|
1
|
Jain SM, Nagainallur Ravichandran S, Murali Kumar M, Banerjee A, Sun-Zhang A, Zhang H, Pathak R, Sun XF, Pathak S. Understanding the molecular mechanism responsible for developing therapeutic radiation-induced radioresistance of rectal cancer and improving the clinical outcomes of radiotherapy - A review. Cancer Biol Ther 2024; 25:2317999. [PMID: 38445632 PMCID: PMC10936619 DOI: 10.1080/15384047.2024.2317999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 02/08/2024] [Indexed: 03/07/2024] Open
Abstract
Rectal cancer accounts for the second highest cancer-related mortality, which is predominant in Western civilizations. The treatment for rectal cancers includes surgery, radiotherapy, chemotherapy, and immunotherapy. Radiotherapy, specifically external beam radiation therapy, is the most common way to treat rectal cancer because radiation not only limits cancer progression but also significantly reduces the risk of local recurrence. However, therapeutic radiation-induced radioresistance to rectal cancer cells and toxicity to normal tissues are major drawbacks. Therefore, understanding the mechanistic basis of developing radioresistance during and after radiation therapy would provide crucial insight to improve clinical outcomes of radiation therapy for rectal cancer patients. Studies by various groups have shown that radiotherapy-mediated changes in the tumor microenvironment play a crucial role in developing radioresistance. Therapeutic radiation-induced hypoxia and functional alterations in the stromal cells, specifically tumor-associated macrophage (TAM) and cancer-associated fibroblasts (CAF), play a crucial role in developing radioresistance. In addition, signaling pathways, such as - the PI3K/AKT pathway, Wnt/β-catenin signaling, and the hippo pathway, modulate the radiation responsiveness of cancer cells. Different radiosensitizers, such as small molecules, microRNA, nanomaterials, and natural and chemical sensitizers, are being used to increase the effectiveness of radiotherapy. This review highlights the mechanism responsible for developing radioresistance of rectal cancer following radiotherapy and potential strategies to enhance the effectiveness of radiotherapy for better management of rectal cancer.
Collapse
Affiliation(s)
- Samatha M Jain
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, India
| | - Shruthi Nagainallur Ravichandran
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, India
| | - Makalakshmi Murali Kumar
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, India
| | - Antara Banerjee
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, India
| | - Alexander Sun-Zhang
- Department of Oncology-Pathology, BioClinicum, Karolinska Institutet, Stockholm, Sweden
| | - Hong Zhang
- School of Medicine, Department of Medical Sciences, Orebro University, Örebro, Sweden
| | - Rupak Pathak
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Xiao-Feng Sun
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, India
| |
Collapse
|
|
2
|
Chen X, Zhou Z, Yazgan Z, Xie L, Rossi F, Liu Y, Zhang B, Polanco PM, Zeh HJ, Kim AC, Huang H. Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.15.623232. [PMID: 39605724 PMCID: PMC11601292 DOI: 10.1101/2024.11.15.623232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Recent studies have identified a unique subtype of cancer-associated fibroblasts (CAFs) termed antigen-presenting CAFs (apCAFs), which remain the least understood CAF subtype. To gain a comprehensive understanding of the origin and function apCAFs, we construct a fibroblast molecular atlas across 14 types of solid tumors. Our integration study unexpectedly reveals two distinct apCAF lineages present in most cancer types: one associated with mesothelial-like cells and the other with fibrocytes. Using a high-resolution single-cell spatial imaging platform, we characterize the spatial niches of these apCAF lineages. We find that mesothelial-like apCAFs are located near cancer cells, while fibrocyte-like apCAFs are associated with tertiary lymphoid structures. Additionally, we discover that both apCAF lineages can up-regulate the secreted protein SPP1, which facilitates primary tumor formation and peritoneal metastasis. Taken together, this study offers an unprecedented resolution in analyzing apCAF lineages and their spatial niches.
Collapse
|
|
3
|
Panda SK, Robinson N, Desiderio V. Decoding secret role of mesenchymal stem cells in regulating cancer stem cells and drug resistance. Biochim Biophys Acta Rev Cancer 2024; 1879:189205. [PMID: 39481663 DOI: 10.1016/j.bbcan.2024.189205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/23/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024]
Abstract
Drug resistance caused by the efflux of chemotherapeutic drugs is one of the most challenging obstacles to successful cancer therapy. Several efflux transporters have been identified since the discovery of the P-gp/ABCB1 transporter in 1976. Over the last four decades, researchers have focused on developing efflux transporter inhibitors to overcome drug resistance. However, even with the third-generation inhibitors available, we are still far from effectively inhibiting the efflux transporters. Additionally, Cancer stem cells (CSCs) pose another significant challenge, contributing to cancer recurrence even after successful treatment. The ability of CSCs to enter dormancy and evade detection makes them almost invulnerable to chemotherapeutic drug treatment. In this review, we discuss how Mesenchymal stem cells (MSCs), one of the key components of the Tumor Microenvironment (TME), regulate both the CSCs and efflux transporters. We propose a new approach focusing on MSCs, which can be crucial to successfully address CSCs and efflux transporters.
Collapse
Affiliation(s)
- Sameer Kumar Panda
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy; Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5001, Australia
| | - Nirmal Robinson
- Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5001, Australia
| | - Vincenzo Desiderio
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
| |
Collapse
|
|
4
|
Takei J, Maeda M, Fukasawa N, Kawashima M, Miyake M, Tomoto K, Nawate S, Teshigawara A, Suzuki T, Yamamoto Y, Nagashima H, Mori R, Fukushima R, Matsushima S, Kino H, Muroi A, Tsurubuchi T, Sakamoto N, Nishiwaki K, Yano S, Hasegawa Y, Murayama Y, Akasaki Y, Shimoda M, Ishikawa E, Tanaka T. Comparative analyses of immune cells and alpha-smooth muscle actin-positive cells under the immunological microenvironment between with and without dense fibrosis in primary central nervous system lymphoma. Brain Tumor Pathol 2024; 41:97-108. [PMID: 39186169 PMCID: PMC11499374 DOI: 10.1007/s10014-024-00488-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 08/05/2024] [Indexed: 08/27/2024]
Abstract
Histopathologic examinations of primary central nervous system lymphoma (PCNSL) reveal concentric accumulation of lymphocytes in the perivascular area with fibrosis. However, the nature of this fibrosis in "stiff" PCNSL remains unclear. We have encountered some PCNSLs with hard masses as surgical findings. This study investigated the dense fibrous status and tumor microenvironment of PCNSLs with or without stiffness. We evaluated by silver-impregnation nine PCNSLs with stiffness and 26 PCNSLs without stiffness. Six of the nine stiff PCNSLs showed pathological features of prominent fibrosis characterized by aggregation of reticulin fibers, and collagen accumulations. Alpha-smooth muscle actin (αSMA)-positive spindle cells as a cancer-associated fibroblast, the populations of T lymphocytes, and macrophages were compared between fibrous and control PCNSLs. Fibrous PCNSLs included abundant αSMA-positive cells in both intra- and extra-tumor environments (5/6, 87% and 3/6, 50%, respectively). Conversely, only one out of the seven control PCNSL contained αSMA-positive cells in the intra-tumoral area. Furthermore, the presence of extra-tumoral αSMA-positive cells was associated with infiltration of T lymphocytes and macrophages. In conclusion, recognizing the presence of dense fibrosis in PCNSL can provide insights into the tumor microenvironment. These results may help stratify patients with PCNSL and improve immunotherapies for these patients.
Collapse
Affiliation(s)
- Jun Takei
- Department of Neurosurgery, The Jikei University Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo, 125-8506, Japan
- Department of Neurosurgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Miku Maeda
- Department of Pathology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Nei Fukasawa
- Department of Pathology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Masaharu Kawashima
- Division of Clinical Oncology and Hematology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Misayo Miyake
- Department of Pathology, The Jikei University Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567, Japan
| | - Kyoichi Tomoto
- Department of Neurosurgery, The Jikei University Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567, Japan
| | - Shohei Nawate
- Department of Neurosurgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Akihiko Teshigawara
- Department of Neurosurgery, The Jikei University Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567, Japan
| | - Tomoya Suzuki
- Department of Neurosurgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Yohei Yamamoto
- Department of Neurosurgery, The Jikei University Daisan Hospital, 4-11-1 Izumi-honcho, Komae-shi, Tokyo, 201-8601, Japan
| | - Hiroyasu Nagashima
- Department of Neurosurgery, The Jikei University Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo, 125-8506, Japan
| | - Ryosuke Mori
- Department of Neurosurgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Ryoko Fukushima
- Division of Clinical Oncology and Hematology, The Jikei University Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567, Japan
| | - Satoshi Matsushima
- Department of Radiology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Hiroyoshi Kino
- Department of Neurosurgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Ai Muroi
- Department of Neurosurgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Takao Tsurubuchi
- Department of Neurosurgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Noriaki Sakamoto
- Department of Clinical Pathology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Kaichi Nishiwaki
- Division of Clinical Oncology and Hematology, The Jikei University Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567, Japan
| | - Shingo Yano
- Division of Clinical Oncology and Hematology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Yuzuru Hasegawa
- Department of Neurosurgery, The Jikei University Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567, Japan
| | - Yuichi Murayama
- Department of Neurosurgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Yasuharu Akasaki
- Department of Neurosurgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Masayuki Shimoda
- Department of Pathology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Eiichi Ishikawa
- Department of Neurosurgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Toshihide Tanaka
- Department of Neurosurgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan.
- Department of Neurosurgery, The Jikei University Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567, Japan.
| |
Collapse
|
|
5
|
Wu L, Liu Q, Li G, Shi W, Peng W. A cancer-associated fibroblasts related risk score (CAFscore) helps to guide prognosis and personal treatment for Glioblastoma. Discov Oncol 2024; 15:420. [PMID: 39254749 PMCID: PMC11387281 DOI: 10.1007/s12672-024-01314-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 09/04/2024] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND Recent studies have identified the presence of cancer-associated fibroblasts (CAFs) within glioblastoma (GBM), yet their biological roles and underlying mechanisms remain poorly understood. This study aimed to construct a CAF-related prognostic model to guide patient prognosis and treatment strategies. METHOD We employed various bioinformatics methods, including enrichment analysis, Weighted Gene Co-expression Network Analysis (WGCNA), Lasso regression analysis, and machine learning techniques such as XGBoost and Random Forest, to develop a novel risk index termed CAFscore. Patients were stratified into high and low CAFscore groups for subsequent survival analysis. The area under the curve (AUC) and concordance index (C-index) for CAFscore were calculated and compared against other clinical characteristics and existing prognostic models. Drug sensitivity assessments were conducted using the Oncopredict package. Functional validation of key genes was performed through scratch and invasion assays in GBM cells. RESULTS Our analyses revealed four core CAF-related genes, leading to the establishment of CAFscore. Notably, patients in the high CAFscore group exhibited significantly reduced survival and exhibited enrichment in epithelial-mesenchymal transition (EMT) and inflammation response pathways. Furthermore, CAFscore showed a significant negative correlation with the sensitivity to irinotecan and its analogs, while demonstrating a positive correlation with sensitivity to 505,124 (a TGFβRI inhibitor). LRP10 emerged as a central gene within the CAFscore, displaying markedly elevated expression in GBM and a strong association with CAF infiltration. Silencing LRP10 significantly inhibited the invasive capabilities of GBM cells. CONCLUSION This study presented the first CAF related prognostic model (CAFscore) in GBM, and demonstrated that the model could effectively guide patient prognosis and potentially inform personalized treatment strategies. The core gene of CAFscore, LRP10, was significantly overexpressed in GBM and might play a pivotal role in regulating CAF infiltration as well as tumor invasion and metastasis, highlighting LRP10 as a promising therapeutic target for GBM management.
Collapse
Affiliation(s)
- Lili Wu
- Department of Encephalopathy, Zhoukou Hospital of Traditional Chinese Medicine, Zhoukou, 466099, China
| | - Qinjian Liu
- Medical Affairs Section, Zhoukou Hospital of Traditional Chinese Medicine, Zhoukou, 466099, China
| | - Guoyin Li
- Department of Encephalopathy, Zhoukou Hospital of Traditional Chinese Medicine, Zhoukou, 466099, China
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466000, China
| | - Weidong Shi
- Department of Orthopedics, Zhoukou Hospital of Traditional Chinese Medicine, Zhoukou, 466099, China.
| | - Weifeng Peng
- Department of Encephalopathy, Zhoukou Hospital of Traditional Chinese Medicine, Zhoukou, 466099, China.
