Matrix Metalloproteinase 9 Induced in Esophageal Squamous Cell Carcinoma Cells via Close Contact with Tumor-Associated Macrophages Contributes to Cancer Progression and Poor Prognosis
All articles published by are made immediately available worldwide under an open access license. No special permission is required to reuse all or part of the article published by , including figures and tables. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited. For more information, please refer to https:///openaccess.
Feature papers represent the most advanced research with significant potential for high impact in the field. A Feature Paper should be a substantial original Article that involves several techniques or approaches, provides an outlook for future research directions and describes possible research applications.
Rethinking Ovarian Cancer Ii: Reducing Mortality From High Grade Serous Ovarian Cancer
Editor’s Choice articles are based on recommendations by the scientific editors of journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.
Solid cancers are composed of a mixture of various cell types. Tumor cells are among this agglomeration and interact with other components through cell-cell contacts and released factors. Pancreatic cancer is particularly rich in additional cell types which are instructed by neighboring cancer cells to behave in a cancer-promoting manner. One of the abundant cell types in pancreatic cancer are the so called cancer-associated fibroblasts (CAFs). CAFs exist as different subsets with distinct properties which can be tumor growth stimulating or even be tumor restraining. This review describes the various CAF subpopulations, their molecular discrimination, and the resulting functional impact of these cells on pancreatic cancer development and therapy approaches.
Pancreatic cancer represents one of the most desmoplastic malignancies and is characterized by an extensive deposition of extracellular matrix. The latter is provided by activated cancer-associated fibroblasts (CAFs), which are abundant cells in the pancreatic tumor microenvironment. Many recent studies have made it clear that CAFs are not a singular cellular entity but represent a multitude of potentially dynamic subgroups that affect tumor biology at several levels. As mentioned before, CAFs significantly contribute to the fibrotic reaction and the biomechanical properties of the tumor, but they can also modulate the local immune environment and the response to targeted, chemo or radiotherapy. As the number of known and emerging CAF subgroups is steadily increasing, it is becoming increasingly difficult to keep up with these developments and to clearly discriminate the cellular subsets identified so far. This review aims to provide a helpful overview that enables readers to quickly familiarize themselves with field of CAF heterogeneity and to grasp the phenotypic, functional and therapeutic distinctions of the various stromal subpopulations.
Journal Of The American College Of Surgeons
Humans are multicellular organisms, and each cell is allocated a specific task to provide selective functionality to the entire body. In order to ensure proper interplay, several cell-intrinsic and cell-extrinsic mechanisms have evolved to remove or control cells which have gained non-physiological properties, such as malignancy. Solid tumors are embedded in the tissue from which they originate, and normal microenvironmental structures often possess a surprising capacity to restrain tumor growth [1]. However, over time, cancer cells acquire control over their surrounding neighbors, essentially reprogramming them into cancer-associated counterparts that foster tumor growth [2, 3]. These processes, which mimic tissue repair and wound healing, almost inevitably involve mesenchymal cells in the form of fibroblasts [4]. This review aims to outline the current knowledge on CAF heterogeneity encountered in solid cancer (with pancreatic cancer being in the focus) and the functional consequences that these individual subpopulations exert on tumor development, maintenance and therapy outcome.
Fibroblasts are ubiquitously encountered constituents of the tumor microenvironment in solid cancers. Since their normal role in physiology is repair and homeostasis, they can be found in virtually all tissues, where they often stay quiescent and do not stand in the functional foreground [5]. This holds true for other independent lines of resident mesenchymal cells, such as the stellate cells of the liver and pancreas. This quiescent scenario changes abruptly when signals associated with tissue damage and repair are induced. Many such signals have been delineated and include transforming growth factor β (TGF-β), Hedgehog (Hh), Wnt, platelet-derived growth factor (PDGF), interleukins or tumor necrosis factor (TNF) [5]. Additionally, mechanical cues can instruct quiescent fibroblasts to become activated through the Hippo-YAP/TAZ and MRTF/SRF pathways [6, 7].
