Cancer-Associated Fibroblasts as Players in Cancer Development and Progression and Their Role in Targeted Radionuclide Imaging and Therapy

Cancer Associated Fibroblasts (CAFs) form a major component of the tumour microenvironment, they have a complex origin and execute diverse functions in tumour development and progression. As such, CAFs constitute an attractive target for novel therapeutic interventions that will aid both diagnosis and treatment of various cancers. There are, however, a few limitations in reaching successful translation of CAF targeted interventions from bench to bedside. Several approaches targeting CAFs have been investigated so far and a few CAF-targeting tracers have successfully been developed and applied. This includes tracers targeting Fibroblast Activation Protein (FAP) on CAFs. A number of FAP-targeting tracers have shown great promise in the clinic. In this review, we summarize our current knowledge of the functional heterogeneity and biology of CAFs in cancer. Moreover, we highlight the latest developments towards theranostic applications that will help tumour characterization, radioligand therapy and staging in cancers with a distinct CAF population.

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Heterogeneity in Pancreatic Cancer Fibroblasts—TGFβ as a Master Regulator?

Cancers ◽

10.3390/cancers13194984 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4984

Author(s):

Dale M. Watt ◽

Jennifer P. Morton

Keyword(s):

Tumour Volume ◽

Tumour Microenvironment ◽

Ductal Adenocarcinoma ◽

Cancer Associated Fibroblasts ◽

Tumour Stroma ◽

Functional Heterogeneity ◽

Aggressive Disease ◽

And Function ◽

High Degree ◽

Shed Light

Pancreatic ductal adenocarcinoma is an aggressive disease for which there are very few available therapies. It is notable for its high degree of tumour complexity, with the tumour microenvironment often accounting for the majority of the tumour volume. Until recently, the biology of the stroma was poorly understood, particularly in terms of heterogeneity. Recent research, however, has shed light on the intricacy of signalling within the stroma and particularly the molecular and functional heterogeneity of the cancer associated fibroblasts. In this review, we summarise the recent improvements in our understanding of the different fibroblast populations within PDAC, with a focus on the role TGFβ plays to dictate their formation and function. These studies have highlighted some of the reasons for the failure of trials targeting the tumour stroma, however, there are still considerable gaps in our knowledge, and more work is needed to make effective fibroblast targeting a reality in the clinic.

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Potential Interventions Against BMPR2-Related Pulmonary Hypertension

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-11.1.25 ◽

2012 ◽

Vol 11 (1) ◽

pp. 25-32 ◽

Cited By ~ 2

Author(s):

James West ◽

James E. Loyd ◽

Rizwan Hamid

Keyword(s):

Therapeutic Interventions ◽

Great Promise ◽

Patient Registries ◽

Metabolic Defects ◽

Pulmonary Arterial ◽

Alternative Approaches ◽

Splicing Defects ◽

Trafficking Defects ◽

Molecular Bases ◽

Near Future

For more than 60 years, researchers have sought to understand the molecular basis of idiopathic pulmonary arterial hypertension (PAH). Recognition of the heritable form of the disease led to the creation of patient registries in the 1980s and 1990s, and discovery of BMPR2 as the cause of roughly 80% of heritable PAH in 2000. With discovery of the disease gene came opportunity for intervention, with focus on 2 alternative approaches. First, it may be possible to correct the effects of BMPR2 mutation directly through interventions targeted at correction of trafficking defects, increasing expression of the unmutated allele, and correction of splicing defects. Second, therapeutic interventions are being targeted at the signaling consequences of BMPR2 mutation. In particular, therapies targeting cytoskeletal and metabolic defects caused by BMPR2 mutation are currently in trials, or will be ready for human trials in the near future. Translation of these findings into therapies is the culmination of decades of research, and holds great promise for treatment of the underlying molecular bases of disease.

