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Cancer Cell Nov 2021Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs' functional distinctions, it remains unclear how...
Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs' functional distinctions, it remains unclear how cancer treatments could be personalized based on CAFs in a patient's tumor. We have established a living biobank of CAFs derived from biopsies of patients' non-small lung cancer (NSCLC) that encompasses a broad molecular spectrum of CAFs in clinical NSCLC. By functionally interrogating CAF heterogeneity using the same therapeutics received by patients, we identify three functional subtypes: (1) robustly protective of cancers and highly expressing HGF and FGF7; (2) moderately protective of cancers and highly expressing FGF7; and (3) those providing minimal protection. These functional differences among CAFs are governed by their intrinsic TGF-β signaling, which suppresses HGF and FGF7 expression. This CAF functional classification correlates with patients' clinical response to targeted therapies and also associates with the tumor immune microenvironment, therefore providing an avenue to guide personalized treatment.
Topics: Biopsy; Cancer-Associated Fibroblasts; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Fibroblast Growth Factor 7; Gene Expression Regulation, Neoplastic; Hepatocyte Growth Factor; Humans; Lung Neoplasms; Precision Medicine; Signal Transduction; Transforming Growth Factor beta; Tumor Microenvironment; Up-Regulation
PubMed: 34624218
DOI: 10.1016/j.ccell.2021.09.003 -
Immunological Reviews May 2016As the primary site of T-cell development, the thymus plays a key role in the generation of a strong yet self-tolerant adaptive immune response, essential in the face of... (Review)
Review
As the primary site of T-cell development, the thymus plays a key role in the generation of a strong yet self-tolerant adaptive immune response, essential in the face of the potential threat from pathogens or neoplasia. As the importance of the role of the thymus has grown, so too has the understanding that it is extremely sensitive to both acute and chronic injury. The thymus undergoes rapid degeneration following a range of toxic insults, and also involutes as part of the aging process, albeit at a faster rate than many other tissues. The thymus is, however, capable of regenerating, restoring its function to a degree. Potential mechanisms for this endogenous thymic regeneration include keratinocyte growth factor (KGF) signaling, and a more recently described pathway in which innate lymphoid cells produce interleukin-22 (IL-22) in response to loss of double positive thymocytes and upregulation of IL-23 by dendritic cells. Endogenous repair is unable to fully restore the thymus, particularly in the aged population, and this paves the way toward the need for exogenous strategies to help regenerate or even replace thymic function. Therapies currently in clinical trials include KGF, use of the cytokines IL-7 and IL-22, and hormonal modulation including growth hormone administration and sex steroid inhibition. Further novel strategies are emerging in the preclinical setting, including the use of precursor T cells and thymus bioengineering. The use of such strategies offers hope that for many patients, the next regeneration of their thymus is a step closer.
Topics: Adaptive Immunity; Aging; Animals; Biological Therapy; Clinical Trials as Topic; Dendritic Cells; Fibroblast Growth Factor 7; Humans; Immunity, Innate; Interleukin-7; Interleukins; Regeneration; Signal Transduction; T-Lymphocytes; Thymus Gland; Interleukin-22
PubMed: 27088907
DOI: 10.1111/imr.12418 -
Experimental Dermatology Jan 2021The incidence of cutaneous keratinocyte-derived cancers is increasing globally. Basal cell carcinoma (BCC) is the most common malignancy worldwide, and cutaneous... (Review)
Review
The incidence of cutaneous keratinocyte-derived cancers is increasing globally. Basal cell carcinoma (BCC) is the most common malignancy worldwide, and cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. BCC can be classified into subtypes based on the histology, and these subtypes are classified further into low- and high-risk tumors. There is an increasing need to identify new therapeutic strategies for the treatment of unresectable and metastatic cSCC, and for aggressive BCC variants such as infiltrating, basosquamous or morpheaform BCCs. The most important risk factor for BCC and cSCC is solar UV radiation, which causes genetic and epigenetic alterations in keratinocytes. Similar gene mutations are noted already in sun-exposed normal skin emphasizing the role of the alterations in the tumor microenvironment in the progression of cSCC. Early events in cSCC progression are alterations in the composition of basement membrane and dermal extracellular matrix induced by influx of microbes, inflammatory cells and activated stromal fibroblasts. Activated fibroblasts promote inflammation and produce growth factors and proteolytic enzymes, including matrix metalloproteinases (MMPs). Transforming growth factor-β produced by tumor cells and fibroblasts induces the expression of MMPs by cSCC cells and promotes their invasion. Fibroblast-derived keratinocyte growth factor suppresses the malignant phenotype of cSCC cells by inhibiting the expression of several MMPs. These findings emphasize the importance of interplay of tumor and stromal cells in the progression of cSCC and BCC and suggest tumor microenvironment as a therapeutic target in cSCC and aggressive subtypes of BCC.
Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Fibroblast Growth Factor 7; Fibroblasts; Humans; Keratinocytes; Matrix Metalloproteinases; Skin Neoplasms; Transforming Growth Factor beta; Tumor Microenvironment
PubMed: 32869366
DOI: 10.1111/exd.14183 -
Phytotherapy Research : PTR Feb 2020Hair loss affects millions of people worldwide, but currently available treatment options are often dissatisfying due to side effects or limited efficacy. Pea sprout...
Hair loss affects millions of people worldwide, but currently available treatment options are often dissatisfying due to side effects or limited efficacy. Pea sprout extract has been shown to improve hair density when applied topically, but its mode of action and effectiveness upon oral administration remain unknown. Our study has now shown that the application of a fluid containing 2% pea sprout extract on a defined scalp zone of 10 volunteers enhances the expression of defined genes relevant for hair, namely fibroblast growth factor-7 (FGF7) and noggin, by 56 and 85%, respectively. Additionally, a subsequent pilot nutrition intervention study in 21 volunteers proved that pea sprout extract is also effective when consumed as dietary supplement. The daily intake of 100 mg pea sprout extract (AnaGain™ Nu) for 8 weeks significantly reduced hair loss already after 28 days of treatment (p < 0.002). No adverse events were reported. Consequently, pea sprout extract may be an effective means to safely promote hair growth and reduce hair loss in individuals experiencing excessive hair shedding.
Topics: Administration, Cutaneous; Administration, Oral; Adult; Alopecia; Carrier Proteins; Dietary Supplements; Female; Fibroblast Growth Factor 7; Gene Expression Regulation; Hair; Humans; Male; Middle Aged; Pisum sativum; Pilot Projects; Plant Extracts; Seedlings; Young Adult
PubMed: 31680356
DOI: 10.1002/ptr.6528 -
Clinical applications of palifermin: amelioration of oral mucositis and other potential indications.Journal of Cellular and Molecular... Nov 2013Mucositis is one of the most significant toxicities in cancer patients undergoing cytotoxic treatment. It can have a negative impact on both quality of life and health... (Review)
Review
Mucositis is one of the most significant toxicities in cancer patients undergoing cytotoxic treatment. It can have a negative impact on both quality of life and health economics. Severe oral mucositis can contribute to hospitalization, need for narcotic analgesics, total parentral nutrition, suboptimal delivery of anti-neoplastic treatment, and morbidity and mortality. Palifermin, a recombinant derivative of human keratinocyte growth factor, is the first active agent approved by the FDA for the prevention of severe oral mucositis in patients undergoing haematopoietic stem cell transplantation (HSCT). Several studies have also shown significant reduction in the incidence, severity and/or duration of oral mucositis in other high-risk settings such as concurrent chemoradiotherapy (CT/RT) for patients with head and neck cancer, and use of mucotoxic chemotherapeutic agents such as doxorubicin in sarcoma and fluorouracil for the treatment of colorectal cancer. The reduction in mucositis has translated into amelioration of symptoms and improvement in daily functioning as measured by patient-reported outcome in multiple studies. The clinical response to palifermin appears to be related in part to epithelial proliferation and mucosal thickening. Palifermin also has other potential clinical applications including the acceleration of immune reconstitution and inhibition of graft-versus-host disease in patients undergoing HSCT, and mitigation of dysphagia in lung cancer patients treated with concurrent CT/RT. Palifermin is generally well tolerated with mild-to-moderate skin and oral adverse events. Future studies may expand the use of palifermin into other areas that would benefit from its cytoprotective and regenerative effects.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Chemoradiotherapy; Clinical Trials as Topic; Deglutition Disorders; Fibroblast Growth Factor 7; Head and Neck Neoplasms; Humans; Lung Neoplasms; Stomatitis; Treatment Outcome
PubMed: 24251854
DOI: 10.1111/jcmm.12169 -
Cellular Physiology and Biochemistry :... 2017Studies in mice and humans have elucidated an important role for Tregs in promoting tissue repair and restoring tissue integrity. Emerging evidence has revealed that... (Review)
Review
Studies in mice and humans have elucidated an important role for Tregs in promoting tissue repair and restoring tissue integrity. Emerging evidence has revealed that Tregs promoted wound healing and repair processes at multiple tissue sites, such as the heart, liver, kidney, muscle, lung, bone and central nervous system. The localization of repair Tregs in the lung, muscle and liver exhibited unique phenotypes and functions. Epidermal growth factor receptor, amphiregulin, CD73/CD39 and keratinocyte growth factor are important repair factors that are produced or expressed by repair Tregs; these factors coordinate with parenchymal cells to limit injury and promote repair. In addition, repair Tregs can be modulated by IL-33/ST2, TCR signals and other cytokines in the context of injured microenvironment cues. In this review, we provide an overview of the emerging knowledge about Treg-mediated repair in damaged tissues and organs.
