Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology

Cancer-associated fibroblasts (CAF) are the most abundant cells of the tumor stroma and they critically influence cancer growth through control of the surrounding tumor microenvironment (TME). CAF-orchestrated reactive stroma, composed of pro-tumorigenic cytokines and growth factors, matrix components, neovessels, and deregulated immune cells, is associated with poor prognosis in multiple carcinomas, including breast cancer. Therefore, beyond cancer cells killing, researchers are currently focusing on TME as strategy to fight breast cancer. In recent years, nanomedicine has provided a number of smart delivery systems based on active targeting of breast CAF and immune-mediated overcome of chemoresistance. Many efforts have been made both to eradicate breast CAF and to reshape their identity and function. Nano-strategies for CAF targeting profoundly contribute to enhance chemosensitivity of breast tumors, enabling access of cytotoxic T-cells and reducing immunosuppressive signals. TME rearrangement also includes reorganization of the extracellular matrix to enhance permeability to chemotherapeutics, and nano-systems for smart coupling of chemo- and immune-therapy, by increasing immunogenicity and stimulating antitumor immunity. The present paper reviews the current state-of-the-art on nano-strategies to target breast CAF and TME. Finally, we consider and discuss future translational perspectives of proposed nano-strategies for clinical application in breast cancer.

Download Full-text

Cancer-Associated Fibroblasts in Pancreatic Cancer: Should They Be Deleted or Reeducated?

Integrative Cancer Therapies ◽

10.1177/1534735418794884 ◽

2018 ◽

Vol 17 (4) ◽

pp. 1016-1019 ◽

Cited By ~ 14

Author(s):

Chao Qu ◽

Qing Wang ◽

Zhiqiang Meng ◽

Peng Wang

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Cancer Biology ◽

Tumor Stroma ◽

Ductal Adenocarcinoma ◽

Migration And Invasion ◽

Therapeutic Effects ◽

Cancer Associated Fibroblasts

Pancreatic ductal adenocarcinoma is characterized by an extensive stromal response called desmoplasia. Within the tumor stroma, cancer-associated fibroblasts (CAFs) are the primary cell type. CAFs have been shown to play a role in pancreatic cancer progression; they secrete growth factors, inflammatory cytokines, and chemokines that stimulate signaling pathways in cancer cells and modulate the cancer biology toward increased aggressiveness. Therefore, targeting CAFs may serve as a powerful weapon against pancreatic cancer and improve therapeutic effects. However, a previous study aiming to deplete CAFs by inhibiting sonic Hedgehog signaling failed to show any benefit in survival time of pancreatic cancer patients. We reported that the natural product curcumin reeducated CAFs in pancreatic cancer treatment. A low concentration of curcumin reversed the activation of fibroblasts without exhibiting growth suppression effects. In addition, curcumin suppressed CAF-induced pancreatic cancer cell migration and invasion in vitro and lung metastasis in vivo. The results of our study suggest that active CAFs can be inactivated by certain natural products such as curcumin. Reeducation of CAFs back to their normal state, rather than their indiscriminate depletion, may broaden our view in the development of therapeutic options for the treatment of pancreatic cancer.

Download Full-text

Altered Calcium Influx Pathways in Cancer-Associated Fibroblasts

Biomedicines ◽

10.3390/biomedicines9060680 ◽

2021 ◽

Vol 9 (6) ◽

pp. 680

Author(s):

Francisco Sadras ◽

Teneale A. Stewart ◽

Mélanie Robitaille ◽

Amelia A. Peters ◽

Priyakshi Kalita-de Croft ◽

...

Keyword(s):

Transforming Growth Factor Beta ◽

Cancer Biology ◽

Transforming Growth Factor ◽

Calcium Influx ◽

Calcium Signalling ◽

Signalling Pathways ◽

Calcium Signal ◽

Cancer Associated Fibroblasts ◽

Functional Changes ◽

Influx Pathways

Cancer-associated fibroblasts (CAFs) represent an important component of the tumour microenvironment and are implicated in disease progression. Two outstanding questions in cancer biology are how CAFs arise and how they might be targeted therapeutically. The calcium signal also has an important role in tumorigenesis. To date, the role of calcium signalling pathways in the induction of the CAF phenotype remains unexplored. A CAF model was generated through exogenous transforming growth factor beta 1 (TGFβ1) stimulation of the normal human mammary fibroblast cell line, HMF3S (HMF3S-CAF), and changes in calcium signalling were investigated. Functional changes in HMF3S-CAF calcium signalling pathways were assessed using a fluorescent indicator, gene expression, gene-silencing and pharmacological approaches. HMF3S-CAF cells demonstrated functionally altered calcium influx pathways with reduced store-operated calcium entry. In support of a calcium signalling switch, two voltage-gated calcium channel (VGCC) family members, CaV1.2 and CaV3.2, were upregulated in HMF3S-CAFs and a subset of patient-derived breast CAFs. Both siRNA-mediated silencing and pharmacological inhibition of CaV1.2 or CaV3.2 significantly impaired CAF activation in HMF3S cells. Our findings show that VGCCs contribute to TGFβ1-mediated induction of HMF3S-CAF cells and both transcriptional interference and pharmacological antagonism of CaV1.2 and CaV3.2 inhibit CAF induction. This suggests a potential therapeutic role for targeting calcium signalling in breast CAFs.

