Carcinoma-associated fibroblasts (CAFs) constitute a substantial proportion of the non-neoplastic mesenchymal cell compartment in various human tumors. These fibroblasts are phenotypically converted ...from their progenitors via interactions with nearby cancer cells during the course of tumor progression. The resulting CAFs, in turn, support the growth and progression of carcinoma cells. These fibroblasts have a major influence on the hallmarks of carcinoma and promote tumor malignancy through the secretion of tumor-promoting growth factors, cytokines and exosomes, as well as through the remodeling of the extracellular matrix. Coevolution of CAFs and carcinoma cells during tumorigenesis is therefore essential for progression into fully malignant tumors. Recent studies have revealed the molecular mechanisms underlying CAF functions, especially in tumor invasion, metastasis and drug resistance and have highlighted the significant heterogeneity among these cells. In this review, we summarize the impacts of recently identified roles of tumor-promoting CAFs and discuss the therapeutic implications of targeting the heterotypic interactions of these fibroblasts with carcinoma cells.
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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. ...Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy.
Metastasis is the leading cause of breast cancer–related deaths. Cancer-associated fibroblasts (CAFs), the predominant stromal cell type in the breast tumour microenvironment, may contribute to ...cancer progression through interaction with tumour cells. Nonetheless, little is known about the details of the underlying mechanism. Here we found that interaction of interleukin 32 (IL32) with integrin β3 (encoded by ITGB3; a member of the integrin family) mediating the cross-talk between CAFs and breast cancer cells plays a crucial role in CAF-induced breast tumour invasiveness. IL32, an ‘RGD’ motif–containing cytokine, was found to be abundantly expressed in CAFs. Integrin β3 turned out to be up-regulated in breast cancer cells during epithelial–mesenchymal transition (EMT). CAF-derived IL32 specifically bound to integrin β3 through the RGD motif, thus activating intracellular downstream p38 MAPK signalling in breast cancer cells. This signalling increased the expression of EMT markers (fibronectin, N-cadherin, and vimentin) and promoted tumour cell invasion. Counteracting IL32 activity, a knockdown of IL32 or integrin β3 led to specific inactivation of p38 MAPK signalling in tumour cells. Blockage of the p38 MAPK pathway also diminished IL32-induced expression of EMT markers and breast cancer cell invasion and metastasis. Thus, our data indicate that CAF-secreted IL32 promotes breast cancer cell invasion and metastasis via integrin β3–p38 MAPK signalling.
•Cancer associated fibroblasts (CAF) secreted Interleukin 32 (IL32) promotes breast cancer cells invasion and metastasis.•IL32 binds to integrin β3 at the cancer cell membrane through the RGD motif.•IL32-integrin β3 interaction activates P38 MAPK signalling to enhance the EMT markers expression to promote tumour invasion.
Immunocorrelates of CAF family adjuvants Pedersen, Gabriel Kristian; Andersen, Peter; Christensen, Dennis
Seminars in immunology,
October 2018, 2018-10-00, 20181001, Letnik:
39
Journal Article
Recenzirano
Odprti dostop
The development of the CAF family adjuvant was initiated around 20 years ago when Statens Serum Institut was preparing its first generation protein based recombinant subunit vaccine against ...tuberculosis for clinical testing, but realized that there were no clinically relevant adjuvants available that would support the strong CMI response needed. Since then the aim for the adjuvant research at Statens Serum Institut has been to provide adjuvants with distinct immunogenicity profiles correlating with protection for any given infectious disease. Two of the adjuvants CAF01 and CAF09 are currently being evaluated in human clinical trials. The purpose of this review is to give an overview of the immunocorrelates of those CAF adjuvants furthest in development. We further aim at giving an overview of the mechanism of action of the CAF adjuvants.
The Themoluminescence (TL) response of CaF2:Dy (TLD-200) as a function of irradiation temperature was studied in the present work. The irradiation of a TL material at elevated temperatures has a ...twofold scope: (a) To provide knowledge and insight regarding the possibilities of radiation dosimetry at high temperature environments; (b) The fact that during irradiation at elevated temperatures trap filling and trap emptying take place simultaneously, makes this pre-conditioning the most promising for the reflection in the net glow-curve of competition effects between traps and centres. The irradiation temperature (Tirr) region was between room temperature (RT) and 270 °C in steps of 10 °C. Using the same conditions as far as dose and temperature are concerned, post irradiation annealing (PIA) measurements were also performed, which give only the results of trap emptying. Both experiments were performed using (a) one sample for all measurements (single-aliquot procedure) and (b) two samples for each temperature (multi-aliquot procedure). Deconvolution was also applied in all cases towards investigating the impact of the two protocols on the kinetic parameters of all peaks for this specific material. The results showed that there is not any dependence of the TL response in the case of multi-aliquot procedure. However, in the case of single-aliquot procedure, a very interesting dependence of the TL response on Tirr is observed only for the last TL peak of TLD-200. These results, although weaker, were also observed in the case of PIA procedure. Activation energies of the high-temperature, more stable peaks yield a dependence on both irradiation and PIA temperatures. The results are discussed in the framework of the trap competition models.
