scholarly journals Cell Lineage Infidelity in PDAC Progression and Therapy Resistance

2021 ◽  
Vol 9 ◽  
Author(s):  
Antonia Malinova ◽  
Lisa Veghini ◽  
Francisco X. Real ◽  
Vincenzo Corbo
Keyword(s):  
Cell Fate ◽  
Wound Repair ◽  
Current Knowledge ◽  
Cell Lineage ◽  
Therapy Resistance ◽  
Ductal Adenocarcinoma ◽  
Cell Phenotype ◽  
Extrinsic Factors ◽  
Lineage Infidelity ◽  
Phenotype Switching

Infidelity to cell fate occurs when differentiated cells lose their original identity and either revert to a more multipotent state or transdifferentiate into a different cell type, either within the same embryonic lineage or in an entirely different one. Whilst in certain circumstances, such as in wound repair, this process is beneficial, it can be hijacked by cancer cells to drive disease initiation and progression. Cell phenotype switching has been shown to also serve as a mechanism of drug resistance in some epithelial cancers. In pancreatic ductal adenocarcinoma (PDAC), the role of lineage infidelity and phenotype switching is still unclear. Two consensus molecular subtypes of PDAC have been proposed that mainly reflect the existence of cell lineages with different degrees of fidelity to pancreatic endodermal precursors. Indeed, the classical subtype of PDAC is characterised by the expression of endodermal lineage specifying transcription factors, while the more aggressive basal-like/squamous subtype is defined by epigenetic downregulation of endodermal genes and alterations in chromatin modifiers. Here, we summarise the current knowledge of mechanisms (genetic and epigenetic) of cell fate switching in PDAC and discuss how pancreatic organoids might help increase our understanding of both cell-intrinsic and cell-extrinsic factors governing lineage infidelity during the distinct phases of PDAC evolution.

scholarly journals Lineage Switching in Acute Leukemias: A Consequence of Stem Cell Plasticity?

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Elisa Dorantes-Acosta ◽  
Rosana Pelayo
Keyword(s):  
Cell Fate ◽  
High Efficiency ◽  
Current Knowledge ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Cell Lineage ◽  
Leukemic Cells ◽  
Acute Leukemias ◽  
Cell Fate Decisions ◽  
Lineage Switch

Acute leukemias are the most common cancer in childhood and characterized by the uncontrolled production of hematopoietic precursor cells of the lymphoid or myeloid series within the bone marrow. Even when a relatively high efficiency of therapeutic agents has increased the overall survival rates in the last years, factors such as cell lineage switching and the rise of mixed lineages at relapses often change the prognosis of the illness. During lineage switching, conversions from lymphoblastic leukemia to myeloid leukemia, or vice versa, are recorded. The central mechanisms involved in these phenomena remain undefined, but recent studies suggest that lineage commitment of plastic hematopoietic progenitors may be multidirectional and reversible upon specific signals provided by both intrinsic and environmental cues. In this paper, we focus on the current knowledge about cell heterogeneity and the lineage switch resulting from leukemic cells plasticity. A number of hypothetical mechanisms that may inspire changes in cell fate decisions are highlighted. Understanding the plasticity of leukemia initiating cells might be fundamental to unravel the pathogenesis of lineage switch in acute leukemias and will illuminate the importance of a flexible hematopoietic development.

scholarly journals Stem Cell Lineage Infidelity Drives Wound Repair and Cancer

Cell ◽  
2017 ◽  
Vol 169 (4) ◽  
pp. 636-650.e14 ◽  
Author(s):  
Yejing Ge ◽  
Nicholas C. Gomez ◽  
Rene C. Adam ◽  
Maria Nikolova ◽  
Hanseul Yang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Wound Repair ◽  
Cell Lineage ◽  
Stem Cell Lineage ◽  
Lineage Infidelity

scholarly journals The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4932
Author(s):  
Young Researchers in Inflammatory Carcinogenesis Group ◽  
Anna Wandmacher ◽  
Anne-Sophie Mehdorn ◽  
Susanne Sebens
Keyword(s):  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Therapy Response ◽  
Therapy Resistance ◽  
Ductal Adenocarcinoma ◽  
Cell Heterogeneity ◽  
Survival Times ◽  
Stromal Compartment ◽  
Therapeutic Concepts ◽  
The Impact

Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at advanced stages and most anti-cancer therapies have failed to substantially improve prognosis of PDAC patients. As a result, PDAC is still one of the deadliest tumors. Tumor heterogeneity, manifesting at multiple levels, provides a conclusive explanation for divergent survival times and therapy responses of PDAC patients. Besides tumor cell heterogeneity, PDAC is characterized by a pronounced inflammatory stroma comprising various non-neoplastic cells such as myofibroblasts, endothelial cells and different leukocyte populations which enrich in the tumor microenvironment (TME) during pancreatic tumorigenesis. Thus, the stromal compartment also displays a high temporal and spatial heterogeneity accounting for diverse effects on the development, progression and therapy responses of PDAC. Adding to this heterogeneity and the impact of the TME, the microbiome of PDAC patients is considerably altered. Understanding this multi-level heterogeneity and considering it for the development of novel therapeutic concepts might finally improve the dismal situation of PDAC patients. Here, we outline the current knowledge on PDAC cell heterogeneity focusing on different stromal cell populations and outline their impact on PDAC progression and therapy resistance. Based on this information, we propose some novel concepts for treatment of PDAC patients.

scholarly journals Notch Signalling in Breast Development and Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Abigail Edwards ◽  
Keith Brennan
Keyword(s):  
Breast Cancer ◽  
Cell Fate ◽  
Therapy Resistance ◽  
Notch Signalling ◽  
Signalling Pathway ◽  
Breast Development ◽  
Cell Phenotype ◽  
Normal Mammary Gland ◽  
Breast Cancer Patients ◽  
Notch Signalling Pathway

The Notch signalling pathway is a highly conserved developmental signalling pathway, with vital roles in determining cell fate during embryonic development and tissue homeostasis. Aberrant Notch signalling has been implicated in many disease pathologies, including cancer. In this review, we will outline the mechanism and regulation of the Notch signalling pathway. We will also outline the role Notch signalling plays in normal mammary gland development and how Notch signalling is implicated in breast cancer tumorigenesis and progression. We will cover how Notch signalling controls several different hallmarks of cancer within epithelial cells with sections focussed on its roles in proliferation, apoptosis, invasion, and metastasis. We will provide evidence for Notch signalling in the breast cancer stem cell phenotype, which also has implications for therapy resistance and disease relapse in breast cancer patients. Finally, we will summarise the developments in therapeutic targeting of Notch signalling, and the pros and cons of this approach for the treatment of breast cancer.

scholarly journals Insight into Hypoxia Stemness Control

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2161
Author(s):  
Miriam Di Di Mattia ◽  
Annunziata Mauro ◽  
Maria Rita Citeroni ◽  
Beatrice Dufrusine ◽  
Alessia Peserico ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Cell Phenotype ◽  
Multilineage Differentiation ◽  
Extrinsic Factors ◽  
Key Factor ◽  
The Status ◽  
Insight Into

Recently, the research on stemness and multilineage differentiation mechanisms has greatly increased its value due to the potential therapeutic impact of stem cell-based approaches. Stem cells modulate their self-renewing and differentiation capacities in response to endogenous and/or extrinsic factors that can control stem cell fate. One key factor controlling stem cell phenotype is oxygen (O2). Several pieces of evidence demonstrated that the complexity of reproducing O2 physiological tensions and gradients in culture is responsible for defective stem cell behavior in vitro and after transplantation. This evidence is still worsened by considering that stem cells are conventionally incubated under non-physiological air O2 tension (21%). Therefore, the study of mechanisms and signaling activated at lower O2 tension, such as those existing under native microenvironments (referred to as hypoxia), represent an effective strategy to define if O2 is essential in preserving naïve stemness potential as well as in modulating their differentiation. Starting from this premise, the goal of the present review is to report the status of the art about the link existing between hypoxia and stemness providing insight into the factors/molecules involved, to design targeted strategies that, recapitulating naïve O2 signals, enable towards the therapeutic use of stem cell for tissue engineering and regenerative medicine.

