|
1
|
Fang J, Rao X, Wang C, Wang Y, Wu C, Zhou R. Role of exosomes in modulating non-small cell lung cancer radiosensitivity. Front Pharmacol 2024; 15:1471476. [PMID: 39737074 PMCID: PMC11683128 DOI: 10.3389/fphar.2024.1471476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Accepted: 12/02/2024] [Indexed: 01/01/2025] Open
Abstract
Non-small cell lung cancer (NSCLC) constitutes a significant proportion of lung cancer cases, and despite advancements in treatment modalities, radiotherapy resistance remains a substantial hurdle in effective cancer management. Exosomes, which are small vesicles secreted by cells, have emerged as pivotal players in intercellular communication and influence various biological processes, including cancer progression and the response to therapy. This review discusses the intricate role of exosomes in the modulation of NSCLC radiosensitivity. The paper focuses on NSCLC and highlights how tumor-derived exosomes contribute to radioresistance by enhancing DNA repair, modulating immune responses, and altering the tumor microenvironment. We further explore the potential of mesenchymal stem cell-derived exosomes to overcome radiotherapy resistance and their potential as biomarkers for predicting therapeutic outcomes. Understanding the mechanisms by which exosomes affect radiotherapy can provide new avenues for enhancing treatment efficacy and improving the survival rates of patients with NSCLC.
Collapse
Affiliation(s)
- Jincheng Fang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinrui Rao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Changjian Wang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yangchenxi Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Chuangyan Wu
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Zhou
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| |
Collapse
|
|
2
|
Valdivia-Silva J, Chinney-Herrera A. Chemokine receptors and their ligands in breast cancer: The key roles in progression and metastasis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 388:124-161. [PMID: 39260935 DOI: 10.1016/bs.ircmb.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Chemokines and their receptors are a family of chemotactic cytokines with important functions in the immune response in both health and disease. Their known physiological roles such as the regulation of leukocyte trafficking and the development of immune organs generated great interest when it was found that they were also related to the control of early and late inflammatory stages in the tumor microenvironment. In fact, in breast cancer, an imbalance in the synthesis of chemokines and/or in the expression of their receptors was attributed to be involved in the regulation of disease progression, including invasion and metastasis. Research in this area is progressing rapidly and the development of new agents based on chemokine and chemokine receptor antagonists are emerging as attractive alternative strategies. This chapter provides a snapshot of the different functions reported for chemokines and their receptors with respect to the potential to regulate breast cancer progression.
Collapse
Affiliation(s)
- Julio Valdivia-Silva
- Centro de Investigación en Bioingenieria (BIO), Universidad de Ingenieria y Tecnologia-UTEC, Barranco, Lima, Peru.
| | - Alberto Chinney-Herrera
- Facultad de Medicina, Universidad Nacional Autonoma de Mexico-UNAM, Ciudad Universitaria, Coyoacan, Ciudad de Mexico, Mexico
| |
Collapse
|
|
3
|
Feng Y, Qiao S, Chen J, Wen X, Chen Y, Song X, Xu J, Qiao X, Yang J, Zhang S, Feng Y, Gao Y. M2-Type Macrophages and Cancer-Associated Fibroblasts Combine to Promote Colorectal Cancer Liver Metastases. Onco Targets Ther 2024; 17:243-260. [PMID: 38558848 PMCID: PMC10981424 DOI: 10.2147/ott.s447502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 03/19/2024] [Indexed: 04/04/2024] Open
Abstract
Purpose This research explored the association between CD163-labeled M2-type macrophages and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) of 38 colorectal cancer (CRC) liver metastases. In addition, we investigated the correlation differences between M2-type macrophages and CAFs in the tumor microenvironments of 38 primary colorectal cancer patients with confirmed liver metastases and 946 colorectal cancer patients, as well as possible mechanisms of action between the two cells. Methods The Immunohistochemistry (IHC) method was applied to detect the expression levels of M2-type macrophages and CAFs in the tissues of 984 cases of CRC and to analyze the correlation between M2-type macrophages and CAFs in colorectal cancer tissues. The IHC method was also applied to detect the expression levels of M2-type macrophages and CAFs in the liver metastases of 38 cases of CRC in the experimental group and to analyze the correlation between the two cells in liver metastases. Results 1. M2-type macrophages and CAFs expression were significantly higher in 38 primary colorectal cancer patients compared to 946 controls, and the expression of M2-type macrophages was significantly positively correlated with CAFs. 2. In 984 CRC cases, M2-type macrophages and CAFs expression levels were significantly higher in the cancer tissues than in the paired paracancerous tissues. 3. The expression levels of M2-type macrophages and CAFs in primary colorectal cancer were significantly higher in the experimental group than in colorectal cancer tissues without distant metastasis. Conclusion M2-type macrophages and CAFs are involved in the development of the colorectal cancer tumor microenvironment, and their interaction influences the initiation and progression of liver metastasis in colorectal cancer. It may provide new clinical ideas for early diagnosis of CRC liver metastases and searching for immune targets.