Topics: Amphiregulin; Animals; ErbB Receptors; Fibroblast Growth Factor 7; Humans; Interleukin-33; Myocardial Infarction; Receptors, Antigen, T-Cell; Signal Transduction; Spinal Cord Injuries; T-Lymphocytes, Regulatory
PubMed: 29069643
DOI: 10.1159/000484295 -
Nature Jun 2022T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs,...
T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs, the size and cellular composition of the thymus are unusually dynamic, as exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells and diminished naive T cell production with age. Single-cell RNA sequencing (scRNA-seq) has uncovered an unexpected heterogeneity of cell types in the thymic epithelium of young and aged adult mice; however, the identities and developmental dynamics of putative pre- and postnatal epithelial progenitors have remained unresolved. Here we combine scRNA-seq and a new CRISPR-Cas9-based cellular barcoding system in mice to determine qualitative and quantitative changes in the thymic epithelium over time. This dual approach enabled us to identify two principal progenitor populations: an early bipotent progenitor type biased towards cortical epithelium and a postnatal bipotent progenitor population biased towards medullary epithelium. We further demonstrate that continuous autocrine provision of Fgf7 leads to sustained expansion of thymic microenvironments without exhausting the epithelial progenitor pools, suggesting a strategy to modulate the extent of thymopoietic activity.
Topics: Aging; Animals; Autocrine Communication; CRISPR-Cas Systems; Cellular Microenvironment; Epithelial Cells; Epithelium; Fibroblast Growth Factor 7; Mice; RNA-Seq; Single-Cell Analysis; Stem Cells; T-Lymphocytes; Thymus Gland
PubMed: 35614226
DOI: 10.1038/s41586-022-04752-8 -
Journal of Cellular and Molecular... Sep 2013
Topics: Animals; Biomedical Research; Clinical Trials as Topic; Drug Approval; Drug Evaluation, Preclinical; Fibroblast Growth Factor 7; Humans
PubMed: 24151974
DOI: 10.1111/jcmm.12132 -
Pediatric Research Dec 2016Glucocorticoid induction of pulmonary surfactant involves a mesenchyme-derived protein first characterized in 1978 by Smith and termed fibroblast-pneumocyte factor... (Review)
Review
Glucocorticoid induction of pulmonary surfactant involves a mesenchyme-derived protein first characterized in 1978 by Smith and termed fibroblast-pneumocyte factor (FPF). Despite a number of agents having been postulated as being FPF, its identity has remained obscure. In the past decade, three strong candidates for FPF have arisen. This review examines the evidence that keratinocyte growth factor (KGF), leptin or neuregulin-1β (NRG-1β) act as FPF or components of it. As with FPF production, glucocorticoids enhance the concentration of each of these agents in fibroblast-conditioned media. Moreover, each stimulates the synthesis of surfactant-associated phospholipids and proteins in type II pneumocytes. Further, some have unique activities, for example, KGF also minimizes lung injury through enhanced epithelial cell proliferation and NRG-1β enhances surfactant phospholipid secretion and β-adrenergic receptor activity in type II cells. However, even though these agents have attributes in common with FPF, it is inappropriate to specify any one of these agents as FPF. Rather, it appears that each contributes to separate mesenchymal-epithelial signaling mechanisms involved in different aspects of lung development. Given that the production of pulmonary surfactant is essential for postnatal survival, it is reasonable to suggest that several mechanisms independently regulate surfactant synthesis.
Topics: Alveolar Epithelial Cells; Animals; Cell Proliferation; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Glucocorticoids; Humans; Leptin; Lung; Neuregulin-1; Phospholipids; Pulmonary Surfactants; Receptor, Fibroblast Growth Factor, Type 2; Signal Transduction
PubMed: 27500537
DOI: 10.1038/pr.2016.161 -
Journal of Cellular and Molecular... Sep 2013Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and... (Review)
Review
Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin.
Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Epithelium; Fibroblast Growth Factor 7; Humans; Protective Agents; Regeneration
PubMed: 24151975
DOI: 10.1111/jcmm.12091