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

Cancers ◽  
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.

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

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1100
Author(s):  
Sofia Koustoulidou ◽  
Mark W. H. Hoorens ◽  
Simone U. Dalm ◽  
Shweta Mahajan ◽  
Reno Debets ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Tumour Microenvironment ◽  
Therapeutic Interventions ◽  
Great Promise ◽  
Cancer Associated Fibroblasts ◽  
Functional Heterogeneity ◽  
Radioligand Therapy ◽  
Targeted Interventions ◽  
Theranostic Applications ◽  
Complex Origin

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.

scholarly journals Cancer-Associated Fibroblasts in Oral Cancer: A Current Perspective on Function and Potential for Therapeutic Targeting

2021 ◽  
Vol 2 ◽  
Author(s):  
Kamila J. Bienkowska ◽  
Christopher J. Hanley ◽  
Gareth J. Thomas
Keyword(s):  
Oral Cancer ◽  
Cancer Progression ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumour Microenvironment ◽  
Cancer Associated Fibroblasts ◽  
Current Perspective ◽  
And Function ◽  
Exciting Development

The role of the tumour microenvironement (TME) in cancer progression and resistance to therapies is now widely recognized. The most prominent non-immune cell type in the microenvironment of oral cancer (OSCC) is cancer-associated fibroblasts (CAF). Although CAF are a poorly characterised and heterogenous cell population, those with an “activated” myofibroblastic phenotype have been shown to support OSCC progression, promoting growth, invasion and numerous other “hallmarks of malignancy.” CAF also confer broad resistance to different types of therapy, including chemo/radiotherapy and EGFR inhibitors; consistent with this, CAF-rich OSCC are associated with poor prognosis. In recent years, much CAF research has focused on their immunological role in the tumour microenvironment, showing that CAF shield tumours from immune attack through multiple mechanisms, and particularly on their role in promoting resistance to anti-PD-1/PD-L1 checkpoint inhibitors, an exciting development for the treatment of recurrent/metastatic oral cancer, but which fails in most patients. This review summarises our current understanding of CAF subtypes and function in OSCC and discusses the potential for targeting these cells therapeutically.

scholarly journals Cancer-Associated Fibroblasts’ Functional Heterogeneity in Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 290 ◽  
Author(s):  
Mohammad Awaji ◽  
Rakesh Singh
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Adverse Outcome ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
Functional Heterogeneity ◽  
Paracrine Factors ◽  
Myofibroblast Phenotype ◽  
The Usa ◽  
The Relationship

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths in the USA. Desmoplasia and inflammation are two major hallmarks of PDAC. Desmoplasia, composed of extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), and infiltrating immune and endothelial cells, acts as a biophysical barrier to hinder chemotherapy and actively contributes to tumor progression and metastasis. CAFs represent a multifunctional subset of PDAC microenvironment and contribute to tumor initiation and progression through ECM deposition and remodeling, as well as the secretion of paracrine factors. Attempts to resolve desmoplasia by targeting CAFs can render an adverse outcome, which is likely due to CAFs heterogeneity. Recent reports describe subsets of CAFs that assume more secretory functions, in addition to the typical myofibroblast phenotype. Here, we review the literature and describe the relationship between CAFs and inflammation and the role of the secretory-CAFs in PDAC.

scholarly journals Reversal of pancreatic desmoplasia by a tumour stroma-targeted nitric oxide nanogel overcomes TRAIL resistance in pancreatic tumours

Gut ◽  
2021 ◽  
pp. gutjnl-2021-325180
Author(s):  
Hsi-Chien Huang ◽  
Yun-Chieh Sung ◽  
Chung-Pin Li ◽  
Dehui Wan ◽  
Po-Han Chao ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Phage Display ◽  
Tumour Microenvironment ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Tumour Stroma ◽  
Desmoplastic Stroma ◽  
Trail Resistance