Download Full-text

Importance of the origin of mesenchymal (stem) stromal cells in cancer biology: “alliance” or “war” in intercellular signals

Cell & Bioscience ◽

10.1186/s13578-021-00620-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Noemi Eiro ◽

Maria Fraile ◽

Silvia Fernández-Francos ◽

Rosario Sánchez ◽

Luis A. Costa ◽

...

Keyword(s):

Stem Cells ◽

Stromal Cells ◽

Cancer Biology ◽

Mononuclear Cells ◽

Specific Effect ◽

Cancer Associated Fibroblasts ◽

Intercellular Signaling ◽

Production Safety ◽

Tumor Tissues ◽

New Research

AbstractMesenchymal stem cells (MSCs) play a central role in the intercellular signaling within the tumor microenvironment (TME), exchanging signals with cancer cells and tumor stromal cells, such as cancer-associated fibroblasts and inflammatory mononuclear cells. Research attributes both pro-tumor and anti-tumor actions to MSCs; however, evidence indicates that MSCs specific effect on the tumor depends on the source of the MSCs and the type of tumor. There are consistent data proving that MSCs from reproductive tissues, such as the uterus, umbilical cord or placenta, have potent anti-tumor effects and tropism towards tumor tissues. More interestingly, products derived from MSCs, such as secretome or extracellular vesicles, seem to reproduce the effects of their parental cells, showing a potential advantage for clinical treatments by avoiding the drawbacks associated with cell therapy. Given these perspectives, it appears necessary new research to optimize the production, safety and antitumor potency of the products derived from the MSCs suitable for oncological therapies.

Download Full-text

Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma

Nature Communications ◽

10.1038/s41467-020-18916-5 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 3

Author(s):

Zhaohui Chen ◽

Lijie Zhou ◽

Lilong Liu ◽

Yaxin Hou ◽

Ming Xiong ◽

...

Keyword(s):

Single Cell ◽

Rna Sequencing ◽

Cancer Biology ◽

Cell Types ◽

Cancer Associated Fibroblasts ◽

Single Cell Rna Sequencing ◽

Substantial Progress ◽

Essential Resource ◽

Immunosuppressive Microenvironment ◽

Public Datasets

AbstractAlthough substantial progress has been made in cancer biology and treatment, clinical outcomes of bladder carcinoma (BC) patients are still not satisfactory. The tumor microenvironment (TME) is a potential target. Here, by single-cell RNA sequencing on 8 BC tumor samples and 3 para tumor samples, we identify 19 different cell types in the BC microenvironment, indicating high intra-tumoral heterogeneity. We find that tumor cells down regulated MHC-II molecules, suggesting that the downregulated immunogenicity of cancer cells may contribute to the formation of an immunosuppressive microenvironment. We also find that monocytes undergo M2 polarization in the tumor region and differentiate. Furthermore, the LAMP3 + DC subgroup may be able to recruit regulatory T cells, potentially taking part in the formation of an immunosuppressive TME. Through correlation analysis using public datasets containing over 3000 BC samples, we identify a role for inflammatory cancer-associated fibroblasts (iCAFs) in tumor progression, which is significantly related to poor prognosis. Additionally, we characterize a regulatory network depending on iCAFs. These results could help elucidate the protumor mechanisms of iCAFs. Our results provide deep insight into cancer immunology and provide an essential resource for drug discovery in the future.