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466000, China.
| |
Collapse
|
|
6
|
Ramos C, Gerakopoulos V, Oehler R. Metastasis-associated fibroblasts in peritoneal surface malignancies. Br J Cancer 2024; 131:407-419. [PMID: 38783165 PMCID: PMC11300623 DOI: 10.1038/s41416-024-02717-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/06/2024] [Accepted: 05/09/2024] [Indexed: 05/25/2024] Open
Abstract
Over decades, peritoneal surface malignancies (PSMs) have been associated with limited treatment options and poor prognosis. However, advancements in perioperative systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) have significantly improved clinical outcomes. PSMs predominantly result from the spread of intra-abdominal neoplasia, which then form secondary peritoneal metastases. Colorectal, ovarian, and gastric cancers are the most common contributors. Despite diverse primary origins, the uniqueness of the peritoneum microenvironment shapes the common features of PSMs. Peritoneal metastization involves complex interactions between tumour cells and the peritoneal microenvironment. Fibroblasts play a crucial role, contributing to tumour development, progression, and therapy resistance. Peritoneal metastasis-associated fibroblasts (MAFs) in PSMs exhibit high heterogeneity. Single-cell RNA sequencing technology has revealed that immune-regulatory cancer-associated fibroblasts (iCAFs) seem to be the most prevalent subtype in PSMs. In addition, other major subtypes as myofibroblastic CAFs (myCAFs) and matrix CAFs (mCAFs) were frequently observed across PSMs studies. Peritoneal MAFs are suggested to originate from mesothelial cells, submesothelial fibroblasts, pericytes, endothelial cells, and omental-resident cells. This plasticity and heterogeneity of CAFs contribute to the complex microenvironment in PSMs, impacting treatment responses. Understanding these interactions is crucial for developing targeted and local therapies to improve PSMs patient outcomes.
Collapse
Affiliation(s)
- Cristiano Ramos
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Vasileios Gerakopoulos
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Rudolf Oehler
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
7
|
Zhang Y, Wang C, Li JJ. Revisiting the role of mesenchymal stromal cells in cancer initiation, metastasis and immunosuppression. Exp Hematol Oncol 2024; 13:64. [PMID: 38951845 PMCID: PMC11218091 DOI: 10.1186/s40164-024-00532-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 06/26/2024] [Indexed: 07/03/2024] Open
Abstract
Immune checkpoint blockade (ICB) necessitates a thorough understanding of intricate cellular interactions within the tumor microenvironment (TME). Mesenchymal stromal cells (MSCs) play a pivotal role in cancer generation, progression, and immunosuppressive tumor microenvironment. Within the TME, MSCs encompass both resident and circulating counterparts that dynamically communicate and actively participate in TME immunosurveillance and response to ICB. This review aims to reevaluate various facets of MSCs, including their potential self-transformation to function as cancer-initiating cells and contributions to the creation of a conducive environment for tumor proliferation and metastasis. Additionally, we explore the immune regulatory functions of tumor-associated MSCs (TA-MSCs) and MSC-derived extracellular vesicles (MSC-EVs) with analysis of potential connections between circulating and tissue-resident MSCs. A comprehensive understanding of the dynamics of MSC-immune cell communication and the heterogeneous cargo of tumor-educated versus naïve MSCs may unveil a new MSC-mediated immunosuppressive pathway that can be targeted to enhance cancer control by ICB.
Collapse
Affiliation(s)
- Yanyan Zhang
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Radiation Oncology, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Charles Wang
- Department of Radiation Oncology, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Jian Jian Li
- Department of Radiation Oncology, School of Medicine, University of California Davis, Sacramento, CA, USA.
- NCI-Designated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, 95817, USA.
| |
Collapse
|
|
8
|
Turano E, Scambi I, Bonafede R, Dusi S, Angelini G, Lopez N, Marostica G, Rossi B, Furlan R, Constantin G, Mariotti R, Bonetti B. Extracellular vesicles from adipose mesenchymal stem cells target inflamed lymph nodes in experimental autoimmune encephalomyelitis. Cytotherapy 2024; 26:276-285. [PMID: 38231166 DOI: 10.1016/j.jcyt.2023.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 11/29/2023] [Accepted: 12/26/2023] [Indexed: 01/18/2024]
Abstract
BACKGROUND AIMS Adipose mesenchymal stem cells (ASCs) represent a promising therapeutic approach in inflammatory neurological disorders, including multiple sclerosis (MS). Recent lines of evidence indicate that most biological activities of ASCs are mediated by the delivery of soluble factors enclosed in extracellular vesicles (EVs). Indeed, we have previously demonstrated that small EVs derived from ASCs (ASC-EVs) ameliorate experimental autoimmune encephalomyelitis (EAE), a murine model of MS. The precise mechanisms and molecular/cellular target of EVs during EAE are still unknown. METHODS To investigate the homing of ASC-EVs, we intravenously injected small EVs loaded with ultra-small superparamagnetic iron oxide nanoparticles (USPIO) at disease onset in EAE-induced C57Bl/6J mice. Histochemical analysis and transmission electron microscopy were carried out 48 h after EV treatment. Moreover, to assess the cellular target of EVs, flow cytometry on cells extracted ex vivo from EAE mouse lymph nodes was performed. RESULTS Histochemical and ultrastructural analysis showed the presence of labeled EVs in lymph nodes but not in lungs and spinal cord of EAE injected mice. Moreover, we identified the cellular target of EVs in EAE lymph nodes by flow cytometry: ASC-EVs were preferentially located in macrophages, with a consistent amount also noted in dendritic cells and CD4+ T lymphocytes. CONCLUSIONS This represents the first direct evidence of the privileged localization of ASC-EVs in draining lymph nodes of EAE after systemic injection. These data provide prominent information on the distribution, uptake and retention of ASC-EVs, which may help in the development of EV-based therapy in MS.
Collapse
Affiliation(s)
- Ermanna Turano
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Ilaria Scambi
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Roberta Bonafede
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Silvia Dusi
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Gabriele Angelini
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Nicola Lopez
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Giulia Marostica
- Clinical Neuroimmunology Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy
| | - Barbara Rossi
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Roberto Furlan
- Clinical Neuroimmunology Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy
| | - Gabriela Constantin
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Raffaella Mariotti
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Bruno Bonetti
- Neurology Unit, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.
| |
Collapse
|
|
9
|
Lootens T, Roman BI, Stevens CV, De Wever O, Raedt R. Glioblastoma-Associated Mesenchymal Stem/Stromal Cells and Cancer-Associated Fibroblasts: Partners in Crime? Int J Mol Sci 2024; 25:2285. [PMID: 38396962 PMCID: PMC10889514 DOI: 10.3390/ijms25042285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/08/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
Tumor-associated mesenchymal stem/stromal cells (TA-MSCs) have been recognized as attractive therapeutic targets in several cancer types, due to their ability to enhance tumor growth and angiogenesis and their contribution to an immunosuppressive tumor microenvironment (TME). In glioblastoma (GB), mesenchymal stem cells (MSCs) seem to be recruited to the tumor site, where they differentiate into glioblastoma-associated mesenchymal stem/stromal cells (GA-MSCs) under the influence of tumor cells and the TME. GA-MSCs are reported to exert important protumoral functions, such as promoting tumor growth and invasion, increasing angiogenesis, stimulating glioblastoma stem cell (GSC) proliferation and stemness, mediating resistance to therapy and contributing to an immunosuppressive TME. Moreover, they could act as precursor cells for cancer-associated fibroblasts (CAFs), which have recently been identified in GB. In this review, we provide an overview of the different functions exerted by GA-MSCs and CAFs and the current knowledge on the relationship between these cell types. Increasing our understanding of the interactions and signaling pathways in relevant models might contribute to future regimens targeting GA-MSCs and GB-associated CAFs to inhibit tumor growth and render the TME less immunosuppressive.
Collapse
Affiliation(s)
- Thibault Lootens
- 4Brain, Department of Head and Skin, Ghent University, 9000 Ghent, Belgium;
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, 9000 Ghent, Belgium;
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; (B.I.R.); (C.V.S.)
| | - Bart I. Roman
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; (B.I.R.); (C.V.S.)
- SynBioC, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, 9000 Ghent, Belgium
| | - Christian V. Stevens
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; (B.I.R.); (C.V.S.)
- SynBioC, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, 9000 Ghent, Belgium
| | - Olivier De Wever
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, 9000 Ghent, Belgium;
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; (B.I.R.); (C.V.S.)
| | - Robrecht Raedt
- 4Brain, Department of Head and Skin, Ghent University, 9000 Ghent, Belgium;
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; (B.I.R.); (C.V.S.)
| |
Collapse
|
|
10
|
Ambrosini G, Cordani M, Zarrabi A, Alcon-Rodriguez S, Sainz RM, Velasco G, Gonzalez-Menendez P, Dando I. Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies. Cell Commun Signal 2024; 22:36. [PMID: 38216942 PMCID: PMC10790277 DOI: 10.1186/s12964-023-01462-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 12/27/2023] [Indexed: 01/14/2024] Open
Abstract
Prostate cancer, as one of the most prevalent malignancies in males, exhibits an approximate 5-year survival rate of 95% in advanced stages. A myriad of molecular events and mutations, including the accumulation of oncometabolites, underpin the genesis and progression of this cancer type. Despite growing research demonstrating the pivotal role of oncometabolites in supporting various cancers, including prostate cancer, the root causes of their accumulation, especially in the absence of enzymatic mutations, remain elusive. Consequently, identifying a tangible therapeutic target poses a formidable challenge. In this review, we aim to delve deeper into the implications of oncometabolite accumulation in prostate cancer. We center our focus on the consequential epigenetic alterations and impacts on cancer stem cells, with the ultimate goal of outlining novel therapeutic strategies.
Collapse
Affiliation(s)
- Giulia Ambrosini
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University, 28040, Madrid, Spain.
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040, Madrid, Spain.
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering & Natural Sciences, Istinye University, Istanbul, 34396, Turkey
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600 077, India
| | - Sergio Alcon-Rodriguez
- Departamento de Morfología y Biología Celular, School of Medicine, Julián Claveria 6, 33006, Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias (HUCA), 33011, Oviedo, Spain
| | - Rosa M Sainz
- Departamento de Morfología y Biología Celular, School of Medicine, Julián Claveria 6, 33006, Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias (HUCA), 33011, Oviedo, Spain
| | - Guillermo Velasco
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University, 28040, Madrid, Spain
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040, Madrid, Spain
| | - Pedro Gonzalez-Menendez
- Departamento de Morfología y Biología Celular, School of Medicine, Julián Claveria 6, 33006, Oviedo, Spain.
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Spain.
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias (HUCA), 33011, Oviedo, Spain.
| | - Ilaria Dando
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy.
| |
Collapse
|
|
11
|
Liu T, Guo S, Ji Y, Zhu W. Role of cancer-educated mesenchymal stromal cells on tumor progression. Biomed Pharmacother 2023; 166:115405. [PMID: 37660642 DOI: 10.1016/j.biopha.2023.115405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/28/2023] [Accepted: 08/28/2023] [Indexed: 09/05/2023] Open
Abstract
The malignant tumor is the main cause of human deaths worldwide. Current therapies focusing on the tumor itself have achieved unprecedented benefits. Various pro-tumorigenic factors in the tumor microenvironment (TME) could abolish the effect of cancer therapy. Mesenchymal stromal cells (MSCs) are one of the substantial components in the tumor microenvironment, contributing to tumor progression. However, MSCs are not inherently tumor-promoting. Indeed, they acquire pro-tumorigenic properties under the education of the TME. We herein review how various elements in the TME including tumor cells, immune cells, pro-inflammatory factors, hypoxia, and extracellular matrix influence the biological characteristics of MSCs through complex interactions and demonstrate the underlying mechanisms. We also highlight the importance of tumor-associated mesenchymal stromal cells (TA-MSCs) in promoting tumor progression. Our review gives a new insight into the TA-MSCs as a potential tumor therapeutic target. It is anticipated that subverting MSCs education will facilitate the outbreak of therapeutic strategies against tumors.
