causes excessive production of estrogen, which drives inflammation via pathologically high levels of estrogen receptor-β. Progesterone receptor deficiency causes progesterone resistance. Populations of endometrial and endometriotic epithelial cells also harbor multiple cancer driver mutations, such as KRAS, which may be associated with the establishment of pelvic endometriosis or ovarian cancer. It is not known how interactions between epigenomically defective stromal cells and the mutated genes in epithelial cells contribute to the pathogenesis of endometriosis. Endometriosis-associated pelvic pain is managed by suppression of ovulatory menses and estrogen production, cyclooxygenase inhibitors, and surgical removal of pelvic lesions, and in vitro fertilization is frequently used to overcome infertility. Although novel targeted treatments are becoming available, as endometriosis pathophysiology is better understood, preventive approaches such as long-term ovulation suppression may play a critical role in the future.
Topics: Animals; Endometriosis; Endometrium; Female; Humans; Mice; Receptors, Progesterone; Stromal Cells; Uterine Diseases
PubMed: 30994890
DOI: 10.1210/er.2018-00242 -
Nature Medicine Nov 2013Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the... (Review)
Review
Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
Topics: Cell Cycle Checkpoints; Disease Progression; Humans; Immunotherapy; Inflammation; Macrophages; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Stromal Cells; Tumor Microenvironment
PubMed: 24202395
DOI: 10.1038/nm.3394 -
Cancer Cell Mar 2012Mutationally corrupted cancer (stem) cells are the driving force of tumor development and progression. Yet, these transformed cells cannot do it alone. Assemblages of... (Review)
Review
Mutationally corrupted cancer (stem) cells are the driving force of tumor development and progression. Yet, these transformed cells cannot do it alone. Assemblages of ostensibly normal tissue and bone marrow-derived (stromal) cells are recruited to constitute tumorigenic microenvironments. Most of the hallmarks of cancer are enabled and sustained to varying degrees through contributions from repertoires of stromal cell types and distinctive subcell types. Their contributory functions to hallmark capabilities are increasingly well understood, as are the reciprocal communications with neoplastic cancer cells that mediate their recruitment, activation, programming, and persistence. This enhanced understanding presents interesting new targets for anticancer therapy.
Topics: Cell Movement; Cell Proliferation; Humans; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells; Signal Transduction; Stromal Cells; Tumor Microenvironment
PubMed: 22439926
DOI: 10.1016/j.ccr.2012.02.022 -
Nature Materials Apr 2021Stromal stiffening accompanies malignancy, compromises treatment and promotes tumour aggression. Clarifying the molecular nature and the factors that regulate stromal...
Stromal stiffening accompanies malignancy, compromises treatment and promotes tumour aggression. Clarifying the molecular nature and the factors that regulate stromal stiffening in tumours should identify biomarkers to stratify patients for therapy and interventions to improve outcome. We profiled lysyl hydroxylase-mediated and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in aggressive human breast cancer subtypes with the stiffest stroma. These tissues harbour the highest number of tumour-associated macrophages, whose therapeutic ablation in experimental models reduced metastasis, and decreased collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme, lysyl oxidase, had no impact on collagen crosslinking in PyMT mammary tumours, whereas stromal cell targeting did. Stromal cells in microdissected human tumours expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of biopsies from a cohort of patients with breast cancer revealed that stromal expression of lysyl hydroxylase 2, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening, correlated significantly with disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumour aggression and identify lysyl hydroxylase 2 as a stromal biomarker.
Topics: Adult; Biopsy; Breast Neoplasms; Cell Line, Tumor; Collagen; Female; Humans; Middle Aged; Protein-Lysine 6-Oxidase; Stromal Cells; Tumor-Associated Macrophages
PubMed: 33257795
DOI: 10.1038/s41563-020-00849-5 -
Cell Reports May 2023Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to...
Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions. The role of sialylation in shaping MSC/CAF immunosuppression in the TME is not well characterized. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid, and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory CD8 PD1 and CD8 Siglec-7/Siglec-9 T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as shown by infiltration of CD25 and granzyme B-expressing CD8 T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.