Download Full-text

Cancer-associated fibroblasts as a potential target in oncology therapy

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0013.5379 ◽

2019 ◽

Vol 73 ◽

pp. 536-549

Author(s):

Agnieszka Dominiak ◽

Tomasz Nowicki ◽

Dominika Łacheta ◽

Grażyna Nowicka

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Early Stage ◽

Normal Fibroblast ◽

Cancer Associated Fibroblasts ◽

Complex Environment ◽

Reactive Stroma ◽

Promising Therapeutic Target ◽

Cell Groups ◽

Phenotypic Transition

Tumors make up a complex environment that consists of intensive proliferating cancer cells surrounded by normal cells. Fibroblasts recruited by cancer termed CAFs, are one of the major cell groups within the reactive stroma of the most common tumors. Because of the crosstalk between quiescent fibroblasts and cancer cells, fibroblasts undergo phenotypic transition and acquire new functions that have been “forced by a tumor”. CAFs affect the development of the drug resistance and cancer progression as they are involved in the growth of cancers, neoangiogenesis, immune evasion and metastatic colonisation in distant organs. Fibroblast-directed therapy offers the opportunity to prevent initiation, progression and metastasis of many invasive tumors. The current studies on CAF-based therapy focus on two strategies. The first strategy leads to the elimination of CAFs and the neutralization of their released factors and the second aims at reverting the CAF-phenotype to a “normal” fibroblast-phenotype. Although the results of preclinical studies conducted on cell cultures and animal models indicate that therapy aimed at reversion or inhibition CAFs function seem to be a promising therapeutic target, available clinical studies have not yet confirmed this. Nevertheless, it is necessary to underline that until now CAF-based therapy has been used in patients with advanced cancer and there is no clinical study using such therapy in the early stage of cancer. The available data also indicates that CAF-based therapy could be used in combination with common anticancer drugs to increase their effectiveness. Therefore, further studies on the usefulness of the proposed CAF-based therapy are needed.

Download Full-text

Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers

Cells ◽

10.3390/cells9092027 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2027

Author(s):

Leonard Kaps ◽

Detlef Schuppan

Keyword(s):

Growth Factor ◽

Cancer Biology ◽

Cyclic Peptide ◽

Smooth Muscle Actin ◽

Growth Factor Receptor ◽

Surface Proteins ◽

Cancer Associated Fibroblasts ◽

Phosphate Binding ◽

Desmoplastic Reaction

Cancer associated fibroblasts (CAF) and the extracellular matrix (ECM) produced by them have been recognized as key players in cancer biology and emerged as important targets for cancer treatment and drug discovery. Apart from their presence in stroma rich tumors, such as biliary, pancreatic and subtypes of hepatocellular cancer (HCC), both CAF and certain ECM components are also present in cancers without an overt intra-tumoral desmoplastic reaction. They support cancer development, growth, metastasis and resistance to chemo- or checkpoint inhibitor therapy by a multitude of mechanisms, including angiogenesis, ECM remodeling and active immunosuppression by secretion of tumor promoting and immune suppressive cytokines, chemokines and growth factors. CAF resemble activated hepatic stellate cells (HSC)/myofibroblasts, expressing α-smooth muscle actin and especially fibroblast activation protein (FAP). Apart from FAP, CAF also upregulate other functional cell surface proteins like platelet-derived growth factor receptor β (PDGFRβ) or the insulin-like growth factor receptor II (IGFRII). Notably, if formulated with adequate size and zeta potential, injected nanoparticles home preferentially to the liver. Several nanoparticular formulations were tested successfully to deliver dugs to activated HSC/myofibroblasts. Thus, surface modified nanocarriers with a cyclic peptide binding to the PDGFRβ or with mannose-6-phosphate binding to the IGFRII, effectively directed drug delivery to activated HSC/CAF in vivo. Even unguided nanohydrogel particles and lipoplexes loaded with siRNA demonstrated a high in vivo uptake and functional siRNA delivery in activated HSC, indicating that liver CAF/HSC are also addressed specifically by well-devised nanocarriers with optimized physicochemical properties. Therefore, CAF have become an attractive target for the development of stroma-based cancer therapies, especially in the liver.

Download Full-text

Functional information from magnetic resonance imaging

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100136799 ◽

1995 ◽

Vol 53 ◽

pp. 84-85

Author(s):

Alan P. Koretsky ◽

Afonso Costa e Silva ◽

Yi-Jen Lin

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

High Resolution ◽

Cancer Biology ◽

Imaging Modality ◽

Magnetic Resonance Images ◽

Great Success ◽

Functional Information ◽

Resonance Imaging ◽

High Resolution Mri

Magnetic resonance imaging (MRI) has become established as an important imaging modality for the clinical management of disease. This is primarily due to the great tissue contrast inherent in magnetic resonance images of normal and diseased organs. Due to the wide availability of high field magnets and the ability to generate large and rapidly switched magnetic field gradients there is growing interest in applying high resolution MRI to obtain microscopic information. This symposium on MRI microscopy highlights new developments that are leading to increased resolution. The application of high resolution MRI to significant problems in developmental biology and cancer biology will illustrate the potential of these techniques.In combination with a growing interest in obtaining high resolution MRI there is also a growing interest in obtaining functional information from MRI. The great success of MRI in clinical applications is due to the inherent contrast obtained from different tissues leading to anatomical information.

Download Full-text