ObjectiveStromal barriers, such as the abundant desmoplastic stroma that is characteristic of pancreatic ductal adenocarcinoma (PDAC), can block the delivery and decrease the tumour-penetrating ability of therapeutics such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which can selectively induce cancer cell apoptosis. This study aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumours but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC.DesignNitric oxide (NO) plays a role in preventing tissue desmoplasia and could thus be delivered to disrupt the stromal barrier and improve TRAIL delivery in PDAC. We applied an in vitro–in vivo combinatorial phage display technique to identify novel peptide ligands to target the desmoplastic stroma in both murine and human orthotopic PDAC. We then constructed a stroma-targeted nanogel modified with phage display-identified tumour stroma-targeting peptides to co-deliver NO and TRAIL to PDAC and examined the anticancer effect in three-dimensional spheroid cultures in vitro and in orthotopic PDAC models in vivo.ResultsThe delivery of NO to the PDAC tumour stroma resulted in reprogramming of activated pancreatic stellate cells, alleviation of tumour desmoplasia and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating tumour penetration by TRAIL and substantially enhancing the antitumour efficacy of TRAIL therapy.ConclusionThe co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC.

The role of Non-coding Genome in Cancer-associated Fibroblasts; state-of-the-art and perspectives in cancer targeted therapy

2021 ◽  
Vol 22 ◽  
Author(s):  
Arezoo Gowhari Shabgah ◽  
Hamed Mohammadi ◽  
Pouya Goleij ◽  
Mahdiyeh Hedayati-Moghadam ◽  
Arash Salmaninejad ◽  
...  
Keyword(s):  
Healing Process ◽  
Wound Healing Process ◽  
Cancer Associated Fibroblasts ◽  
Therapeutic Approaches ◽  
Signaling Center ◽  
Non Coding Rnas ◽  
And Function ◽  
Cancer Targeted Therapy ◽  
Shed Light

: Cancer-associated fibroblasts (CAFs) are senescent fibroblasts in tumor nest, which trigger a signaling center to remodel a desmoplastic tumor niche. CAF’s functions in cancer are closely similar to myofibroblasts during the wound healing process. They can produce cytokine, enzymes, and protein- or RNA-containing exosomes to alter the function of surrounding cells. Non-coding RNAs, including microRNAs and long non-coding RNAs, modulate pathologic mechanisms in cancer. Dysregulation of these RNAs influences the formation and function of CAFs. Furthermore, it has been demonstrated that CAFs, by releasing non-coding RNAs-containing exosomes, affect the tumor cells’ behavior. CAFs also secrete mediators such as chemokines to alter the expression of non-coding RNAs in the tumor microenvironment. This study aimed to discuss the role of non-coding RNAs in CAF development in cancer situations. Additionally, we are going to shed light on the therapeutic approaches to develop the strategies based-on the alteration of non-coding RNAs in cancer.

scholarly journals Pancreatic Fibroblast Heterogeneity: From Development to Cancer

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2464
Author(s):  
Paloma E. Garcia ◽  
Michael K. Scales ◽  
Benjamin L. Allen ◽  
Marina Pasca di Magliano
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Disease Progression ◽  
Current Literature ◽  
Healthy Adult ◽  
Cellular Component ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
Heterogeneous Nature ◽  
And Function ◽  
Fibroblast Heterogeneity

Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive fibroinflammatory microenvironment that accumulates from the onset of disease progression. Cancer-associated fibroblasts (CAFs) are a prominent cellular component of the stroma, but their role during carcinogenesis remains controversial, with both tumor-supporting and tumor-restraining functions reported in different studies. One explanation for these contradictory findings is the heterogeneous nature of the fibroblast populations, and the different roles each subset might play in carcinogenesis. Here, we review the current literature on the origin and function of pancreatic fibroblasts, from the developing organ to the healthy adult pancreas, and throughout the initiation and progression of PDA. We also discuss clinical approaches to targeting fibroblasts in PDA.

scholarly journals Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition

2020 ◽  
Author(s):  
George Sharbeen ◽  
Joshua A. McCarroll ◽  
Anouschka Akerman ◽  
Chantal Kopecky ◽  
Janet Youkhana ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumour Growth ◽  
Prognostic Significance ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
Tumour Stroma ◽  
Genetic Ablation ◽  
Cystine Transporter ◽  
Paradigm Shifting