Collapse
Affiliation(s)
- Ting Liu
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Shuwei Guo
- Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Yong Ji
- Department of Surgery, Jingjiang People's Hospital, Jingjiang 214500, China
| | - Wei Zhu
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China.
| |
Collapse
|
|
12
|
Yang D, Liu J, Qian H, Zhuang Q. Cancer-associated fibroblasts: from basic science to anticancer therapy. Exp Mol Med 2023; 55:1322-1332. [PMID: 37394578 PMCID: PMC10394065 DOI: 10.1038/s12276-023-01013-0] [Citation(s) in RCA: 185] [Impact Index Per Article: 92.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 03/09/2023] [Accepted: 03/15/2023] [Indexed: 07/04/2023] Open
Abstract
Cancer-associated fibroblasts (CAFs), as a central component of the tumor microenvironment in primary and metastatic tumors, profoundly influence the behavior of cancer cells and are involved in cancer progression through extensive interactions with cancer cells and other stromal cells. Furthermore, the innate versatility and plasticity of CAFs allow their education by cancer cells, resulting in dynamic alterations in stromal fibroblast populations in a context-dependent manner, which highlights the importance of precise assessment of CAF phenotypical and functional heterogeneity. In this review, we summarize the proposed origins and heterogeneity of CAFs as well as the molecular mechanisms regulating the diversity of CAF subpopulations. We also discuss current strategies to selectively target tumor-promoting CAFs, providing insights and perspectives for future research and clinical studies involving stromal targeting.
Collapse
Affiliation(s)
- Dakai Yang
- Department of General Practice, Affiliated Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China.
| | - Jing Liu
- Microbiology and Immunity Department, Shanghai, People's Republic of China
- Collaborative Innovation Center for Biomedicines, Shanghai University of Medicine & Health Sciences, Shanghai, People's Republic of China
| | - Hui Qian
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China.
| | - Qin Zhuang
- Department of General Practice, Affiliated Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
| |
Collapse
|
|
13
|
Ai W, Liu T, Lv C, Feng X, Wang Q. Modulation of cancer-associated fibroblasts by nanodelivery system to enhance efficacy of tumor therapy. Nanomedicine (Lond) 2023; 18:1025-1039. [PMID: 37584613 DOI: 10.2217/nnm-2023-0088] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/17/2023] Open
Abstract
Cancer-associated fibroblasts (CAFs) are the most common cells in the tumor stroma and are essential for tumor development and metastasis. While decreasing the release and infiltration of nanomedicine through nonspecific internalization, CAFs specifically increase solid tumor pressure and interstitial fluid pressure by secreting tumor growth- and migration-promoting cytokines, which increases vascular and organ pressure caused by solid tumor pressure. Nanoparticles have good permeability and can penetrate tumor tissue to reach the lesion area, inhibiting tumor growth. Thus, CAFs are used as modifiable targets. Here, the authors review the biological functions, origins and biomarkers of CAFs and summarize strategies for modulating CAFs in nanodelivery systems. This study provides a prospective guide to modulating CAFs to enhance oncology treatment.
Collapse
Affiliation(s)
- Wei Ai
- College of Life Science & Technology, Changchun University of Science & Technology, Changchun, Jilin, 130022, China
| | - Tianhui Liu
- College of Life Science & Technology, Changchun University of Science & Technology, Changchun, Jilin, 130022, China
| | - Changshun Lv
- College of Life Science & Technology, Changchun University of Science & Technology, Changchun, Jilin, 130022, China
| | - Xiangru Feng
- College of Life Science & Technology, Changchun University of Science & Technology, Changchun, Jilin, 130022, China
| | - Qingshuang Wang
- College of Life Science & Technology, Changchun University of Science & Technology, Changchun, Jilin, 130022, China
| |
Collapse
|
|
14
|
Pederzoli F, Raffo M, Pakula H, Ravera F, Nuzzo PV, Loda M. "Stromal cells in prostate cancer pathobiology: friends or foes?". Br J Cancer 2023; 128:930-939. [PMID: 36482187 PMCID: PMC10006214 DOI: 10.1038/s41416-022-02085-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 12/13/2022] Open
Abstract
The genomic, epigenetic and metabolic determinants of prostate cancer pathobiology have been extensively studied in epithelial cancer cells. However, malignant cells constantly interact with the surrounding environment-the so-called tumour microenvironment (TME)-which may influence tumour cells to proliferate and invade or to starve and die. In that regard, stromal cells-including fibroblasts, smooth muscle cells and vasculature-associated cells-constitute an essential fraction of the prostate cancer TME. However, they have been largely overlooked compared to other cell types (i.e. immune cells). Indeed, their importance in prostate physiology starts at organogenesis, as the soon-to-be prostate stroma determines embryonal epithelial cells to commit toward prostatic differentiation. Later in life, the appearance of a reactive stroma is linked to the malignant transformation of epithelial cells and cancer progression. In this Review, we discuss the main mesenchymal cell populations of the prostate stroma, highlighting their dynamic role in the transition of the healthy prostate epithelium to cancer. A thorough understanding of those populations, their phenotypes and their transcriptional programs may improve our understanding of prostate cancer pathobiology and may help to exploit prostate stroma as a biomarker of patient stratification and as a therapeutic target.
Collapse
Affiliation(s)
- Filippo Pederzoli
- Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA.
| | - Massimiliano Raffo
- Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA
- Vita-Salute San Raffaele University, Milan, Italy
| | - Hubert Pakula
- Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA
| | - Francesco Ravera
- Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA
- Department of Internal Medicine, Università Degli Studi di Genova, Genova, Italy
| | - Pier Vitale Nuzzo
- Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA
| | - Massimo Loda
- Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| |
Collapse
|
|
15
|
Jain S, Rick JW, Joshi RS, Beniwal A, Spatz J, Gill S, Chang ACC, Choudhary N, Nguyen AT, Sudhir S, Chalif EJ, Chen JS, Chandra A, Haddad AF, Wadhwa H, Shah SS, Choi S, Hayes JL, Wang L, Yagnik G, Costello JF, Diaz A, Heiland DH, Aghi MK. Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects. J Clin Invest 2023; 133:e147087. [PMID: 36856115 PMCID: PMC9974099 DOI: 10.1172/jci147087] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 01/12/2023] [Indexed: 03/02/2023] Open
Abstract
Cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of glioblastoma specimens yielded cells with CAF morphology and single-cell transcriptomic profiles based on their lack of copy number variations (CNVs) and elevated individual cell CAF probability scores derived from the expression of 9 CAF markers and absence of 5 markers from non-CAF stromal cells sharing features with CAFs. Cells without CNVs and with high CAF probability scores were identified in single-cell RNA-Seq of 12 patient glioblastomas. Pseudotime reconstruction revealed that immature CAFs evolved into subtypes, with mature CAFs expressing actin alpha 2, smooth muscle (ACTA2). Spatial transcriptomics from 16 patient glioblastomas confirmed CAF proximity to mesenchymal glioblastoma stem cells (GSCs), endothelial cells, and M2 macrophages. CAFs were chemotactically attracted to GSCs, and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF and TGF-β as mediators of GSC effects on CAFs and osteopontin and HGF as mediators of CAF-induced GSC enrichment. CAFs induced M2 macrophage polarization by producing the extra domain A (EDA) fibronectin variant that binds macrophage TLR4. Supplementing GSC-derived xenografts with CAFs enhanced in vivo tumor growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target.
Collapse
Affiliation(s)
- Saket Jain
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Jonathan W. Rick
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | | | - Angad Beniwal
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Jordan Spatz
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Sabraj Gill
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | | | - Nikita Choudhary
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Alan T. Nguyen
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Sweta Sudhir
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Eric J. Chalif
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Jia-Shu Chen
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Ankush Chandra
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | | | - Harsh Wadhwa
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Sumedh S. Shah
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Serah Choi
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Josie L. Hayes
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Lin Wang
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | - Garima Yagnik
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | | | - Aaron Diaz
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| | | | - Manish K. Aghi
- Department of Neurosurgery, UCSF, San Francisco, California, USA
| |
Collapse
|
|
16
|
Abstract
The theory that cancer-associated fibroblasts (CAFs) are immunosuppressive cells has prevailed throughout the past decade. However, recent high-throughput, high-resolution mesenchyme-directed single-cell studies have harnessed computational advances to functionally characterize cell states, highlighting the existence of immunostimulatory CAFs. Our group and others have uncovered and experimentally substantiated key functions of cancer antigen-presenting CAFs in T cell immunity, both in vitro and in vivo, refuting the conventional assumption that CAFs impede adaptive immune rejection of tumours. In this Perspective, I unify the follicular and non-follicular, non-endothelial stroma of tumours under the 'peripheral adaptive immune mesenchyme' framework and position subsets of CAFs as direct positive regulators of the adaptive immune system. Building on the understanding of cancer antigen presentation by CAFs and the second touch hypothesis, which postulates that full T cell polarization requires interaction with antigen-presenting cells in the non-lymphoid tissue where the antigen resides, I re-design the 'cancer-immunity cycle' to incorporate intratumoural activation of cancer-specific CD4+ T cells. Lastly, a road map to therapeutic harnessing of immunostimulatory CAF states is proposed.
Collapse
Affiliation(s)
- Maria Tsoumakidou
- Institute of Bioinnovation, Biomedical Sciences Research Center 'Alexander Fleming', Vari, Greece.
| |
Collapse
|
|
17
|
Barrera LN, Ridley PM, Bermejo-Rodriguez C, Costello E, Perez-Mancera PA. The role of microRNAs in the modulation of cancer-associated fibroblasts activity during pancreatic cancer pathogenesis. J Physiol Biochem 2023; 79:193-204. [PMID: 35767180 PMCID: PMC9905185 DOI: 10.1007/s13105-022-00899-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 05/17/2022] [Indexed: 02/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the deadliest of the common cancers. A major hallmark of PDAC is an abundant and dense fibrotic stroma, the result of a disproportionate deposition of extracellular matrix (ECM) proteins. Cancer-associated fibroblasts (CAFs) are the main mediators of PDAC desmoplasia. CAFs represent a heterogenous group of activated fibroblasts with different origins and activation mechanisms. microRNAs (miRNAs) are small non-coding RNAs with critical activity during tumour development and resistance to chemotherapy. Increasing evidence has revealed that miRNAs play a relevant role in the differentiation of normal fibroblasts into CAFs in PDAC. In this review, we discuss recent findings on the role of miRNAs in the activation of CAFs during the progression of PDAC and its response to therapy, as well as the potential role that PDAC-derived exosomal miRNAs may play in the activation of hepatic stellate cells (HSCs) and formation of liver metastasis. Since targeting of CAF activation may be a viable strategy for PDAC therapy, and miRNAs have emerged as potential therapeutic targets, understanding the biology underpinning miRNA-mediated tumour cell-CAF interactions is an important component in guiding rational approaches to treating this deadly disease.
Collapse
Affiliation(s)
- Lawrence N Barrera
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
- Department of Molecular Cell Biology, School of Medicine, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Preston, PR1 1JQ, UK
| | - P Matthew Ridley
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | | | - Eithne Costello
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
| | - Pedro A Perez-Mancera
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
| |
Collapse
|
|
18
|
Owen JS, Clayton A, Pearson HB. Cancer-Associated Fibroblast Heterogeneity, Activation and Function: Implications for Prostate Cancer. Biomolecules 2022; 13:67. [PMID: 36671452 PMCID: PMC9856041 DOI: 10.3390/biom13010067] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/19/2022] [Accepted: 12/27/2022] [Indexed: 01/01/2023] Open
Abstract
The continuous remodeling of the tumor microenvironment (TME) during prostate tumorigenesis is emerging as a critical event that facilitates cancer growth, progression and drug-resistance. Recent advances have identified extensive communication networks that enable tumor-stroma cross-talk, and emphasized the functional importance of diverse, heterogeneous stromal fibroblast populations during malignant growth. Cancer-associated fibroblasts (CAFs) are a vital component of the TME, which mediate key oncogenic events including angiogenesis, immunosuppression, metastatic progression and therapeutic resistance, thus presenting an attractive therapeutic target. Nevertheless, how fibroblast heterogeneity, recruitment, cell-of-origin and differential functions contribute to prostate cancer remains to be fully delineated. Developing our molecular understanding of these processes is fundamental to developing new therapies and biomarkers that can ultimately improve clinical outcomes. In this review, we explore the current challenges surrounding fibroblast identification, discuss new mechanistic insights into fibroblast functions during normal prostate tissue homeostasis and tumorigenesis, and illustrate the diverse nature of fibroblast recruitment and CAF generation. We also highlight the promise of CAF-targeted therapies for the treatment of prostate cancer.