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Effects of Maternal Obesity and Gestational Diabetes Mellitus on the Placenta: Current Knowledge and Targets for Therapeutic Interventions

Current Vascular Pharmacology ◽

10.2174/1570161118666200616144512 ◽

2020 ◽

Vol 19 (2) ◽

pp. 176-192

Author(s):

Samantha Bedell ◽

Janine Hutson ◽

Barbra de Vrijer ◽

Genevieve Eastabrook

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Maternal Obesity ◽

Environmental Changes ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Placental Development ◽

Exchange Site ◽

And Function

: Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development as well as metabolic and cardiovascular abnormalities in the offspring. This review aims to summarize current knowledge on the effects of obesity and GDM on placental development and function. Understanding these processes is key in developing therapeutic interventions with the goal of mitigating these effects and preventing future cardiovascular and metabolic pathology in subsequent generations.

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Cellular and Molecular Players in the Interplay between Adipose Tissue and Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22031359 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1359

Author(s):

Francesca Reggiani ◽

Paolo Falvo ◽

Francesco Bertolini

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Metabolic Disorders ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Preclinical Research ◽

The World ◽

Adipose Cells

The incidence and severity of obesity are rising in most of the world. In addition to metabolic disorders, obesity is associated with an increase in the incidence and severity of a variety of types of cancer, including breast cancer (BC). The bidirectional interaction between BC and adipose cells has been deeply investigated, although the molecular and cellular players involved in these mechanisms are far from being fully elucidated. Here, we review the current knowledge on these interactions and describe how preclinical research might be used to clarify the effects of obesity over BC progression and morbidity, with particular attention paid to promising therapeutic interventions.

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Interactions between Cancer-Associated Fibroblasts and T Cells in the Pancreatic Tumor Microenvironment and the Role of Chemokines

Cancers ◽

10.3390/cancers13122995 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2995

Author(s):

Laia Gorchs ◽

Helen Kaipe

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Current Knowledge ◽

Ductal Adenocarcinoma ◽

Pancreatic Tumors ◽

Cell Trafficking ◽

Cancer Associated Fibroblasts ◽

Cell Axis ◽

Combinational Treatment

Less than 10% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive 5 years or more, making it one of the most fatal cancers. Accumulation of T cells in pancreatic tumors is associated with better prognosis, but immunotherapies to enhance the anti-tumor activity of infiltrating T cells are failing in this devastating disease. Pancreatic tumors are characterized by a desmoplastic stroma, which mainly consists of activated cancer-associated fibroblasts (CAFs). Pancreatic CAFs have emerged as important regulators of the tumor microenvironment by contributing to immune evasion through the release of chemokines, cytokines, and growth factors, which alters T-cell migration, differentiation and cytotoxic activity. However, recent discoveries have also revealed that subsets of CAFs with diverse functions can either restrain or promote tumor progression. Here, we discuss our current knowledge about the interactions between CAFs and T cells in PDAC and summarize different therapy strategies targeting the CAF–T cell axis with focus on CAF-derived soluble immunosuppressive factors and chemokines. Identifying the functions of different CAF subsets and understanding their roles in T-cell trafficking within the tumor may be fundamental for the development of an effective combinational treatment for PDAC.

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Nuclear receptor Nur77: its role in chronic inflammatory diseases

Essays in Biochemistry ◽

10.1042/ebc20210004 ◽

2021 ◽

Author(s):

Sanne C. Lith ◽

Carlie J.M. de Vries

Keyword(s):

Nuclear Receptor ◽

Inflammatory Disease ◽

Inflammatory Responses ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Cell Types ◽

Experimental Models ◽

Therapeutic Interventions ◽

Alternative Mechanism ◽

Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

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Development of a Hypoxia-Activated Trehalose Diester for the Treatment of Solid Tumours

10.26686/wgtn.17147243 ◽

2021 ◽

Author(s):

◽

Amy Jane Foster

Keyword(s):