Of these, the prototypic TGF-β ligands are the best understood members of extracellular ligands, which promote the transition from resident fibroblasts to wound-healing myofibroblastic CAFs by activating SMAD-dependent transcription (myCAFs, discussed later) [8]. Much of the older literature focuses on TGF-β and myCAFs in wound healing, fibrosis and cancer, as additional CAF subtypes were unknown until recently. Moreover, several general mediators of CAF activation have been identified, which function as nodes in an intricate signaling network, often in a self-amplifying manner. For instance, heat-shock factor 1 (HSF1) has been delineated as important promoter of overall CAF activation in several cancer entities, including PDAC [9, 10, 11]. HSF1 performs a transcriptional program distinct from classical heat stress and induces the expression of TGF-β ligands and CXCL12, supporting an autocrine signaling loop of CAF activation [9]. Another HSF1 target gene is DKK3, leading to the promotion of Wnt signaling and the subsequent activation of the Hippo pathway members YAP/TAZ [6, 12]. The transcriptional co-activators YAP/TAZ are critical mediators of the CAF state in cancer, including PDAC [6, 13]. Similar processes apply to disease-related fibroblasts, where the key fibrotic regulator PU.1 drives the production of the YAP/TAZ interactor TEAD1 and the expression of smooth muscle actin and collagen: two cardinal markers of myofibroblasts [14].
Worldwide Burden Of, Risk Factors For, And Trends In Pancreatic Cancer
As producers of collagenous ECM, CAFs are embedded in a stiff environment. Tissue stiffness further stimulates YAP/TAZ activity through integrin-induced remodeling of the actin cytoskeleton [6, 15]. Other modulators of the actin network, such as the actin-severing and capping protein gelsolin, can also impact the process of fibroblast activation [16]. Along these lines, mechano-sensitive focal adhesion kinase (FAK), which lies downstream of integrin receptors, also contributes to fibroblast activation, ECM deposition, fibrosis and immune suppression [17]. However, the precise role of FAK in pancreatic CAFs might require additional investigations, as another study ascribed a tumor-suppressive function to stromal FAK [18].
As stromal mesenchymal cells transition from a quiescent to an activated state with strongly distinct characteristics, it is not surprising that epigenetic changes play important roles in this transdifferentiation. The processes involved are not fully elucidated, but some studies shed light on the underlying molecular steps. For instance, DNA methylation, as regulated through DNMT3B and DNMT1, controls CAF features in human lung and head–neck carcinomas [19]. Along these lines of research, the cellular availability of methyl groups to epigenetically modify DNA or histones is subject to negative regulation by nicotinamide N-methyl transferase (NNMT). High stromal NNMT levels have been found in breast, colon and ovarian cancer, and its activity is critically required for CAF function. NNMT reduces the overall available methyl group pool, thereby favoring the hypomethylation of repressive chromatin/DNA marks and the induction of CAF-related gene transcription [20].
Although stromal fibroblasts are considered not to harbor major driver gene mutations, they may acquire changes in basal gene expression that predispose them to activation by environmentally provided signaling cues. For example, stromal downregulation of the p62/SQSTM1 protein results in the activation of fibroblasts and hepatic stellate cells (HSCs), the latter being functionally similar to pancreatic stellate cells (PSCs) [21, 22]. The p62 adapter typically binds to the Vitamin D receptor (VDR) and promotes the heterodimerization of VDR and the Retinoic X receptor (RXR). As VDR-induced target genes drive stellate cells into quiescence [23], loss of p62 generally maintains an activated state. Furthermore, P62 plays a role in autophagy, which has been deemed critical for CAF activation [24, 25]. Interestingly, p62 can be transcriptionally suppressed by lactate, an abundant metabolite in the TME of several cancers [26], or by hypoxia [25], providing mechanistic explanations of how the local microenvironment can generally modulate and stimulate overall CAF activity.