Collapse
Affiliation(s)
- Jasmine S. Owen
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff CF24 4HQ, UK
| | - Aled Clayton
- Tissue Microenvironment Group, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - Helen B. Pearson
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff CF24 4HQ, UK
| |
Collapse
|
|
19
|
San Martin R, Das P, Sanders JT, Hill AM, McCord RP. Transcriptional profiling of Hutchinson-Gilford Progeria syndrome fibroblasts reveals deficits in mesenchymal stem cell commitment to differentiation related to early events in endochondral ossification. eLife 2022; 11:e81290. [PMID: 36579892 PMCID: PMC9833827 DOI: 10.7554/elife.81290] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 12/29/2022] [Indexed: 12/30/2022] Open
Abstract
The expression of a mutant Lamin A, progerin, in Hutchinson-Gilford Progeria Syndrome leads to alterations in genome architecture, nuclear morphology, epigenetic states, and altered phenotypes in all cells of the mesenchymal lineage. Here, we report a comprehensive analysis of the transcriptional status of patient derived HGPS fibroblasts, including nine cell lines not previously reported, in comparison with age-matched controls, adults, and old adults. We find that Progeria fibroblasts carry abnormal transcriptional signatures, centering around several functional hubs: DNA maintenance and epigenetics, bone development and homeostasis, blood vessel maturation and development, fat deposition and lipid management, and processes related to muscle growth. Stratification of patients by age revealed misregulated expression of genes related to endochondral ossification and chondrogenic commitment in children aged 4-7 years old, where this differentiation program starts in earnest. Hi-C measurements on patient fibroblasts show weakening of genome compartmentalization strength but increases in TAD strength. While the majority of gene misregulation occurs in regions which do not change spatial chromosome organization, some expression changes in key mesenchymal lineage genes coincide with lamin associated domain misregulation and shifts in genome compartmentalization.
Collapse
Affiliation(s)
- Rebeca San Martin
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee at KnoxvilleKnoxvilleUnited States
| | - Priyojit Das
- UT-ORNL Graduate School of Genome Science and Technology, University of Tennessee at KnoxvilleKnoxvilleUnited States
| | - Jacob T Sanders
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee at KnoxvilleKnoxvilleUnited States
- Department of Pathology, University of Texas Southwestern Medical CenterDallasUnited States
| | - Ashtyn M Hill
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee at KnoxvilleKnoxvilleUnited States
| | - Rachel Patton McCord
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee at KnoxvilleKnoxvilleUnited States
| |
Collapse
|
|
20
|
Zarubova J, Hasani-Sadrabadi MM, Norris SCP, Majedi FS, Xiao C, Kasko AM, Li S. Cell-Taxi: Mesenchymal Cells Carry and Transport Clusters of Cancer Cells. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2203515. [PMID: 36307906 PMCID: PMC9772300 DOI: 10.1002/smll.202203515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 09/09/2022] [Indexed: 06/16/2023]
Abstract
Cell clusters that collectively migrate from primary tumors appear to be far more potent in forming distant metastases than single cancer cells. A better understanding of the collective cell migration phenomenon and the involvement of various cell types during this process is needed. Here, an in vitro platform based on inverted-pyramidal microwells to follow and quantify the collective migration of hundreds of tumor cell clusters at once is developed. These results indicate that mesenchymal stromal cells (MSCs) or cancer-associated fibroblasts (CAFs) in the heterotypic tumor cell clusters may facilitate metastatic dissemination by transporting low-motile cancer cells in a Rac-dependent manner and that extracellular vesicles secreted by mesenchymal cells only play a minor role in this process. Furthermore, in vivo studies show that cancer cell spheroids containing MSCs or CAFs have faster spreading rates. These findings highlight the active role of co-traveling stromal cells in the collective migration of tumor cell clusters and may help in developing better-targeted therapies.
Collapse
Affiliation(s)
- Jana Zarubova
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
- Department of Biomaterials and Tissue Engineering, Institute of Physiology of the Czech Academy of Sciences, Prague, 14220, Czech Republic
| | - Mohammad Mahdi Hasani-Sadrabadi
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
| | - Sam C P Norris
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
| | - Fatemeh Sadat Majedi
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
| | - Crystal Xiao
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
| | - Andrea M Kasko
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
| | - Song Li
- Department of Bioengineering, University of California, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA, 90095-1600, USA
| |
Collapse
|
|
21
|
Mesenchymal/stromal stem cells: necessary factors in tumour progression. Cell Death Discov 2022; 8:333. [PMID: 35869057 PMCID: PMC9307857 DOI: 10.1038/s41420-022-01107-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 06/21/2022] [Accepted: 06/28/2022] [Indexed: 11/08/2022] Open
Abstract
Mesenchymal/stromal stem cells (MSCs) are a crucial component of the tumour microenvironment (TME). They can be recruited from normal tissues into the TME and educated by tumour cells to transform into tumour-associated MSCs, which are oncogenic cells that promote tumour development and progression by impacting or transforming into various kinds of cells, such as immune cells and endothelial cells. Targeting MSCs in the TME is a novel strategy to prevent malignant processes. Exosomes, as communicators, carry various RNAs and proteins and thus link MSCs and the TME, which provides options for improving outcomes and developing targeted treatment.
Collapse
|
|
22
|
Low V, Li Z, Blenis J. Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment. Sci Signal 2022; 15:eabj4220. [DOI: 10.1126/scisignal.abj4220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The role of metabolites exchanged in the tumor microenvironment is largely thought of as fuels to drive the increased biosynthetic and bioenergetic demands of growing tumors. However, this view is shifting as metabolites are increasingly shown to function as signaling molecules that directly regulate oncogenic pathways. Combined with our growing understanding of the essential role of stromal cells, this shift has led to increased interest in how the collective and interconnected metabolome of the tumor microenvironment can drive malignant transformation, epithelial-to-mesenchymal transition, drug resistance, immune evasion, and metastasis. In this review, we discuss how metabolite exchange between tumors and various cell types in the tumor microenvironment—such as fibroblasts, adipocytes, and immune cells—can activate signaling pathways that drive cancer progression.
Collapse
Affiliation(s)
- Vivien Low
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Zhongchi Li
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA
| | - John Blenis
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA
| |
Collapse
|
|
23
|
Thiery J. Modulation of the antitumor immune response by cancer-associated fibroblasts: mechanisms and targeting strategies to hamper their immunosuppressive functions. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:598-629. [PMID: 36338519 PMCID: PMC9630350 DOI: 10.37349/etat.2022.00103] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are highly heterogeneous players that shape the tumor microenvironment and influence tumor progression, metastasis formation, and response to conventional therapies. During the past years, some CAFs subsets have also been involved in the modulation of immune cell functions, affecting the efficacy of both innate and adaptive anti-tumor immune responses. Consequently, the implication of these stromal cells in the response to immunotherapeutic strategies raised major concerns. In this review, current knowledge of CAFs origins and heterogeneity in the tumor stroma, as well as their effects on several immune cell populations that explain their immunosuppressive capabilities are summarized. The current development of therapeutic strategies for targeting this population and their implication in the field of cancer immunotherapy is also highlighted.
Collapse
Affiliation(s)
- Jerome Thiery
- INSERM, UMR 1186, 94800 Villejuif, France
- Gustave Roussy Cancer Campus, 94805 Villejuif, France
- University Paris Saclay, Faculty of Medicine, 94270 Le Kremlin Bicêtre, France
| |
Collapse
|
|
24
|
Wong KY, Cheung AH, Chen B, Chan WN, Yu J, Lo KW, Kang W, To KF. Cancer-associated fibroblasts in nonsmall cell lung cancer: From molecular mechanisms to clinical implications. Int J Cancer 2022; 151:1195-1215. [PMID: 35603909 PMCID: PMC9545594 DOI: 10.1002/ijc.34127] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 05/08/2022] [Accepted: 05/12/2022] [Indexed: 11/14/2022]
Abstract
Lung cancer is the common and leading cause of cancer death worldwide. The tumor microenvironment has been recognized to be instrumental in tumorigenesis. To have a deep understanding of the molecular mechanism of nonsmall cell lung carcinoma (NSCLC), cancer-associated fibroblasts (CAFs) have gained increasing research interests. CAFs belong to the crucial and dominant cell population in the tumor microenvironment to support the cancer cells. The interplay and partnership between cancer cells and CAFs contribute to each stage of tumorigenesis. CAFs exhibit prominent heterogeneity and secrete different kinds of cytokines and chemokines, growth factors and extracellular matrix proteins involved in cancer cell proliferation, invasion, metastasis and chemoresistance. Many studies focused on the protumorigenic functions of CAFs, yet many challenges about the heterogeneity of CAFS remain unresolved. This review comprehensively summarized the tumor-promoting role and molecular mechanisms of CAFs in NSCLC, including their origin, phenotypic changes and heterogeneity and their functional roles in carcinogenesis. Meanwhile, we also highlighted the updated molecular classifications based on the molecular features and functional roles of CAFs. With the development of cutting-edge platforms and further investigations of CAFs, novel therapeutic strategies for accurately targeting CAFs in NSCLC may be developed based on the increased understanding of the relevant molecular mechanisms.
Collapse
Affiliation(s)
- Kit Yee Wong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| | - Alvin Ho‐Kwan Cheung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| | - Bonan Chen
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| | - Wai Nok Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| | - Jun Yu
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongSARChina
| | - Kwok Wai Lo
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| |
Collapse
|
|
25
|
Loh JK, Wang ML, Cheong SK, Tsai FT, Huang SH, Wu JR, Yang YP, Chiou SH, Ong AHK. The study of cancer cell in stromal environment through induced pluripotent stem cell-derived mesenchymal stem cells. J Chin Med Assoc 2022; 85:821-830. [PMID: 35666590 DOI: 10.1097/jcma.0000000000000759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND The development of mesenchymal stem cells (MSCs) has gained reputation from its therapeutic potential in stem cell regeneration, anti-inflammation, tumor suppression, and drug delivery treatment. Previous studies have shown MSCs have both promoting and suppressing effects against cancer cells. While the limitation of obtaining a large quantity of homologous MSCs for studies and treatment remains a challenge, an alternative approach involving the production of MSCs derived from induced pluripotent stem cells (iPSCs; induced MSCs [iMSCs]) may be a promising prospect given its ability to undergo prolonged passage and with similar therapeutic profiles as that of their MSC counterparts. However, the influence of iMSC in the interaction of cancer cells remains to be explored as such studies are not well established. In this study, we aim to differentiate iPSCs into MSC-like cells as a potential substitute for adult MSCs and evaluate its effect on non-small-cell lung cancer (NSCLC). METHODS iMSCs were derived from iPSCs and validated with reference to the International Society of Cellular Therapy guidelines on MSC criteria. To create a stromal environment, the conditioned medium (CM) of iMSCs was harvested and applied for coculturing of NSCLC of H1975 at different concentrations. The H1975 was then harvested for RNA extraction and subjected to next-generation sequencing (NGS) for analysis. RESULTS The morphology of iMSCs-CM-treated H1975 was different from an untreated H1975. Our NGS data suggest the occurrence of apoptotic events and the presence of cytokines from H1975's RNA that are treated with iMSCs-CM. CONCLUSION Our results have shown that iMSCs may suppress the growth of H1975 by releasing proapoptotic cytokines into coculture media. Using iPSC-derived MSC models allows a deeper study of tumor cross talk between MSC and cancer cells that can be applied for potential future cancer therapy.
Collapse
Affiliation(s)
- Jit-Kai Loh
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Faculty of Medicine and Health Sciences, Universitiy Tunku Abdul Rahman, Cheras, Malaysia
| | - Mong-Lien Wang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Food Safety and Health Risk Assessment, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Soon-Keng Cheong
- Faculty of Medicine and Health Sciences, Universitiy Tunku Abdul Rahman, Cheras, Malaysia
- National Cancer Council (MAKNA), Kuala Lumpur, Malaysia
| | - Fu-Ting Tsai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shu-Huei Huang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Jing-Rong Wu
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Ping Yang
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shih-Hwa Chiou
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Genomic Research Center, Academia Sinica, Taipei, Taiwan, ROC
| | - Alan Han-Kiat Ong
- Faculty of Medicine and Health Sciences, Universitiy Tunku Abdul Rahman, Cheras, Malaysia
| |
Collapse
|
|
26
|
Antoon R, Wang XH, Saleh AH, Warrington J, Hedley DW, Keating A. Pancreatic cancer growth promoted by bone marrow mesenchymal stromal cell-derived IL-6 is reversed predominantly by IL-6 blockade. Cytotherapy 2022; 24:699-710. [PMID: 35473998 DOI: 10.1016/j.jcyt.2021.12.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 11/17/2021] [Accepted: 12/06/2021] [Indexed: 12/26/2022]
Abstract
Pancreatic cancer is a highly lethal cancer characterized by local invasiveness, early metastasis, recurrence and high resistance to current therapies. Extensive stroma or desmoplasia is a key histological feature of the disease, and interactions between cancer and stromal cells are critical for pancreatic cancer development and progression. Mesenchymal stromal cells [MSCs] exhibit preferential tropism to primary and metastatic tumor sites and may either suppress or support tumor growth. Although MSCs represent a potential source of pancreatic cancer stroma, their contribution to pancreatic tumor growth remains poorly known. Here, we show that bone marrow MSCs significantly contribute to pancreatic cancer growth in vitro and in vivo. Furthermore, MSCs create a pro-carcinogenic microenvironment through the release of key factors mediating growth and angiogenesis, including interleukin (IL)-6, IL-8, vascular endothelial growth factor and activation of STAT3 signaling in tumor cells. IL-6 released by MSCs was largely responsible for the pro-tumorigenic effects of MSCs. Knockdown of IL-6 expression in MSCs by small interfering RNA (siRNA) abolished the MSC growth-promoting effect in vitro, reducing tumor cell proliferation and clonogenic potential. In addition, in a heterotopic nude mouse model of human pancreatic tumor xenografts, blockade of IL-6 with the anti-IL-6 receptor antibody, tocilizumab, or of its downstream effector STAT3 with the small molecule STAT3 inhibitor S3I-201, abrogated MSC-mediated tumor promotion and delayed tumor formation significantly. Our data demonstrate that MSCs promote pancreatic cancer growth, with IL-6 produced by MSCs playing a pivotal role.