scholarly journals EBF1 is expressed in pericytes and contributes to pericyte cell commitment

2021 ◽  
Author(s):  
Francesca Pagani ◽  
Elisa Tratta ◽  
Patrizia Dell’Era ◽  
Manuela Cominelli ◽  
Pietro Luigi Poliani
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
B Cell ◽  
Cell Fate ◽  
Early Stage ◽  
Cell Lineage ◽  
Cell Maturation ◽  
Cell Commitment

AbstractEarly B-cell factor-1 (EBF1) is a transcription factor with an important role in cell lineage specification and commitment during the early stage of cell maturation. Originally described during B-cell maturation, EBF1 was subsequently identified as a crucial molecule for proper cell fate commitment of mesenchymal stem cells into adipocytes, osteoblasts and muscle cells. In vessels, EBF1 expression and function have never been documented. Our data indicate that EBF1 is highly expressed in peri-endothelial cells in both tumor vessels and in physiological conditions. Immunohistochemistry, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and fluorescence-activated cell sorting (FACS) analysis suggest that EBF1-expressing peri-endothelial cells represent bona fide pericytes and selectively express well-recognized markers employed in the identification of the pericyte phenotype (SMA, PDGFRβ, CD146, NG2). This observation was also confirmed in vitro in human placenta-derived pericytes and in human brain vascular pericytes (HBVP). Of note, in accord with the key role of EBF1 in the cell lineage commitment of mesenchymal stem cells, EBF1-silenced HBVP cells showed a significant reduction in PDGFRβ and CD146, but not CD90, a marker mostly associated with a prominent mesenchymal phenotype. Moreover, the expression levels of VEGF, angiopoietin-1, NG2 and TGF-β, cytokines produced by pericytes during angiogenesis and linked to their differentiation and activation, were also significantly reduced. Overall, the data suggest a functional role of EBF1 in the cell fate commitment toward the pericyte phenotype.

scholarly journals Pre-Operative Imaging and Pathological Diagnosis of Localized High-Grade Pancreatic Intra-Epithelial Neoplasia without Invasive Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 945
Author(s):  
Ryota Sagami ◽  
Kentaro Yamao ◽  
Jun Nakahodo ◽  
Ryuki Minami ◽  
Masakatsu Tsurusaki ◽  
...  
Keyword(s):  
Pancreatic Duct ◽  
Invasive Carcinoma ◽  
Current Knowledge ◽  
Precancerous Lesions ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Ducts ◽  
High Grade ◽  
Cytologic Examination ◽  
Imaging Characteristics ◽  
Retention Cysts

Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions, such as pancreatic intra-epithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). The prognosis of high-grade precancerous lesions, including high-grade PanIN and high-grade IPMN, without invasive carcinoma is good, despite the overall poor prognosis of PDAC. High-grade PanIN, as a lesion preceding invasive PDAC, is therefore a primary target for intervention. However, detection of localized high-grade PanIN is difficult when using standard radiological approaches. Therefore, most studies of high-grade PanIN have been conducted using specimens that harbor invasive PDAC. Recently, imaging characteristics of high-grade PanIN have been revealed. Obstruction of the pancreatic duct due to high-grade PanIN may induce a loss of acinar cells replaced by fibrosis and lobular parenchymal atrophy. These changes and additional inflammation around the branch pancreatic ducts (BPDs) result in main pancreatic duct (MPD) stenosis, dilation, retention cysts (BPD dilation), focal pancreatic parenchymal atrophy, and/or hypoechoic changes around the MPD. These indirect imaging findings have become important clues for localized, high-grade PanIN detection. To obtain pre-operative histopathological confirmation of suspected cases, serial pancreatic-juice aspiration cytologic examination is effective. In this review, we outline current knowledge on imaging characteristics of high-grade PanIN.

Current knowledge of immunomodulation strategies for chronic skin wound repair

2021 ◽  
Author(s):  
Parisa Heydari ◽  
Mahshid Kharaziha ◽  
Jaleh Varshosaz ◽  
Shaghayegh Haghjooy Javanmard
Keyword(s):  
Wound Repair ◽  
Current Knowledge ◽  
Skin Wound ◽  
Chronic Skin
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