Collapse
Affiliation(s)
- Yunpeng Feng
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Shifeng Qiao
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Jie Chen
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Xin Wen
- Department of Pathology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Yanlei Chen
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Xiaoyu Song
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Jiaxin Xu
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Xiucheng Qiao
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Jing Yang
- Department of Pathology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Shenshen Zhang
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Yang Feng
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| | - Yu Gao
- School of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China
| |
Collapse
|
|
4
|
Cao Y. Neural induction drives body axis formation during embryogenesis, but a neural induction-like process drives tumorigenesis in postnatal animals. Front Cell Dev Biol 2023; 11:1092667. [PMID: 37228646 PMCID: PMC10203556 DOI: 10.3389/fcell.2023.1092667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 04/17/2023] [Indexed: 05/27/2023] Open
Abstract
Characterization of cancer cells and neural stem cells indicates that tumorigenicity and pluripotency are coupled cell properties determined by neural stemness, and tumorigenesis represents a process of progressive loss of original cell identity and gain of neural stemness. This reminds of a most fundamental process required for the development of the nervous system and body axis during embryogenesis, i.e., embryonic neural induction. Neural induction is that, in response to extracellular signals that are secreted by the Spemann-Mangold organizer in amphibians or the node in mammals and inhibit epidermal fate in ectoderm, the ectodermal cells lose their epidermal fate and assume the neural default fate and consequently, turn into neuroectodermal cells. They further differentiate into the nervous system and also some non-neural cells via interaction with adjacent tissues. Failure in neural induction leads to failure of embryogenesis, and ectopic neural induction due to ectopic organizer or node activity or activation of embryonic neural genes causes a formation of secondary body axis or a conjoined twin. During tumorigenesis, cells progressively lose their original cell identity and gain of neural stemness, and consequently, gain of tumorigenicity and pluripotency, due to various intra-/extracellular insults in cells of a postnatal animal. Tumorigenic cells can be induced to differentiation into normal cells and integrate into normal embryonic development within an embryo. However, they form tumors and cannot integrate into animal tissues/organs in a postnatal animal because of lack of embryonic inducing signals. Combination of studies of developmental and cancer biology indicates that neural induction drives embryogenesis in gastrulating embryos but a similar process drives tumorigenesis in a postnatal animal. Tumorigenicity is by nature the manifestation of aberrant occurrence of pluripotent state in a postnatal animal. Pluripotency and tumorigenicity are both but different manifestations of neural stemness in pre- and postnatal stages of animal life, respectively. Based on these findings, I discuss about some confusion in cancer research, propose to distinguish the causality and associations and discriminate causal and supporting factors involved in tumorigenesis, and suggest revisiting the focus of cancer research.