Cancer And Diet
Several cell populations have been suggested to give rise to pancreatic CAFs, such as resident fibroblasts or stellate cells (PSCs) [27, 28], bone marrow- or adipose tissue-derived mesenchymal stem cells (MSCs) or monocytes [29, 30], pericytes that have undergone an endothelial-to-mesenchymal transition (EndMT) [31], or cancer cells that have completed an epithelial-to-mesenchymal transition (EMT) [32]. However, most studies favor the view that the majority of CAFs derive from local sources within the pancreas. As a result of the highly complex interplay between different cell types in the tumor microenvironment (TME), CAF heterogeneity is created. Nevertheless, novel studies applying lineage tracing approaches indeed suggest a pre-existing fibroblast heterogeneity that would ultimately lead to distinct CAF subpopulations in the context of disease (see section on HOXB6
CAFs below). This pre-existing heterogeneity might already be established during embryogenesis [33]. Thus, it is currently debated whether CAF heterogeneity
As producers of collagenous ECM, CAFs are embedded in a stiff environment. Tissue stiffness further stimulates YAP/TAZ activity through integrin-induced remodeling of the actin cytoskeleton [6, 15]. Other modulators of the actin network, such as the actin-severing and capping protein gelsolin, can also impact the process of fibroblast activation [16]. Along these lines, mechano-sensitive focal adhesion kinase (FAK), which lies downstream of integrin receptors, also contributes to fibroblast activation, ECM deposition, fibrosis and immune suppression [17]. However, the precise role of FAK in pancreatic CAFs might require additional investigations, as another study ascribed a tumor-suppressive function to stromal FAK [18].
As stromal mesenchymal cells transition from a quiescent to an activated state with strongly distinct characteristics, it is not surprising that epigenetic changes play important roles in this transdifferentiation. The processes involved are not fully elucidated, but some studies shed light on the underlying molecular steps. For instance, DNA methylation, as regulated through DNMT3B and DNMT1, controls CAF features in human lung and head–neck carcinomas [19]. Along these lines of research, the cellular availability of methyl groups to epigenetically modify DNA or histones is subject to negative regulation by nicotinamide N-methyl transferase (NNMT). High stromal NNMT levels have been found in breast, colon and ovarian cancer, and its activity is critically required for CAF function. NNMT reduces the overall available methyl group pool, thereby favoring the hypomethylation of repressive chromatin/DNA marks and the induction of CAF-related gene transcription [20].
Although stromal fibroblasts are considered not to harbor major driver gene mutations, they may acquire changes in basal gene expression that predispose them to activation by environmentally provided signaling cues. For example, stromal downregulation of the p62/SQSTM1 protein results in the activation of fibroblasts and hepatic stellate cells (HSCs), the latter being functionally similar to pancreatic stellate cells (PSCs) [21, 22]. The p62 adapter typically binds to the Vitamin D receptor (VDR) and promotes the heterodimerization of VDR and the Retinoic X receptor (RXR). As VDR-induced target genes drive stellate cells into quiescence [23], loss of p62 generally maintains an activated state. Furthermore, P62 plays a role in autophagy, which has been deemed critical for CAF activation [24, 25]. Interestingly, p62 can be transcriptionally suppressed by lactate, an abundant metabolite in the TME of several cancers [26], or by hypoxia [25], providing mechanistic explanations of how the local microenvironment can generally modulate and stimulate overall CAF activity.
Cancer And Diet
Several cell populations have been suggested to give rise to pancreatic CAFs, such as resident fibroblasts or stellate cells (PSCs) [27, 28], bone marrow- or adipose tissue-derived mesenchymal stem cells (MSCs) or monocytes [29, 30], pericytes that have undergone an endothelial-to-mesenchymal transition (EndMT) [31], or cancer cells that have completed an epithelial-to-mesenchymal transition (EMT) [32]. However, most studies favor the view that the majority of CAFs derive from local sources within the pancreas. As a result of the highly complex interplay between different cell types in the tumor microenvironment (TME), CAF heterogeneity is created. Nevertheless, novel studies applying lineage tracing approaches indeed suggest a pre-existing fibroblast heterogeneity that would ultimately lead to distinct CAF subpopulations in the context of disease (see section on HOXB6
CAFs below). This pre-existing heterogeneity might already be established during embryogenesis [33]. Thus, it is currently debated whether CAF heterogeneity
0 komentar:
Posting Komentar