ABSTRACTCancer-Associated Fibroblasts (CAFs) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression, through pro-tumour cross-talk and the generation of fibrosis (physical barrier to drugs). CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumour stroma and its prognostic significance. Herein we show that high expression of SLC7A11 in PDAC tumour stroma (but not tumour cells) is independently prognostic of poorer overall survival. We demonstrate using orthogonal approaches that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis, and that SLC7A11 inhibition significantly decreases their proliferation, reduces their resistance to oxidative stress and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, our paradigm-shifting work demonstrates the need to inhibit SLC7A11 in the PDAC stroma, as genetic ablation of SLC7A11 in PDAC cells alone is not enough to reduce tumour growth. Finally, our work validates that a nano-based gene-silencing drug against SLC7A11, developed by our group, reduces PDAC tumour growth, CAF activation and fibrosis in a mouse model of PDAC.

scholarly journals Core–shell nanoparticles suppress metastasis and modify the tumour-supportive activity of cancer-associated fibroblasts

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Dávid Kovács ◽  
Nóra Igaz ◽  
Annamária Marton ◽  
Andrea Rónavári ◽  
Péter Bélteky ◽  
...  
Keyword(s):  
Tumour Microenvironment ◽  
Cancer Associated Fibroblasts ◽  
Malignant Cells ◽  
Tumour Stroma ◽  
Shell Nanoparticles ◽  
Stromal Fibroblasts ◽  
Metastatic Dissemination ◽  
Gold Core ◽  
Silver Shell

Abstract Background Although accumulating evidence suggests that the crosstalk between malignant cells and cancer-associated fibroblasts (CAFs) actively contributes to tumour growth and metastatic dissemination, therapeutic strategies targeting tumour stroma are still not common in the clinical practice. Metal-based nanomaterials have been shown to exert excellent cytotoxic and anti-cancerous activities, however, their effects on the reactive stroma have never been investigated in details. Thus, using feasible in vitro and in vivo systems to model tumour microenvironment, we tested whether the presence of gold, silver or gold-core silver-shell nanoparticles exerts anti-tumour and metastasis suppressing activities by influencing the tumour-supporting activity of stromal fibroblasts. Results We found that the presence of gold-core silver-shell hybrid nanomaterials in the tumour microenvironment attenuated the tumour cell-promoting behaviour of CAFs, and this phenomenon led to a prominent attenuation of metastatic dissemination in vivo as well. Mechanistically, transcriptome analysis on tumour-promoting CAFs revealed that silver-based nanomaterials trigger expressional changes in genes related to cancer invasion and tumour metastasis. Conclusions Here we report that metal nanoparticles can influence the cancer-promoting activity of tumour stroma by affecting the gene expressional and secretory profiles of stromal fibroblasts and thereby altering their intrinsic crosstalk with malignant cells. This potential of metal nanomaterials should be exploited in multimodal treatment approaches and translated into improved therapeutic outcomes.

scholarly journals The tumour microenvironment shapes dendritic cell plasticity in a human organotypic melanoma culture

2019 ◽  
Author(s):  
S Di Blasio ◽  
M Tazzari ◽  
G van Wigcheren ◽  
A van Duffelen ◽  
I Stefanini ◽  
...  
Keyword(s):  
Clinical Success ◽  
Malignant Cell ◽  
Tumour Microenvironment ◽  
Cellular Tissue ◽  
Cell Plasticity ◽  
Approaches To Study ◽  
Valuable Complement ◽  
And Function ◽  
Shed Light ◽  
Physiological Complexity

AbstractThe tumour microenvironment (TME) forms a major obstacle in effective cancer treatment and for clinical success of immunotherapy. Conventional co-cultures have shed light into multiple aspects of cancer immunobiology, but they are limited by the lack of physiological complexity. We developed a novel human, organotypic skin melanoma culture (OMC) that allows real-time study of host-malignant cell interactions within a multi-cellular tissue architecture. By co-culturing keratinocytes, fibroblasts and immune cells with melanoma cells, onto a de-cellularized dermis, we generated a reconstructed TME that closely recapitulates tumour growth as observed in human lesions and supports cell survival and function. We demonstrate that the OMC is suitable and outperforms conventional 2D co-cultures for the study of TME-imprinting mechanisms. Within the OMC we observed the tumour-driven conversion of cDC2s into CD14+ DCs, characterized by a an immunosuppressive phenotype. The OMC provides a valuable complement to current approaches to study the TME.

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