Collapse
Affiliation(s)
- Ying Cao
- Shenzhen Research Institute of Nanjing University, Shenzhen, China
- MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Medical School, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory of Molecular Medicine of Medical School, Nanjing University, Nanjing, China
| |
Collapse
|
|
5
|
Wu J, Wang F, Dong J, Zhang S, Li N, Zhao H, Liu X, Gao Z, Zhang B, Tian G. Therapeutic Response of Multifunctional Lipid and Micelle Formulation in Hepatocellular Carcinoma. ACS APPLIED MATERIALS & INTERFACES 2022; 14:45110-45123. [PMID: 36167351 DOI: 10.1021/acsami.2c10446] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Hepatic stellate cells (HSCs), as an important part of the tumor microenvironment (TME), could be activated by tumor cells as cancer-associated fibroblasts (CAFs), thereby promoting the production of extracellular matrix (ECM) and favoring the development of tumors. Therefore, blocking the "CAFs-ECM" axis is a promising pathway to improve antitumor efficacy. Based on this, we developed a multifunctional nanosized delivery system composed of hyaluronic acid-modified pH-sensitive liposomes (CTHLs) and glycyrrheic acid-modified nanomicelles (DGNs), which combines the advantages of targeted delivery, pH-sensitivity, and deep drug penetration. To mimic actual TME, a novel HSCs+BEL-7402 cocultured cell model and a m-HSCs+H22 coimplanted mice model were established. As expected, CTHLs and DGNs could target CAFs and tumor cells, respectively, and promote the drug penetration and retention in tumor regions. Notably, CTHLs+DGNs not only exhibited a superior antitumor effect in three-level tumor-bearing mice but also presented excellent antimetastasis efficiency in lung-metastatic mice. The antitumor mechanism revealed that the lipid&micelle mixed formulations effectively inhibited the activation of CAFs, reduced the deposition of ECM, and reversed the epithelial-mesenchymal transition (EMT) of tumor cells. In brief, the nanosized delivery system composed of CTHLs and DGNs could effectively improve the therapeutic effect of liver cancer by blocking the "CAFs-ECM" axis, which has a good clinical application prospect.
Collapse
Affiliation(s)
- Jingliang Wu
- School of Nursing, Weifang University of Science and Technology, Weifang, 262700, P.R. China
| | - Fangqing Wang
- School of Nursing, Weifang University of Science and Technology, Weifang, 262700, P.R. China
- School of Life Science and Technology, Weifang Medical University, Weifang, 261053, P.R. China
| | - Jinping Dong
- School of Nursing, Weifang University of Science and Technology, Weifang, 262700, P.R. China
| | - Suqiu Zhang
- School of Nursing, Weifang University of Science and Technology, Weifang, 262700, P.R. China
| | - Na Li
- School of Nursing, Weifang University of Science and Technology, Weifang, 262700, P.R. China
| | - Huifang Zhao
- School of Nursing, Weifang University of Science and Technology, Weifang, 262700, P.R. China
| | - Xuemin Liu
- School of Nursing, Weifang University of Science and Technology, Weifang, 262700, P.R. China
| | - Zhiqin Gao
- School of Life Science and Technology, Weifang Medical University, Weifang, 261053, P.R. China
| | - Bo Zhang
- School of Pharmacy, Weifang Medical University, Weifang, 261053, P.R. China
| | - Guixiang Tian
- School of Life Science and Technology, Weifang Medical University, Weifang, 261053, P.R. China
| |
Collapse
|
|
6
|
Dominguez-Gutierrez PR, Kwenda EP, Donelan W, Miranda M, Doty A, O'Malley P, Crispen PL, Kusmartsev S. Detection of PD-L1-Expressing Myeloid Cell Clusters in the Hyaluronan-Enriched Stroma in Tumor Tissue and Tumor-Draining Lymph Nodes. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:2829-2836. [PMID: 35589125 DOI: 10.4049/jimmunol.2100026] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/03/2022] [Indexed: 12/30/2022]
Abstract
Expression of the transmembrane protein PD-L1 is frequently upregulated in cancer. Because PD-L1-expressing cells can induce apoptosis or anergy of T lymphocytes through binding to the PD1 receptor, the PD-L1-mediated inhibition of activated PD1+ T cells is considered a major pathway for tumor immune escape. However, the mechanisms that regulate the expression of PD-L1 in the tumor microenvironment are not fully understood. Analysis of organotypic tumor tissue slice cultures, obtained from mice with implanted syngeneic tumors (MBT2 bladder tumors in C3H mice, Renca kidney, and CT26 colon tumors in BALB/c mice), as well as from patients with cancer, revealed that tumor-associated hyaluronan (HA) supports the development of immunosuppressive PD-L1+ macrophages. Using genetically modified tumor cells, we identified epithelial tumor cells and cancer-associated mesenchymal fibroblast-like cells as a major source of HA in the tumor microenvironment. These HA-producing tumor cells, and particularly the vimentin-positive fibroblast-like cells of bone marrow origin, directly interact with tumor-recruited myeloid cells to form large stromal congregates/clusters that are highly enriched for both HA and PD-L1. Furthermore, similar cell clusters composed of HA-producing fibroblast-like cells and PD-L1+ macrophages were detected in tumor-draining, but not in distant, lymph nodes. Collectively, our findings indicate that the formation of multiple large HA-enriched stromal clusters that support the development of PD-L1-expressing APCs in the tumor microenvironment and draining lymph nodes could contribute to the immune escape and resistance to immunotherapy in cancer.