Topics: Humans; CD8-Positive T-Lymphocytes; Tumor Microenvironment; Immunosuppression Therapy; Stromal Cells; Neoplasms; Cancer-Associated Fibroblasts; Sialic Acid Binding Immunoglobulin-like Lectins
PubMed: 37167967
DOI: 10.1016/j.celrep.2023.112475 -
Cell Communication and Signaling : CCS Feb 2023Multipotent mesenchymal stromal cells (MSCs) are precursors of various cell types. Through soluble factors, direct cell-cell interactions and other intercellular...
BACKGROUND
Multipotent mesenchymal stromal cells (MSCs) are precursors of various cell types. Through soluble factors, direct cell-cell interactions and other intercellular communication mechanisms such as extracellular vesicles and tunneling nanotubes, MSCs support tissue homeostasis. In the bone marrow microenvironment, they promote hematopoiesis. The interaction between MSCs and cancer cells enhances the cancer and metastatic potential. Here, we have demonstrated that plastic-adherent MSCs isolated from human bone marrow generate migrasomes, a newly discovered organelle playing a role in intercellular communication.
RESULTS
Migrasomes are forming a network with retraction fibers behind the migrating MSCs or surrounding them after membrane retraction. The MSC markers, CD44, CD73, CD90, CD105 and CD166 are present on the migrasome network, the latter being specific to migrasomes. Some migrasomes harbor the late endosomal GTPase Rab7 and exosomal marker CD63 indicating the presence of multivesicular bodies. Stromal cell-derived factor 1 (SDF-1) was detected in migrasomes, suggesting that they play a chemoattractant role. Co-cultures with KG-1a leukemic cells or primary CD34 hematopoietic progenitors revealed that MSC-associated migrasomes attracted them, a process intercepted by the addition of AMD3100, a specific CXCR4 receptor inhibitor, or recombinant SDF-1. An antibody directed against CD166 reduced the association of hematopoietic cells and MSC-associated migrasomes. In contrast to primary CD34 progenitors, leukemic cells can take up migrasomes.
CONCLUSION
Overall, we described a novel mechanism used by MSCs to communicate with cells of hematopoietic origin and further studies are needed to decipher all biological aspects of migrasomes in the healthy and transformed bone marrow microenvironment. Video Abstract.
Topics: Humans; Chemotactic Factors; Mesenchymal Stem Cells; Hematopoietic Stem Cells; Cells, Cultured; Antigens, CD34; Bone Marrow Cells; Cell Differentiation; Stromal Cells
PubMed: 36788616
DOI: 10.1186/s12964-022-01028-6 -
Current Opinion in Hematology Jul 2018In addition to the recent progresses in the description of the genetic landscape of B-cell non-Hodgkin's lymphomas, tumor microenvironment has progressively emerged as a... (Review)
Review
PURPOSE OF REVIEW
In addition to the recent progresses in the description of the genetic landscape of B-cell non-Hodgkin's lymphomas, tumor microenvironment has progressively emerged as a central determinant of early lymphomagenesis, subclonal evolution, drug resistance, and late progression/transformation. The purpose of this review is to outline the most recent findings regarding malignant B-cell niche composition and organization supporting direct and indirect tumor-promoting functions of lymphoma microenvironment.
RECENT FINDINGS
Lymphoma supportive niche integrates a dynamic and orchestrated network of immune and stromal cell subsets producing, with a high level of spatial and kinetic heterogeneity, extracellular and membrane factors regulating tumor migration, survival, proliferation, immune escape, as well as tumor microarchitecture, and mechanical constraints. Some recent insights have improved our understanding of these various components of lymphoma microenvironment, taking into account the mechanisms underlying the coevolution of malignant and nonmalignant cells within the tumor niche.
SUMMARY
Deciphering tumor niche characteristics, functions, and origin could offer new therapeutic opportunities through the targeting of pivotal cellular and molecular components of the supportive microenvironment, favoring immune cell reactivation and infiltration, and/or limiting tumor retention within this protective niche.