Collapse
Affiliation(s)
- Roula Antoon
- Krembil Research Institute, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | | | - Amr H Saleh
- Krembil Research Institute, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | | | - David W Hedley
- Princess Margaret Cancer Centre, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Armand Keating
- Krembil Research Institute, Toronto, ON, Canada; Princess Margaret Cancer Centre, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
| |
Collapse
|
|
27
|
Menezes S, Okail MH, Jalil SMA, Kocher HM, Cameron AJM. Cancer-associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets. J Pathol 2022; 257:526-544. [PMID: 35533046 PMCID: PMC9327514 DOI: 10.1002/path.5926] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/03/2022] [Accepted: 05/05/2022] [Indexed: 11/29/2022]
Abstract
Cancer-associated fibroblasts (CAFs) have conflicting roles in the suppression and promotion of cancer. Current research focuses on targeting the undesirable properties of CAFs, while attempting to maintain tumour-suppressive roles. CAFs have been widely associated with primary or secondary therapeutic resistance, and strategies to modify CAF function have therefore largely focussed on their combination with existing therapies. Despite significant progress in preclinical studies, clinical translation of CAF targeted therapies has achieved limited success. Here we will review our emerging understanding of heterogeneous CAF populations in tumour biology and use examples from pancreatic ductal adenocarcinoma to explore why successful clinical targeting of protumourigenic CAF functions remains elusive. Single-cell technologies have allowed the identification of CAF subtypes with a differential impact on prognosis and response to therapy, but currently without clear consensus. Identification and pharmacological targeting of CAF subtypes associated with immunotherapy response offers new hope to expand clinical options for pancreatic cancer. Various CAF subtype markers may represent biomarkers for patient stratification, to obtain enhanced response with existing and emerging combinatorial therapeutic strategies. Thus, CAF subtyping is the next frontier in understanding and exploiting the tumour microenvironment for therapeutic benefit. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Shinelle Menezes
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
| | - Mohamed Hazem Okail
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
| | - Siti Munira Abd Jalil
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
| | - Hemant M Kocher
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
- Barts and the London HPB Centre, The Royal London HospitalBarts Health NHS TrustLondonUK
| | - Angus J M Cameron
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
| |
Collapse
|
|
28
|
Obradovic A, Graves D, Korrer M, Wang Y, Roy S, Naveed A, Xu Y, Luginbuhl A, Curry J, Gibson M, Idrees K, Hurley P, Jiang P, Liu XS, Uppaluri R, Drake CG, Califano A, Kim YJ. Immunostimulatory Cancer-Associated Fibroblast Subpopulations Can Predict Immunotherapy Response in Head and Neck Cancer. Clin Cancer Res 2022; 28:2094-2109. [PMID: 35262677 PMCID: PMC9161438 DOI: 10.1158/1078-0432.ccr-21-3570] [Citation(s) in RCA: 102] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 12/15/2021] [Accepted: 03/07/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE Cancer-associated fibroblasts (CAF) have been implicated as potential mediators of checkpoint immunotherapy response. However, the extensive heterogeneity of these cells has precluded rigorous understanding of their immunoregulatory role in the tumor microenvironment. EXPERIMENTAL DESIGN We performed high-dimensional single-cell RNA sequencing (scRNA-seq) on four patient tumors pretreatment and posttreatment from a neoadjuvant trial of patients with advanced-stage head and neck squamous cell carcinoma that were treated with the αPD-1 therapy, nivolumab. The head and neck CAF (HNCAF) protein activity profiles, derived from this cohort of paired scRNA-seq, were used to perform protein activity enrichment analysis on the 28-patient parental cohort of clinically annotated bulk transcriptomic profiles. Ex vivo coculture assays were used to test functional relevance of HNCAF subtypes. RESULTS Fourteen distinct cell types were identified with the fibroblast population showing significant changes in abundance following nivolumab treatment. Among the fibroblast subtypes, HNCAF-0/3 emerged as predictive of nivolumab response, while HNCAF-1 was associated with immunosuppression. Functionally, HNCAF-0/3 were found to reduce TGFβ-dependent PD-1+TIM-3+ exhaustion of CD8 T cells, increase CD103+NKG2A+ resident memory phenotypes, and enhance the overall cytolytic profile of T cells. CONCLUSIONS Our findings demonstrate the functional importance of distinct HNCAF subsets in modulating the immunoregulatory milieu of human HNSCC. In addition, we have identified clinically actionable HNCAF subtypes that can be used as a biomarker of response and resistance in future clinical trials.
Collapse
Affiliation(s)
- Aleksandar Obradovic
- Columbia Center for Translational Immunology (CCTI), Columbia University Irving Medical Center (CUMC), New York, NY, USA
- Department of Systems Biology, HICC, New York, NY, USA
| | - Diana Graves
- Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, TN, USA
| | - Michael Korrer
- Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yu Wang
- Department of Biostatistics, Vanderbilt University Medical Center. Nashville, TN, USA
| | - Sohini Roy
- Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Abdullah Naveed
- Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yaomin Xu
- Department of Biostatistics, Vanderbilt University Medical Center. Nashville, TN, USA
| | - Adam Luginbuhl
- Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Joseph Curry
- Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Michael Gibson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kamran Idrees
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Paula Hurley
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Peng Jiang
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - X. Shirley Liu
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ravindra Uppaluri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA
| | - Charles G. Drake
- Columbia Center for Translational Immunology (CCTI), Columbia University Irving Medical Center (CUMC), New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Andrea Califano
- Department of Systems Biology, HICC, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
- Department of Biomedical Informatics, Columbia University, New York, NY, USA
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
- J.P. Sulzberger Columbia Genome Center, New York, NY, USA
| | - Young J. Kim
- Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, TN, USA
- Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Regeneron Pharmaceutical, Tarrytown, NY, USA
| |
Collapse
|
|
29
|
Ge R, Wang Z, Cheng L. Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance. NPJ Precis Oncol 2022; 6:31. [PMID: 35508696 PMCID: PMC9068628 DOI: 10.1038/s41698-022-00272-w] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 03/16/2022] [Indexed: 12/20/2022] Open
Abstract
Prostate cancer is characterized by a high degree of heterogeneity, which poses a major challenge to precision therapy and drug development. In this review, we discuss how nongenetic factors contribute to heterogeneity of prostate cancer. We also discuss tumor heterogeneity and phenotypic switching related to anticancer therapies. Lastly, we summarize the challenges targeting the tumor environments, and emphasize that continued exploration of tumor heterogeneity is needed in order to offer a personalized therapy for advanced prostate cancer patients.
Collapse
Affiliation(s)
- Rongbin Ge
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Zongwei Wang
- Department of Surgery, Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. .,Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA.
| |
Collapse
|
|
30
|
Sánchez-Ramírez D, Medrano-Guzmán R, Candanedo-González F, De Anda-González J, García-Rios LE, Pérez-Koldenkova V, Gutiérrez-de la Barrera M, Rodríguez-Enríquez S, Velasco-Velázquez M, Pacheco-Velázquez SC, Piña-Sánchez P, Mayani H, Gómez-Delgado A, Monroy-García A, Martínez-Lara AK, Montesinos JJ. High expression of both desmoplastic stroma and epithelial to mesenchymal transition markers associate with shorter survival in pancreatic ductal adenocarcinoma. Eur J Histochem 2022; 66:3360. [PMID: 35174683 PMCID: PMC8883614 DOI: 10.4081/ejh.2022.3360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 02/09/2022] [Indexed: 12/24/2022] Open
Abstract
Desmoplastic stroma (DS) and the epithelial-to-mesenchymal transition (EMT) play a key role in pancreatic ductal adenocarcinoma (PDAC) progression. To date, however, the combined expression of DS and EMT markers, and their association with variations in survival within each clinical stage and degree of tumor differentiation is unknown. The purpose of this study was to investigate the association between expression of DS and EMT markers and survival variability in patients diagnosed with PDAC. We examined the expression levels of DS markers alpha smooth muscle actin (α-SMA), fibronectin, and vimentin, and the EMT markers epithelial cell adhesion molecule (EPCAM), pan-cytokeratin, and vimentin, by immunohistochemistry using a tissue microarray of a retrospective cohort of 25 patients with PDAC. The results were examined for association with survival by clinical stage and by degree of tumor differentiation. High DS markers expression -α-SMA, fibronectin, and vimentin- was associated with decreased survival at intermediate and advanced clinical stages (p=0.006-0.03), as well as with both poorly and moderately differentiated tumor grades (p=0.01-0.02). Interestingly, the same pattern was observed for EMT markers, i.e., EPCAM, pan-cytokeratin, and vimentin (p=0.00008-0.03). High expression of DS and EMT markers within each clinical stage and degree of tumor differentiation was associated with lower PDAC survival. Evaluation of these markers may have a prognostic impact on survival time variation in patients with PDAC.
Collapse
Affiliation(s)
- Damián Sánchez-Ramírez
- Mesenchymal Stem Cells Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Mexico City.
| | - Rafael Medrano-Guzmán
- Department of Sarcomas, Oncology Hospital, High Specialty Medical Unit (UMAE), National Medical Center, IMSS, Mexico City.
| | - Fernando Candanedo-González
- Department of Pathology, Oncology Hospital, High Specialty Medical Unit (UMAE), National Medical Center, IMSS, Mexico City.
| | - Jazmín De Anda-González
- Department of Pathology, Oncology Hospital, High Specialty Medical Unit (UMAE), National Medical Center, IMSS, Mexico City.
| | - Luis Enrique García-Rios
- Department of Sarcomas, Oncology Hospital, High Specialty Medical Unit (UMAE), National Medical Center, IMSS, Mexico City.
| | - Vadim Pérez-Koldenkova
- National Laboratory of Advanced Microscopy-IMSS, National Medical Center, Siglo XXI IMSS, Mexico City.
| | | | | | - Marco Velasco-Velázquez
- Department of Pharmacology and Peripheral Research Unit in Translational Biomedicine (CMN 20 de noviembre, ISSSTE), School of Medicine, UNAM, Mexico City.
| | | | - Patricia Piña-Sánchez
- Molecular Oncology Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Mexico City.
| | - Héctor Mayani
- Hematopoietic Stem Cells Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Mexico City.
| | - Alejandro Gómez-Delgado
- Infectious and Parasitic Diseases, Medical Research Unit, Pediatric Hospital, National Medical Center, IMSS, Mexico City.
| | - Alberto Monroy-García
- Immunology and Cancer Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center (IMSS), Mexico City.
| | - Ana Karen Martínez-Lara
- Mesenchymal Stem Cells Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Mexico City.
| | - Juan José Montesinos
- Mesenchymal Stem Cells Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Mexico City.
| |
Collapse
|
|
31
|
Tanaka M. Crosstalk of tumor stromal cells orchestrates invasion and spreading of gastric cancer. Pathol Int 2022; 72:219-233. [PMID: 35112770 DOI: 10.1111/pin.13211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 01/18/2022] [Indexed: 01/22/2023]
Abstract
Tumors contain various stromal cells that support cancer progression. Some types of cancer, such as scirrhous gastric cancer, are characterized by large areas of fibrosis accompanied by cancer-associated fibroblasts (CAFs). Asporin (ASPN) is a small leucine-rich proteoglycan highly expressed in CAFs of various tumors. ASPN accelerates CAF migration and invasion, resulting in CAF-led cancer cell invasion. In addition, ASPN further upregulated the expression of genes specific to a characteristic subgroup of fibroblasts in tumors. These cells were preferentially located at the tumor periphery and could be generated by a unique mechanism involving the CAF-mediated education of normal fibroblasts (CEFs). In this review, we at first describe recent findings regarding the function of ASPN in the tumor microenvironment, as well as the mechanism involved in the generation of CEFs. CAFs are derived from heterogeneous origins besides resident normal fibroblasts. Among them, CAFs derived from mesothelial cells (mesothelial cell-derived CAF [MC-CAFs]) play pivotal roles in peritoneal carcinomatosis. We observed that MC-CAFs on the surfaces of organs also participate in tumor formation by infiltrating into the parenchyma, promoting local invasion by gastric cancers. This review also highlights the potential functions of macrophages in the formation of MC-CAFs in gastric cancers, by transfer the contents of cancer cell-derived extracellular vesicles.