Cell Wall ◽

Tumour Microenvironment ◽

Solid Tumours ◽

Great Promise ◽

Tumour Regression ◽

Tumour Burden ◽

Isolation And Identification ◽

Enzymatic Reduction ◽

Thesis Work ◽

Wall Components

The potential of bacterial cell wall components in the treatment of various cancers was initially realised in the late 1800s during pioneering work with Coley’s toxins. Since this preliminary work, efforts have been concentrated on the isolation and identification of bacterial components that lead to tumour regression. Trehalose dimycolates (TDMs) are compounds isolated from the M. tuberculosis cell wall and are known to activate macrophages to give a polarised Th1 immune response resulting in reduced tumour burden. Consequently, TDMs have shown great promise in the treatment of solid tumours. In this thesis, work is presented towards the synthesis of trehalose glycolipid prodrugs that will be specifically activated inside the hypoxic tumour microenvironment, and thereby lead to a more selective form of cancer therapy. These hypoxia-activated trehalose glycolipids incorporate a nitroimidazole trigger that fragments upon enzymatic reduction (in the absence of oxygen) to give the active glycolipid. Throughout the course of this work, it was determined that the nitroimidazole trigger group could not be directly attached to the glycolipid and thus, an alternative carbonate-linker strategy was explored through the use of a reporter fluoroprobe. The validity of this approach was determined in various enzyme and cell-based assays.

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Missing links — epigenetic regulators of the pancreatic cancer–associated inflammation

Clinical Science ◽

10.1042/cs20210181 ◽

2021 ◽

Vol 135 (10) ◽

pp. 1289-1293

Author(s):

Gregor Werba ◽

Tamas A. Gonda

Keyword(s):

Pancreatic Cancer ◽

Noncoding Rna ◽

Current Knowledge ◽

Treatment Strategies ◽

Therapeutic Interventions ◽

Ductal Adenocarcinoma ◽

Gastrointestinal Cancers ◽

Novel Treatment ◽

Epigenetic Regulator ◽

Novel Treatment Strategies

Abstract Pancreatic ductal adenocarcinoma (PDAC) features a hostile tumor microenvironment (TME) that renders it remarkably resistant to most therapeutic interventions. Consequently, survival remains among the poorest compared with other gastrointestinal cancers. Concerted efforts are underway to decipher the complex PDAC TME, break down barriers to efficacious therapies and identify novel treatment strategies. In the recent Clinical Science, Li and colleagues identify the long noncoding RNA KLHDC7B-DT as a crucial epigenetic regulator of IL-6 transcription in PDAC and illustrate its potent influences on the pancreatic TME. In this commentary, we introduce epigenetics in pancreatic cancer and put the findings by Li et al. in context with current knowledge.

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The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

Cancers ◽

10.3390/cancers12071887 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1887 ◽

Cited By ~ 1

Author(s):

Francesco Bonollo ◽

George N. Thalmann ◽

Marianna Kruithof-de Julio ◽

Sofia Karkampouna

Keyword(s):

Prostate Cancer ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Current Knowledge ◽

Therapy Resistance ◽

Cancer Associated Fibroblasts ◽

Metastatic Progression ◽

Normal Prostate ◽

Prostate Tumorigenesis

Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.

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MIlitary Combat Mental Health Framework

BMJ Military Health ◽

10.1136/bmjmilitary-2020-001439 ◽

2020 ◽

pp. bmjmilitary-2020-001439

Author(s):

Martin Bricknell

Keyword(s):

Mental Health ◽

Military Service ◽

Current Knowledge ◽

Armed Forces ◽

Well Being ◽

Therapeutic Interventions ◽

Future Research ◽

The Subject ◽

Mental Well Being ◽

Military Combat

This paper describes a framework for understanding military combat mental health based on the possible mental ill-health consequences of exposure to ‘potential trauma events’ for members of the armed forces and after their military service as veterans. It uses a life course approach that maps an individual’s mental well-being against four ‘states’: fit, reacting, injured and ill. It then considers five categories of factors that influence the risk of mental illness from this exposure based on research evidence; prejoining vulnerability, resilience, precipitating, treatment and recovery. This framework offers a structure to debate current knowledge, inform policy and therapeutic interventions, provide education and to guide future research into the subject.

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