Topics: Animals; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Humans; Lymphoma, B-Cell; Stromal Cells; Tumor Microenvironment
PubMed: 29746265
DOI: 10.1097/MOH.0000000000000440 -
Cells Apr 2020Adipose tissue (AT) is comprised of a diverse number of cell types, including adipocytes, stromal cells, endothelial cells, and infiltrating leukocytes. Adipose stromal... (Review)
Review
Adipose tissue (AT) is comprised of a diverse number of cell types, including adipocytes, stromal cells, endothelial cells, and infiltrating leukocytes. Adipose stromal cells (ASCs) are a mixed population containing adipose progenitor cells (APCs) as well as fibro-inflammatory precursors and cells supporting the vasculature. There is growing evidence that the ability of ASCs to renew and undergo adipogenesis into new, healthy adipocytes is a hallmark of healthy fat, preventing disease-inducing adipocyte hypertrophy and the spillover of lipids into other organs, such as the liver and muscles. However, there is building evidence indicating that the ability for ASCs to self-renew is not infinite. With rates of ASC proliferation and adipogenesis tightly controlled by diet and the circadian clock, the capacity to maintain healthy AT via the generation of new, healthy adipocytes appears to be tightly regulated. Here, we review the contributions of ASCs to the maintenance of distinct adipocyte pools as well as pathogenic fibroblasts in cancer and fibrosis. We also discuss aging and diet-induced obesity as factors that might lead to ASC senescence, and the consequences for metabolic health.
Topics: Adipocytes; Adipose Tissue; Animals; Cell Differentiation; Circadian Clocks; Humans; Mice; Obesity; Stromal Cells; Tissue Expansion
PubMed: 32252348
DOI: 10.3390/cells9040863 -
Biomolecular Concepts Oct 2014Telocytes (TCs) are a novel interstitial (stromal) cell type described in many tissues and organs (www.telocytes.com). A TC is characterized by a small cell body (9-15... (Review)
Review
Telocytes (TCs) are a novel interstitial (stromal) cell type described in many tissues and organs (www.telocytes.com). A TC is characterized by a small cell body (9-15 μm) and a variable number (one to five) of extremely long and thin telopodes (Tps), with alternating regions of podomers (∼80 nm) and podoms (250-300 nm). Tps are interconnected by homo- and heterocellular junctions and form three-dimensional networks. Moreover, Tps release three types of extracellular vesicles: exosomes, ectosomes, and multivesicular cargos, which are involved in paracrine signaling. Different techniques have been used to characterize TCs, from classical methods (light microscopy, electron microscopy) to modern 'omics'. It is considered that electron microscopy is essential for their identification, and CD34/PDGFRα double immunohistochemistry can orientate the diagnosis. Functional evidence is accumulating that TCs may be intimately involved in the maintenance of tissue homeostasis and renewal by short- and long-distance intercellular communication. This review focuses on the most recent findings regarding TC features and locations and the principal hypotheses about their functions in normal and diseased organs. TC involvement in regenerative medicine is also considered.
Topics: Animals; Cell Communication; Cell-Derived Microparticles; Exosomes; Humans; Regeneration; Stromal Cells
PubMed: 25367617
DOI: 10.1515/bmc-2014-0029 -
Seminars in Immunopathology Feb 2021As the primary site for T cell development, the thymus is responsible for the production and selection of a functional, yet self-tolerant T cell repertoire. This... (Review)
Review
As the primary site for T cell development, the thymus is responsible for the production and selection of a functional, yet self-tolerant T cell repertoire. This critically depends on thymic stromal cells, derived from the pharyngeal apparatus during embryogenesis. Thymic epithelial cells, mesenchymal and vascular elements together form the unique and highly specialised microenvironment required to support all aspects of thymopoiesis and T cell central tolerance induction. Although rare, inborn errors of thymic stromal cells constitute a clinically important group of conditions because their immunological consequences, which include autoimmune disease and T cell immunodeficiency, can be life-threatening if unrecognised and untreated. In this review, we describe the molecular and environmental aetiologies of the thymic stromal cell defects known to cause disease in humans, placing particular emphasis on those with a propensity to cause thymic hypoplasia or aplasia and consequently severe congenital immunodeficiency. We discuss the principles underpinning their diagnosis and management, including the use of novel tools to aid in their identification and strategies for curative treatment, principally transplantation of allogeneic thymus tissue.
Topics: Autoimmune Diseases; Cell Differentiation; Epithelial Cells; Humans; Stromal Cells; T-Lymphocytes; Thymus Gland
PubMed: 33257998
DOI: 10.1007/s00281-020-00826-9