Collapse
Affiliation(s)
- Masamitsu Tanaka
- Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan
| |
Collapse
|
|
32
|
Rogers MP, Mi Z, Li NY, Wai PY, Kuo PC. Tumor: Stroma Interaction and Cancer. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:59-87. [PMID: 35165860 DOI: 10.1007/978-3-030-91311-3_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The understanding of how normal cells transform into tumor cells and progress to invasive cancer and metastases continues to evolve. The tumor mass is comprised of a heterogeneous population of cells that include recruited host immune cells, stromal cells, matrix components, and endothelial cells. This tumor microenvironment plays a fundamental role in the acquisition of hallmark traits, and has been the intense focus of current research. A key regulatory mechanism triggered by these tumor-stroma interactions includes processes that resemble epithelial-mesenchymal transition, a physiologic program that allows a polarized epithelial cell to undergo biochemical and cellular changes and adopt mesenchymal cell characteristics. These cellular adaptations facilitate enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components. Indeed, it has been postulated that cancer cells undergo epithelial-mesenchymal transition to invade and metastasize.In the following discussion, the physiology of chronic inflammation, wound healing, fibrosis, and tumor invasion will be explored. The key regulatory cytokines, transforming growth factor β and osteopontin, and their roles in cancer metastasis will be highlighted.
Collapse
Affiliation(s)
- Michael P Rogers
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Zhiyong Mi
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Neill Y Li
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Philip Y Wai
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Paul C Kuo
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
| |
Collapse
|
|
33
|
Abstract
The intimate involvement of pathogens with the heightened risk for developing certain cancers is an area of research that has captured a great deal of attention over the last 10 years. One firmly established paradigm that highlights this aspect of disease progression is in the instance of Helicobacter pylori infection and the contribution it makes in elevating the risk for developing gastric cancer. Whilst the molecular mechanisms that pinpoint the contribution that this microorganism inflicts towards host cells during gastric cancer initiation have come into greater focus, another picture that has also emerged is one that implicates the host's immune system, and the chronic inflammation that can arise therefrom, as being a central contributory factor in disease progression. Consequently, when taken with the underlying role that the extracellular matrix plays in the development of most cancers, and how this dynamic can be modulated by proteases expressed from the tumor or inflammatory cells, a complex and detailed relationship shared between the individual cellular components and their surroundings is coming into focus. In this review article, we draw attention to the emerging role played by the cathepsin proteases in modulating the stage-specific progression of Helicobacter pylori-initiated gastric cancer and the underlying immune response, while highlighting the therapeutic significance of this dynamic and how it may be amenable for novel intervention strategies within a basic research or clinical setting.
Collapse
|
|
34
|
Harryvan TJ, de Lange S, Hawinkels LJ, Verdegaal EM. The ABCs of Antigen Presentation by Stromal Non-Professional Antigen-Presenting Cells. Int J Mol Sci 2021; 23:ijms23010137. [PMID: 35008560 PMCID: PMC8745042 DOI: 10.3390/ijms23010137] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/29/2022] Open
Abstract
Professional antigen-presenting cells (APCs), such as dendritic cells and macrophages, are known for their ability to present exogenous antigens to T cells. However, many other cell types, including endothelial cells, fibroblasts, and lymph node stromal cells, are also capable of presenting exogenous antigens to either CD8+ or CD4+ T cells via cross-presentation or major histocompatibility complex (MHC) class II-mediated presentation, respectively. Antigen presentation by these stromal nonprofessional APCs differentially affect T cell function, depending on the type of cells that present the antigen, as well as the local (inflammatory) micro-environment. It has been recently appreciated that nonprofessional APCs can, as such, orchestrate immunity against pathogens, tumor survival, or rejection, and aid in the progression of various auto-immune pathologies. Therefore, the interest for these nonprofessional APCs is growing as they might be an important target for enhancing various immunotherapies. In this review, the different nonprofessional APCs are discussed, as well as their functional consequences on the T cell response, with a focus on immuno-oncology.
Collapse
Affiliation(s)
- Tom J. Harryvan
- Department of Gastroenterology & Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
- Correspondence: (T.J.H.); (L.J.A.C.H.); (E.M.E.V.); Tel.: +0031-715266736 (L.J.A.C.H.)
| | - Sabine de Lange
- Department of Gastroenterology & Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | - Lukas J.A.C. Hawinkels
- Department of Gastroenterology & Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
- Correspondence: (T.J.H.); (L.J.A.C.H.); (E.M.E.V.); Tel.: +0031-715266736 (L.J.A.C.H.)
| | - Els M.E. Verdegaal
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
- Correspondence: (T.J.H.); (L.J.A.C.H.); (E.M.E.V.); Tel.: +0031-715266736 (L.J.A.C.H.)
| |
Collapse
|
|
35
|
Fibroblasts as immune regulators in infection, inflammation and cancer. Nat Rev Immunol 2021; 21:704-717. [PMID: 33911232 DOI: 10.1038/s41577-021-00540-z] [Citation(s) in RCA: 320] [Impact Index Per Article: 80.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2021] [Indexed: 02/07/2023]
Abstract
In chronic infection, inflammation and cancer, the tissue microenvironment controls how local immune cells behave, with tissue-resident fibroblasts emerging as a key cell type in regulating activation or suppression of an immune response. Fibroblasts are heterogeneous cells, encompassing functionally distinct populations, the phenotypes of which differ according to their tissue of origin and type of inciting disease. Their immunological properties are also diverse, ranging from the maintenance of a potent inflammatory environment in chronic inflammation to promoting immunosuppression in malignancy, and encapsulating and incarcerating infectious agents within tissues. In this Review, we compare the mechanisms by which fibroblasts control local immune responses, as well as the factors regulating their inflammatory and suppressive profiles, in different tissues and pathological settings. This cross-disease perspective highlights the importance of tissue context in determining fibroblast-immune cell interactions, as well as potential therapeutic avenues to exploit this knowledge for the benefit of patients with chronic infection, inflammation and cancer.
Collapse
|
|
36
|
Zheng H, Liu H, Ge Y, Wang X. Integrated single-cell and bulk RNA sequencing analysis identifies a cancer associated fibroblast-related signature for predicting prognosis and therapeutic responses in colorectal cancer. Cancer Cell Int 2021; 21:552. [PMID: 34670584 PMCID: PMC8529760 DOI: 10.1186/s12935-021-02252-9] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 10/07/2021] [Indexed: 12/14/2022] Open
Abstract
Background Cancer-associated fibroblasts (CAFs) contribute notably to colorectal cancer (CRC) tumorigenesis, stiffness, angiogenesis, immunosuppression and metastasis, and could serve as a promising therapeutic target. Our purpose was to construct CAF-related prognostic signature for CRC. Methods We performed bioinformatics analysis on single-cell transcriptome data derived from Gene Expression Omnibus (GEO) and identified 208 differentially expressed cell markers from fibroblasts cluster. Bulk gene expression data of CRC was obtained from The Cancer Genome Atlas (TCGA) and GEO databases. Univariate Cox regression and least absolute shrinkage operator (LASSO) analyses were performed on TCGA training cohort (n = 308) for model construction, and was validated in TCGA validation (n = 133), TCGA total (n = 441), GSE39582 (n = 470) and GSE17536 (n = 177) datasets. Microenvironment Cell Populations-counter (MCP-counter) and Estimate the Proportion of Immune and Cancer cells (EPIC) methods were applied to evaluated CAFs infiltrations from bulk gene expression data. Real-time polymerase chain reaction (qPCR) was performed in tissue microarrays containing 80 colon cancer samples to further validate the prognostic value of the CAF model. pRRophetic and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms were utilized to predict chemosensitivity and immunotherapy response. Human Protein Atlas (HPA) databases and immunohistochemistry were used to evaluate the protein expressions. Results A nine-gene prognostic CAF-related signature was established in training cohort. Kaplan–Meier survival analyses revealed patients with higher CAF risk scores were correlated with adverse prognosis in each cohort. MCP-counter and EPIC results consistently revealed CAFs infiltrations were significantly higher in high CAF risk group. Patients with higher CAF risk scores were more prone to not respond to immunotherapy, but were more sensitive to several conventional chemotherapeutics, suggesting a potential strategy of combining chemotherapy with anti-CAF therapy to improve the efficacy of current T-cell based immunotherapies. Univariate and multivariate Cox regression analyses verified the CAF model was as an independent prognostic indicator in predicting overall survival, and a CAF-based nomogram was then built for clinical utility in predicting prognosis of CRC. Conclusion To conclude, the CAF-related signature could serve as a robust prognostic indicator in CRC, which provides novel genomics evidence for anti-CAF immunotherapeutic strategies. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02252-9.
Collapse
Affiliation(s)
- Hang Zheng
- Department of General Surgery, Peking University First Hospital, Peking University, Beijing, People's Republic of China
| | - Heshu Liu
- Department of Oncology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yang Ge
- Department of Oncology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China.
| | - Xin Wang
- Department of General Surgery, Peking University First Hospital, Peking University, Beijing, People's Republic of China.
| |
Collapse
|
|
37
|
Ziani L, Buart S, Chouaib S, Thiery J. Hypoxia increases melanoma-associated fibroblasts immunosuppressive potential and inhibitory effect on T cell-mediated cytotoxicity. Oncoimmunology 2021; 10:1950953. [PMID: 34367731 PMCID: PMC8312612 DOI: 10.1080/2162402x.2021.1950953] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/29/2021] [Accepted: 06/29/2021] [Indexed: 12/26/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) and hypoxia are central players in the complex process of tumor cell-stroma interaction and are involved in the alteration of the anti-tumor immune response by impacting both cancer and immune cell populations. However, even if their independent immunomodulatory properties are now well documented, whether the interaction between these two components of the tumor microenvironment can affect CAFs ability to alter the anti-tumor immune response is still poorly defined. In this study, we provide evidence that hypoxia increases melanoma-associated fibroblasts expression and/or secretion of several immunosuppressive factors (including TGF-β, IL6, IL10, VEGF and PD-L1). Moreover, we demonstrate that hypoxic CAF secretome exerts a more profound effect on T cell-mediated cytotoxicity than its normoxic counterpart. Together, our data suggest that the crosstalk between hypoxia and CAFs is probably an important determinant in the complex immunosuppressive tumor microenvironment.
Collapse
Affiliation(s)
- Linda Ziani
- INSERM, UMR 1186 “Human Tumor Immunology and Cancer Immunotherapy”, Villejuif, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Faculty of Medicine, University Paris Saclay, France
| | - Stéphanie Buart
- INSERM, UMR 1186 “Human Tumor Immunology and Cancer Immunotherapy”, Villejuif, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Faculty of Medicine, University Paris Saclay, France
| | - Salem Chouaib
- INSERM, UMR 1186 “Human Tumor Immunology and Cancer Immunotherapy”, Villejuif, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Faculty of Medicine, University Paris Saclay, France
- Thumbay Research Institute of Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Jerome Thiery
- INSERM, UMR 1186 “Human Tumor Immunology and Cancer Immunotherapy”, Villejuif, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Faculty of Medicine, University Paris Saclay, France
| |
Collapse
|
|
38
|
Balaji S, Kim U, Muthukkaruppan V, Vanniarajan A. Emerging role of tumor microenvironment derived exosomes in therapeutic resistance and metastasis through epithelial-to-mesenchymal transition. Life Sci 2021; 280:119750. [PMID: 34171378 DOI: 10.1016/j.lfs.2021.119750] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 06/09/2021] [Accepted: 06/16/2021] [Indexed: 12/18/2022]
Abstract
The tumor microenvironment (TME) constitutes multiple cell types including cancerous and non-cancerous cells. The intercellular communication between these cells through TME derived exosomes may either enhance or suppress the tumorigenic processes. The tumor-derived exosomes could convert an anti-tumor environment into a pro-tumor environment by inducing the differentiation of stromal cells into tumor-associated cells. The exosomes from tumor-associated stromal cells reciprocally trigger epithelial-to-mesenchymal transition (EMT) in tumor cells, which impose therapeutic resistance and metastasis. It is well known that these exosomes contain the signals of EMT, but how these signals execute chemoresistance and metastasis in tumors remains elusive. Understanding the significance and molecular signatures of exosomes transmitting EMT signals would aid in developing appropriate methods of inhibiting them. In this review, we focus on molecular signatures of exosomes that shuttle between cancer cells and their stromal populations in TME to explicate their impact on therapeutic resistance and metastasis through EMT. Especially Wnt signaling is found to be involved in multiple ways of exosomal transport and hence we decipher the biomolecules of Wnt signaling trafficked through exosomes and their potential in serving as therapeutic targets.