•The dependence of TL response and glow curve shape of TLD-200 on the temperature during irradiation was studied.•Irradiation temperature effects do not appear at all when different samples are used for each irradiation temperature.•No irradiation temperature effect appears on TL glow peaks 1–5 when only one sample is used for all irradiation temperatures.•Response of dosimetric peak 6 depends strongly on both irradiation temperature and post irradiation annealing temperature.
The presence of functionally efficient cytotoxic T lymphocytes (CTL) in the Tumour nest is crucial in mediating a successful immune response to cancer. The detection and elimination of cancer cells ...by CTL can be impaired by cancer-mediated immune evasion. In recent years, it has become increasingly clear that not only neoplastic cells themselves, but also cells of the tumour microenvironment (TME) exert immunosuppressive functions and thereby play an integral part in the immune escape of cancer. The most abundant stromal cells of the TME, cancer associated fibroblasts (CAFs), promote tumour progression
multiple pathways and play a role in dampening the immune response to cancer. Recent research indicates that T cells react to CAF signalling and establish bidirectional crosstalk that plays a significant role in the tumour immune response. This review discusses the various mechanisms by which the CAF/T cell crosstalk may impede anti-cancer immunity.
As one of the most abundant constituents of the tumour microenvironment (TME), cancer-associated fibroblasts (CAF) display critical roles during tumour progression and metastasis. Multiple classes of ...molecules including growth factors, cytokines, proteases and extracellular matrix proteins, are produced by CAF to act as mediators of the stroma-tumour interactions. One of the main channels for this communication is associated with extracellular vesicles (EV), which are secreted particles loaded with protein and genetic information. In this study, we evaluated the effects of EV derived from CAF primary human cell lines (n = 5) on proliferation, survival, migration, and invasion of oral squamous cell carcinoma (OSCC) cells. As controls, EV from human primary-established normal oral fibroblasts (NOF, n = 5) were used. Our in vitro assays showed that CAF-EV significantly induces migration and invasion of OSCC cells and promote a disseminated pattern of HSC-3 cell invasion in the 3D organotypic assay. Furthermore, gene expression analysis of EV-treated cancer cells revealed changes in the pathways associated with tumour metabolism and up-regulation of tumour invasion genes. Our findings suggest a significant role of CAF-EV in promoting the migration and invasion of OSCC cells, which are related to the activation of cancer-related pathways.
Fluorite single crystals, CaF2 are multifunctional crystals that have potential applications in environmental, thermo-luminescent and accidental dosimetry. A comprehensive investigation of the ...co-located naturally occurring colourless and coloured (yellow, sea-green, purple, blue, black) fluorites (CaF2) doped with bivalent and multivalent cations was carried out for the cationic and anionic sub-lattice defects generated due to natural irradiation from associated actinide containing pyrochlore grains. Detailed spectroscopic analyses have been used to map the various cationic and anionic defect structures such as O3− and O2--Vacancy type defect complexes in yellow fluorites, F-centres and irradiation induced metallic Ca in purple, blue and black fluorites. The confinement of the radiation damage only to the anionic sub-lattice was explained in terms of higher displacement cross-section for F (59 b) as compared to Ca (33 b) as well as lower energy requirement to create F displacements and vacancies. It is observed that the fluorite retained its phase stability under natural radiation exposure and elemental substitutions.
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•Description of the colour variations in the co-located natural fluorite crystals in terms of cationic and anionic sub-lattice defects.•Role of radiation induced metallic calcium colloids on the observed colour variation in the fluorites is explained.•Radiation damage is confined to anionic sub-lattice only owing to higher displacement cross section for F− as compared to Ca2+.•Stable anionic defects in fluorites without radiation exposure are identified.
Calcifying aponeurotic fibromas (CAFs) are rare benign tumors that typically develop in the soft tissue of the extremities. We report a case of 64-year-old woman with a CAF in the soft tissue ...surrounding her left clavicle. A plain radiograph showed an asymmetrical increase in opacity of the left internal clavicular region. Computed tomography and magnetic resonance imaging confirmed the presence of a heterogeneous lesion of the periclavicular soft tissue, with peripheral calcifications, and remodeling of the adjacent clavicular bone. Following ultrasound-guided biopsy and surgical resection of the mass, the final histological diagnosis was made. To the best of our knowledge, this is the first case of a CAF described in the soft tissue adjacent to the clavicle. It is essential to use all the diagnostic methods available (X-ray, ultrasound, CT, MRI, and percutaneous biopsy) to obtain the final diagnosis of this rare disease.
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