Collapse
Affiliation(s)
| | - Elizabeth P Kwenda
- Department of Urology and Shands Cancer Center, University of Florida, Gainesville, FL; and
| | - William Donelan
- Department of Urology and Shands Cancer Center, University of Florida, Gainesville, FL; and
| | - Mariza Miranda
- Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL
| | - Andria Doty
- Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL
| | - Padraic O'Malley
- Department of Urology and Shands Cancer Center, University of Florida, Gainesville, FL; and
| | - Paul L Crispen
- Department of Urology and Shands Cancer Center, University of Florida, Gainesville, FL; and
| | - Sergei Kusmartsev
- Department of Urology and Shands Cancer Center, University of Florida, Gainesville, FL; and
| |
Collapse
|
|
7
|
Li Q. Role of exosomes in cellular communication between tumor cells and the tumor microenvironment (Review). Oncol Lett 2022; 24:240. [PMID: 35720493 PMCID: PMC9185148 DOI: 10.3892/ol.2022.13360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 04/26/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Qiao Li
- Department of Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, Hubei 430000, P.R. China
| |
Collapse
|
|
8
|
Gül D, Schweitzer A, Khamis A, Knauer SK, Ding GB, Freudelsperger L, Karampinis I, Strieth S, Hagemann J, Stauber RH. Impact of Secretion-Active Osteoblast-Specific Factor 2 in Promoting Progression and Metastasis of Head and Neck Cancer. Cancers (Basel) 2022; 14:2337. [PMID: 35565465 PMCID: PMC9106029 DOI: 10.3390/cancers14092337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/28/2022] [Accepted: 05/05/2022] [Indexed: 11/16/2022] Open
Abstract
Treatment success of head and neck cancer (HNC) is still hampered by tumor relapse due to metastases. Our study aimed to identify biomarkers by exploiting transcriptomics profiles of patient-matched metastases, primary tumors, and normal tissue mucosa as well as the TCGA HNC cohort data sets. Analyses identified osteoblast-specific factor 2 (OSF-2) as significantly overexpressed in lymph node metastases and primary tumors compared to normal tissue. High OSF-2 levels correlate with metastatic disease and reduced overall survival of predominantly HPV-negative HNC patients. No significant correlation was observed with tumor localization or therapy response. These findings were supported by the fact that OSF-2 expression was not elevated in cisplatin-resistant HNC cell lines. OSF-2 was strongly expressed in tumor-associated fibroblasts, suggesting a tumor microenvironment-promoting function. Molecular cloning and expression studies of OSF-2 variants from patients identified an evolutionary conserved bona fide protein secretion signal (1MIPFLPMFSLLLLLIVNPINA21). OSF-2 enhanced cell migration and cellular survival under stress conditions, which could be mimicked by the extracellular administration of recombinant protein. Here, OSF-2 executes its functions via ß1 integrin, resulting in the phosphorylation of PI3K and activation of the Akt/PKB signaling pathway. Collectively, we suggest OSF-2 as a potential prognostic biomarker and drug target, promoting metastases by supporting the tumor microenvironment and lymph node metastases survival rather than by enhancing primary tumor proliferation or therapy resistance.
Collapse
Affiliation(s)
- Désirée Gül
- Department of Otorhinolaryngology, Head and Neck Surgery, Molecular and Cellular Oncology, University Medical Center, 55131 Mainz, Germany; (A.S.); (A.K.); (L.F.); (J.H.)
| | - Andrea Schweitzer
- Department of Otorhinolaryngology, Head and Neck Surgery, Molecular and Cellular Oncology, University Medical Center, 55131 Mainz, Germany; (A.S.); (A.K.); (L.F.); (J.H.)
| | - Aya Khamis
- Department of Otorhinolaryngology, Head and Neck Surgery, Molecular and Cellular Oncology, University Medical Center, 55131 Mainz, Germany; (A.S.); (A.K.); (L.F.); (J.H.)