Collapse
Affiliation(s)
- Sekaran Balaji
- Department of Molecular Genetics, Aravind Medical Research Foundation, Madurai, Tamil Nadu 625 020, India
| | - Usha Kim
- Department of Orbit, Oculoplasty and Ocular Oncology, Aravind Eye Hospital, Madurai, Tamil Nadu 625 020, India
| | - Veerappan Muthukkaruppan
- Department of Immunology and Stem Cell Biology, Aravind Medical Research Foundation, Madurai, Tamil Nadu 625 020, India
| | - Ayyasamy Vanniarajan
- Department of Molecular Genetics, Aravind Medical Research Foundation, Madurai, Tamil Nadu 625 020, India.
| |
Collapse
|
|
39
|
Wei H, Wang J, Xu Z, Li W, Wu X, Zhuo C, Lu Y, Long X, Tang Q, Pu J. Hepatoma Cell-Derived Extracellular Vesicles Promote Liver Cancer Metastasis by Inducing the Differentiation of Bone Marrow Stem Cells Through microRNA-181d-5p and the FAK/Src Pathway. Front Cell Dev Biol 2021; 9:607001. [PMID: 34124029 PMCID: PMC8194264 DOI: 10.3389/fcell.2021.607001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 02/08/2021] [Indexed: 01/19/2023] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs) are beneficial to repair the damaged liver. Tumor-derived extracellular vesicles (EV) are notorious in tumor metastasis. But the mechanism underlying hepatoma cell-derived EVs in BMSCs and liver cancer remains unclear. We hypothesize that hepatoma cell-derived EVs compromise the effects of BMSCs on the metastasis of liver cancer. The differentially expressed microRNAs (miRNAs) were screened. HepG2 cells were transfected with miR-181d-5p mimic or inhibitor, and the EVs were isolated and incubated with BMSCs to evaluate the differentiation of BMSCs into fibroblasts. Hepatoma cells were cultured with BMSCs conditioned medium (CM) treated with HepG2-EVs to assess the malignant behaviors of hepatoma cells. The downstream genes and pathways of miR-181d-5p were analyzed and their involvement in the effect of EVs on BMSC differentiation was verified through functional rescue experiments. The nude mice were transplanted with BMSCs-CM or BMSCs-CM treated with HepG2-EVs, and then tumor growth and metastasis in vivo were assessed. HepG2-EVs promoted fibroblastic differentiation of BMSCs, and elevated levels of α-SMA, vimentin, and collagen in BMSCs. BMSCs-CM treated with HepG2-EVs stimulated the proliferation, migration, invasion and epithelial-mesenchymal-transition (EMT) of hepatoma cells. miR-181d-5p was the most upregulated in HepG2-EVs-treated BMSCs. miR-181d-5p targeted SOCS3 to activate the FAK/Src pathway and SOCS3 overexpression inactivated the FAK/Src pathway. Reduction of miR-181d-5p in HepG2-EVs or SOCS3 overexpression reduced the differentiation of BMSCs into fibroblasts, and compromised the promoting effect of HepG2-EVs-treated BMSCs-CM on hepatoma cells. In vivo, HepG2-EVs-treated BMSCs facilitated liver cancer growth and metastasis. In conclusion, HepG2-EVs promote the differentiation of BMSCs, and promote liver cancer metastasis through the delivery of miR-181d-5p and the SOCS3/FAK/Src pathway.
Collapse
Affiliation(s)
- Huamei Wei
- Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
- Clinic Medicine Research Center of Hepatobiliary Diseases, Guangxi, China
| | - Jianchu Wang
- Clinic Medicine Research Center of Hepatobiliary Diseases, Guangxi, China
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Zuoming Xu
- Clinic Medicine Research Center of Hepatobiliary Diseases, Guangxi, China
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Wenchuan Li
- Clinic Medicine Research Center of Hepatobiliary Diseases, Guangxi, China
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Xianjian Wu
- Clinic Medicine Research Center of Hepatobiliary Diseases, Guangxi, China
| | - Chenyi Zhuo
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Yuan Lu
- Clinic Medicine Research Center of Hepatobiliary Diseases, Guangxi, China
| | - Xidai Long
- Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
- Clinic Medicine Research Center of Hepatobiliary Diseases, Guangxi, China
| | - Qianli Tang
- Clinic Medicine Research Center of Hepatobiliary Diseases, Guangxi, China
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Jian Pu
- Clinic Medicine Research Center of Hepatobiliary Diseases, Guangxi, China
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| |
Collapse
|
|
40
|
Choi S, Yu J, Kim W, Park KS. N-cadherin mediates the migration of bone marrow-derived mesenchymal stem cells toward breast tumor cells. Theranostics 2021; 11:6786-6799. [PMID: 34093853 PMCID: PMC8171089 DOI: 10.7150/thno.59703] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/21/2021] [Indexed: 12/18/2022] Open
Abstract
Rationale: Bone marrow-derived mesenchymal stem cells (BM-MSCs) recruited into breast tumors regulate the behavior of tumor cells via various mechanisms and affect clinical outcomes. Although signaling molecules, such as transforming growth factor β (TGF-β), are known to transmit signals between BM-MSCs and breast tumor cells for recruiting BM-MSCs, it is unclear which specific intrinsic molecules involved in cell motility mediate the migration of BM-MSCs into breast tumor. It is also unclear as to how specific intrinsic molecules contribute to the migration. Methods: Conditioned medium (CM) from breast tumor cells (MCF-7 and MDA-MB-231) that simulates breast tumor secreting TGF-β was used to examine the migration of BM-MSCs into breast tumors. A three-dimensional migration assay was performed to investigate the collective migration of BM-MSCs, maintaining cell-cell adhesion, toward breast tumor cells. Results: N-cadherin formed adherens junction-like structures on the intercellular borders of BM-MSCs, and TGF-β increased the expression of N-cadherin on these borders. Knockdown of Smad4 impaired the TGF-β-mediated increase in N-cadherin expression in BM-MSCs, but inhibitors of non-canonical TGF-β pathways, such as extracellular signal-regulated kinases, Akt, and p38, did not affect it. siRNA-mediated knockdown of N-cadherin and Smad4 impaired the migration of BM-MSCs in response to TGF-β. Conditioned medium from breast tumor cells also enhanced the expression of N-cadherin in BM-MSCs, but inactivation of TGF-β type 1 receptor (TGFBR1) with SB505124 and TGFBR1 knockdown abolished the increase in N-cadherin expression. BM-MSCs collectively migrated toward CM from MDA-MB-231 in vitro while maintaining cell-cell adhesion through N-cadherin. Knockdown of N-cadherin abolished the migration of BM-MSCs toward the CM from breast tumor cells. Conclusion: In the present study, we identified N-cadherin, an intrinsic transmembrane molecule in adherens junction-like structures, on BM-MSCs as a mediator for the migration of these cells toward breast tumor. The expression of N-cadherin increases on the intercellular borders of BM-MSCs through the TGF-β canonical signaling and they collectively migrate in response to breast tumor cells expressing TGF-β via N-cadherin-dependent cell-cell adhesion. We, herein, introduce a novel promising strategy for controlling and re-engineering the breast tumor microenvironment.
Collapse
Affiliation(s)
- Sanghyuk Choi
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Republic of Korea
| | - Jinyeong Yu
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Republic of Korea
| | - Wootak Kim
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Ki-Sook Park
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- East-West Medical Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| |
Collapse
|
|
41
|
Joshi RS, Kanugula SS, Sudhir S, Pereira MP, Jain S, Aghi MK. The Role of Cancer-Associated Fibroblasts in Tumor Progression. Cancers (Basel) 2021; 13:cancers13061399. [PMID: 33808627 PMCID: PMC8003545 DOI: 10.3390/cancers13061399] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/10/2021] [Accepted: 03/14/2021] [Indexed: 12/15/2022] Open
Abstract
In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics.
Collapse
Affiliation(s)
- Rushikesh S. Joshi
- School of Medicine, University of California, San Diego, La Jolla, CA 92092, USA;
| | | | - Sweta Sudhir
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Matheus P. Pereira
- School of Medicine, University of California, San Francisco, CA 94143, USA;
| | - Saket Jain
- Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA;
| | - Manish K. Aghi
- Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA;
- Correspondence: ; Tel.: +1-415-514-9820
| |
Collapse
|
|
42
|
Ham IH, Lee D, Hur H. Cancer-Associated Fibroblast-Induced Resistance to Chemotherapy and Radiotherapy in Gastrointestinal Cancers. Cancers (Basel) 2021; 13:1172. [PMID: 33803229 PMCID: PMC7963167 DOI: 10.3390/cancers13051172] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/28/2021] [Accepted: 03/04/2021] [Indexed: 12/24/2022] Open
Abstract
In the past few decades, the role of cancer-associated fibroblasts (CAFs) in resistance to therapies for gastrointestinal (GI) cancers has emerged. Clinical studies focusing on GI cancers have revealed that the high expression of CAF-related molecules within tumors is significantly correlated with unfavorable therapeutic outcomes; however, the exact mechanisms whereby CAFs enhance resistance to chemotherapy and radiotherapy in GI cancers remain unclear. The cells of origin of CAFs in GI cancers include normal resident fibroblasts, mesenchymal stem cells, endothelial cells, pericytes, and even epithelial cells. CAFs accumulated within GI cancers produce cytokines, chemokines, and growth factors involved in resistance to therapies. CAF-derived exosomes can be engaged in stroma-related resistance to treatments, and several non-coding RNAs, such as miR-92a, miR-106b, CCAL, and H19, are present in CAF-derived exosomes and transferred to GI cancer cells. The CAF-induced desmoplastic reaction interferes with drug delivery to GI cancer cells, evoking resistance to chemotherapy. However, due to the heterogeneity of CAFs in GI cancers, identifying the exact mechanism underlying CAF-induced resistance may be difficult. Recent advancements in single-cell "omics" technologies could offer clues for revealing the specific subtypes and biomarkers related to resistance.
Collapse
Affiliation(s)
- In-Hye Ham
- Department of Surgery, Ajou University School of Medicine, Suwon 16499, Korea; (I.-H.H.); (D.L.)
- Infamm-aging Translational Research Center, Ajou University School of Medicine, Suwon 16499, Korea
| | - Dagyeong Lee
- Department of Surgery, Ajou University School of Medicine, Suwon 16499, Korea; (I.-H.H.); (D.L.)
- Department of Biomedical Science, Graduate School of Ajou University, Suwon 16499, Korea
| | - Hoon Hur
- Department of Surgery, Ajou University School of Medicine, Suwon 16499, Korea; (I.-H.H.); (D.L.)
- Infamm-aging Translational Research Center, Ajou University School of Medicine, Suwon 16499, Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon 16499, Korea
| |
Collapse
|
|
43
|
Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol 2021; 14:24. [PMID: 33579329 PMCID: PMC7880217 DOI: 10.1186/s13045-021-01037-x] [Citation(s) in RCA: 396] [Impact Index Per Article: 99.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been intensely investigated for clinical applications within the last decades. However, the majority of registered clinical trials applying MSC therapy for diverse human diseases have fallen short of expectations, despite the encouraging pre-clinical outcomes in varied animal disease models. This can be attributable to inconsistent criteria for MSCs identity across studies and their inherited heterogeneity. Nowadays, with the emergence of advanced biological techniques and substantial improvements in bio-engineered materials, strategies have been developed to overcome clinical challenges in MSC application. Here in this review, we will discuss the major challenges of MSC therapies in clinical application, the factors impacting the diversity of MSCs, the potential approaches that modify MSC products with the highest therapeutic potential, and finally the usage of MSCs for COVID-19 pandemic disease.
Collapse
|
|
44
|
Hochheuser C, Windt LJ, Kunze NY, de Vos DL, Tytgat GA, Voermans C, Timmerman I. Mesenchymal Stromal Cells in Neuroblastoma: Exploring Crosstalk and Therapeutic Implications. Stem Cells Dev 2021; 30:59-78. [PMID: 33287630 PMCID: PMC7826431 DOI: 10.1089/scd.2020.0142] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 12/07/2020] [Indexed: 02/07/2023] Open
Abstract
Neuroblastoma (NB) is the second most common solid cancer in childhood, accounting for 15% of cancer-related deaths in children. In high-risk NB patients, the majority suffers from metastasis. Despite intensive multimodal treatment, long-term survival remains <40%. The bone marrow (BM) is among the most common sites of distant metastasis in patients with high-risk NB. In this environment, small populations of tumor cells can persist after treatment (minimal residual disease) and induce relapse. Therapy resistance of these residual tumor cells in BM remains a major obstacle for the cure of NB. A detailed understanding of the microenvironment and its role in tumor progression is of utmost importance for improving the treatment efficiency of NB. In BM, mesenchymal stromal cells (MSCs) constitute an important part of the microenvironment, where they support hematopoiesis and modulate immune responses. Their role in tumor progression is not completely understood, especially for NB. Although MSCs have been found to promote epithelial-mesenchymal transition, tumor growth, and metastasis and to induce chemoresistance, some reports point toward a tumor-suppressive effect of MSCs. In this review, we aim to compile current knowledge about the role of MSCs in NB development and progression. We evaluate arguments that depict tumor-supportive versus -suppressive properties of MSCs in the context of NB and give an overview of factors involved in MSC-NB crosstalk. A focus lies on the BM as a metastatic niche, since that is the predominant site for NB metastasis and relapse. Finally, we will present opportunities and challenges for therapeutic targeting of MSCs in the BM microenvironment.
Collapse
Affiliation(s)
- Caroline Hochheuser
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Laurens J. Windt
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Nina Y. Kunze
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Dieuwke L. de Vos
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Carlijn Voermans
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Ilse Timmerman
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands
| |
Collapse
|
|
45
|
Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers. Cancers (Basel) 2020; 13:cancers13010068. [PMID: 33383723 PMCID: PMC7794884 DOI: 10.3390/cancers13010068] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/16/2020] [Accepted: 12/24/2020] [Indexed: 12/13/2022] Open
Abstract
Simple Summary As for many other cancers, the risk of developing hematologic malignancies increases considerably as people age. In recent years, a growing number of studies have highlighted the influence of the aging microenvironment on hematopoiesis and tumor progression. Mesenchymal stromal cells are a major player in intercellular communication inside the bone marrow microenvironment involved in hematopoiesis support. With aging, their functions may be altered, leading to hematopoiesis disturbances which can lead to hematologic cancers. A good understanding of the mechanisms involved in mesenchymal stem cell aging and the consequences on hematopoiesis and tumor progression is therefore necessary for a better comprehension of hematologic malignancies and for the development of therapeutic approaches. Abstract Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.
Collapse
|
|
46
|
Aghakhani S, Zerrouk N, Niarakis A. Metabolic Reprogramming of Fibroblasts as Therapeutic Target in Rheumatoid Arthritis and Cancer: Deciphering Key Mechanisms Using Computational Systems Biology Approaches. Cancers (Basel) 2020; 13:E35. [PMID: 33374292 PMCID: PMC7795338 DOI: 10.3390/cancers13010035] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/12/2020] [Accepted: 12/17/2020] [Indexed: 12/29/2022] Open
Abstract
Fibroblasts, the most abundant cells in the connective tissue, are key modulators of the extracellular matrix (ECM) composition. These spindle-shaped cells are capable of synthesizing various extracellular matrix proteins and collagen. They also provide the structural framework (stroma) for tissues and play a pivotal role in the wound healing process. While they are maintainers of the ECM turnover and regulate several physiological processes, they can also undergo transformations responding to certain stimuli and display aggressive phenotypes that contribute to disease pathophysiology. In this review, we focus on the metabolic pathways of glucose and highlight metabolic reprogramming as a critical event that contributes to the transition of fibroblasts from quiescent to activated and aggressive cells. We also cover the emerging evidence that allows us to draw parallels between fibroblasts in autoimmune disorders and more specifically in rheumatoid arthritis and cancer. We link the metabolic changes of fibroblasts to the toxic environment created by the disease condition and discuss how targeting of metabolic reprogramming could be employed in the treatment of such diseases. Lastly, we discuss Systems Biology approaches, and more specifically, computational modeling, as a means to elucidate pathogenetic mechanisms and accelerate the identification of novel therapeutic targets.
Collapse
Affiliation(s)
- Sahar Aghakhani
- GenHotel, University of Evry, University of Paris-Saclay, Genopole, 91000 Evry, France; (S.A.); (N.Z.)
- Lifeware Group, Inria Saclay, 91120 Palaiseau, France
| | - Naouel Zerrouk
- GenHotel, University of Evry, University of Paris-Saclay, Genopole, 91000 Evry, France; (S.A.); (N.Z.)
| | - Anna Niarakis
- GenHotel, University of Evry, University of Paris-Saclay, Genopole, 91000 Evry, France; (S.A.); (N.Z.)
- Lifeware Group, Inria Saclay, 91120 Palaiseau, France
| |
Collapse
|
|
47
|
Uddin MN, Wang X. The landscape of long non-coding RNAs in tumor stroma. Life Sci 2020; 264:118725. [PMID: 33166593 DOI: 10.1016/j.lfs.2020.118725] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 10/26/2020] [Accepted: 11/03/2020] [Indexed: 02/06/2023]
Abstract
AIMS Long non-coding RNAs (lncRNAs) are associated with cancer development, while their relationship with the cancer-associated stromal components remains poorly understood. In this review, we performed a broad description of the functional landscape of stroma-associated lncRNAs in various cancers and their roles in regulating the tumor-stroma crosstalk. MATERIALS AND METHODS We carried out a systematic literature review of PubMed, Scopus, Medline, Bentham, and EMBASE (Elsevier) databases by using the keywords "LncRNAs in cancer," "LncRNAs in tumor stroma," "stroma," "cancer-associated stroma," "stroma in the tumor microenvironment," "tumor-stroma crosstalk," "drug resistance of stroma," and "stroma in immunosuppression" till July 2020. We collected the latest articles addressing the biological functions of stroma-associated lncRNAs in cancer. KEY FINDINGS These articles reported that dysregulated stroma-associated lncRNAs play significant roles in modulating the tumor microenvironment (TME) by the regulation of tumor-stroma crosstalk, epithelial to mesenchymal transition (EMT), endothelial to mesenchymal transition (EndMT), extracellular matrix (ECM) turnover, and tumor immunity. SIGNIFICANCE The tumor stroma is a substantial portion of the TME, and the dysregulation of tumor stroma-associated lncRNAs significantly contributes to cancer initiation, progression, angiogenesis, immune evasion, metastasis, and drug resistance. Thus, stroma-associated lncRNAs could be potentially useful targets for cancer therapy.
Collapse
Affiliation(s)
- Md Nazim Uddin
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China; Institute of Food Science and Technology, Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhaka 1205, Bangladesh
| | - Xiaosheng Wang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China.
| |
Collapse
|
|
48
|
Louault K, Li RR, DeClerck YA. Cancer-Associated Fibroblasts: Understanding Their Heterogeneity. Cancers (Basel) 2020; 12:E3108. [PMID: 33114328 PMCID: PMC7690906 DOI: 10.3390/cancers12113108] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 10/12/2020] [Accepted: 10/21/2020] [Indexed: 02/06/2023] Open
Abstract
The tumor microenvironment (TME) plays a critical role in tumor progression. Among its multiple components are cancer-associated fibroblasts (CAFs) that are the main suppliers of extracellular matrix molecules and important contributors to inflammation. As a source of growth factors, cytokines, chemokines and other regulatory molecules, they participate in cancer progression, metastasis, angiogenesis, immune cell reprogramming and therapeutic resistance. Nevertheless, their role is not fully understood, and is sometimes controversial due to their heterogeneity. CAFs are heterogeneous in their origin, phenotype, function and presence within tumors. As a result, strategies to target CAFs in cancer therapy have been hampered by the difficulties in better defining the various populations of CAFs and by the lack of clear recognition of their specific function in cancer progression. This review discusses how a greater understanding of the heterogeneous nature of CAFs could lead to better approaches aimed at their use or at their targeting in the treatment of cancer.
Collapse
Affiliation(s)
- Kévin Louault
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
- Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Rong-Rong Li
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA;
| | - Yves A. DeClerck
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
- Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
- Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
| |
Collapse
|
|
49
|
Pietrobono D, Giacomelli C, Marchetti L, Martini C, Trincavelli ML. High Adenosine Extracellular Levels Induce Glioblastoma Aggressive Traits Modulating the Mesenchymal Stromal Cell Secretome. Int J Mol Sci 2020; 21:E7706. [PMID: 33081024 PMCID: PMC7589183 DOI: 10.3390/ijms21207706] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/01/2020] [Accepted: 10/16/2020] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma is an aggressive, fast-growing brain tumor influenced by the composition of the tumor microenvironment (TME) in which mesenchymal stromal cell (MSCs) play a pivotal role. Adenosine (ADO), a purinergic signal molecule, can reach up to high micromolar concentrations in TME. The activity of specific adenosine receptor subtypes on glioma cells has been widely explored, as have the effects of MSCs on tumor progression. However, the effects of high levels of ADO on glioma aggressive traits are still unclear as is its role in cancer cells-MSC cross-talk. Herein, we first studied the role of extracellular Adenosine (ADO) on isolated human U343MG cells as a glioblastoma cellular model, finding that at high concentrations it was able to prompt the gene expression of Snail and ZEB1, which regulate the epithelial-mesenchymal transition (EMT) process, even if a complete transition was not reached. These effects were mediated by the induction of ERK1/2 phosphorylation. Additionally, ADO affected isolated bone marrow derived MSCs (BM-MSCs) by modifying the pattern of secreted inflammatory cytokines. Then, the conditioned medium (CM) of BM-MSCs stimulated with ADO and a co-culture system were used to investigate the role of extracellular ADO in GBM-MSC cross-talk. The CM promoted the increase of glioma motility and induced a partial phenotypic change of glioblastoma cells. These effects were maintained when U343MG cells and BM-MSCs were co-cultured. In conclusion, ADO may affect glioma biology directly and through the modulation of the paracrine factors released by MSCs overall promoting a more aggressive phenotype. These results point out the importance to deeply investigate the role of extracellular soluble factors in the glioma cross-talk with other cell types of the TME to better understand its pathological mechanisms.
Collapse
Affiliation(s)
| | - Chiara Giacomelli
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (D.P.); (L.M.); (C.M.); (M.L.T.)
| | | | | | | |
Collapse
|
|
50
|
Blavier L, Yang RM, DeClerck YA. The Tumor Microenvironment in Neuroblastoma: New Players, New Mechanisms of Interaction and New Perspectives. Cancers (Basel) 2020; 12:E2912. [PMID: 33050533 PMCID: PMC7599920 DOI: 10.3390/cancers12102912] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 09/28/2020] [Accepted: 09/29/2020] [Indexed: 02/08/2023] Open
Abstract
The contribution of the tumor microenvironment (TME) to cancer progression has been well recognized in recent decades. As cancer therapeutic strategies are increasingly precise and include immunotherapies, knowledge of the nature and function of the TME in a tumor becomes essential. Our understanding of the TME in neuroblastoma (NB), the second most common solid tumor in children, has significantly progressed from an initial focus on its Schwannian component to a better awareness of its complex nature, which includes not only immune but also non-immune cells such as cancer-associated fibroblasts (CAFs), the contribution of which to inflammation and interaction with tumor-associated macrophages (TAMs) is now recognized. Recent studies on the TME landscape of NB tumors also suggest significant differences between MYCN-amplified (MYCN-A) and non-amplified (MYCN-NA) tumors, in their content in stromal and inflammatory cells and their immunosuppressive activity. Extracellular vesicles (EVs) released by cells in the TME and microRNAs (miRs) present in their cargo could play important roles in the communication between NB cells and the TME. This review article discusses these new aspects of the TME in NB and the impact that information on the TME landscape in NB will have in the design of precise, biomarker-integrated clinical trials.
Collapse
Affiliation(s)
- Laurence Blavier
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (L.B.); (R.-M.Y.)
- Division of Hematology, Oncology and Blood and Bone Marrow Transplantation, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Ren-Ming Yang
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (L.B.); (R.-M.Y.)
- Division of Hematology, Oncology and Blood and Bone Marrow Transplantation, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Yves A. DeClerck
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (L.B.); (R.-M.Y.)
- Division of Hematology, Oncology and Blood and Bone Marrow Transplantation, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| |
Collapse
|