- Oral Pathology Department, Faculty of Dentistry, Alexandria University, El Azareta, Alexandria, Egypt
| | - Shirley K. Knauer
- Institute for Molecular Biology, Centre for Medical Biotechnology (ZMB), University Duisburg-Essen, Universitätsstraße, 45117 Essen, Germany;
| | - Guo-Bin Ding
- Institute of Biotechnology, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China;
| | - Laura Freudelsperger
- Department of Otorhinolaryngology, Head and Neck Surgery, Molecular and Cellular Oncology, University Medical Center, 55131 Mainz, Germany; (A.S.); (A.K.); (L.F.); (J.H.)
| | - Ioannis Karampinis
- Academic Thoracic Center, University Medical Center Mainz, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
| | - Sebastian Strieth
- Department of Otorhinolaryngology, University Medical Center Bonn, 53127 Bonn, Germany;
| | - Jan Hagemann
- Department of Otorhinolaryngology, Head and Neck Surgery, Molecular and Cellular Oncology, University Medical Center, 55131 Mainz, Germany; (A.S.); (A.K.); (L.F.); (J.H.)
| | - Roland H. Stauber
- Department of Otorhinolaryngology, Head and Neck Surgery, Molecular and Cellular Oncology, University Medical Center, 55131 Mainz, Germany; (A.S.); (A.K.); (L.F.); (J.H.)
- Institute of Biotechnology, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China;
| |
Collapse
|
|
9
|
Li Z, Liu C, Li C, Wang F, Liu J, Zheng Z, Wu J, Zhang B. Irinotecan/scFv co-loaded liposomes coaction on tumor cells and CAFs for enhanced colorectal cancer therapy. J Nanobiotechnology 2021; 19:421. [PMID: 34906155 PMCID: PMC8670172 DOI: 10.1186/s12951-021-01172-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 11/30/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Cancer-associated fibroblasts (CAFs), as an important component of stroma, not only supply the "soils" to promote tumor invasion and metastasis, but also form a physical barrier to hinder the penetration of therapeutic agents. Based on this, the combinational strategy that action on both tumor cells and CAFs simultaneously would be a promising approach for improving the antitumor effect. RESULTS In this study, the novel multifunctional liposomes (IRI-RGD/R9-sLip) were designed, which integrated the advantages including IRI and scFv co-loading, different targets, RGD mediated active targeting, R9 promoting cell efficient permeation and lysosomal escape. As expected, IRI-RGD/R9-sLip showed enhanced cytotoxicity in different cell models, effectively increased the accumulation in tumor sites, as well as exhibited deep permeation ability both in vitro and in vivo. Notably, IRI-RGD/R9-sLip not only exhibited superior in vivo anti-tumor effect in both CAFs-free and CAFs-abundant bearing mice models, but also presented excellent anti-metastasis efficiency in lung metastasis model. CONCLUSION In a word, the novel combinational strategy by coaction on both "seeds" and "soils" of the tumor provides a new approach for cancer therapy, and the prepared liposomes could efficiently improve the antitumor effect with promising clinical application prospects.
Collapse
Affiliation(s)
- Zhaohuan Li
- School of Pharmacy, Weifang Medical University Weifang, Shandong, 261053, People's Republic of China
| | - Chunxi Liu
- Department of Pharmacy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, 250012, Shandong, People's Republic of China
| | - Chenglei Li
- School of Pharmacy, Weifang Medical University Weifang, Shandong, 261053, People's Republic of China
| | - Fangqing Wang
- School of Bioscience and Technology, Weifang Medical University, Weifang, 261053, Shandong, People's Republic of China
| | - Jianhao Liu
- School of Pharmacy, Weifang Medical University Weifang, Shandong, 261053, People's Republic of China
| | - Zengjuan Zheng
- School of Pharmacy, Weifang Medical University Weifang, Shandong, 261053, People's Republic of China
| | - Jingliang Wu
- School of Bioscience and Technology, Weifang Medical University, Weifang, 261053, Shandong, People's Republic of China.
| | - Bo Zhang
- School of Pharmacy, Weifang Medical University Weifang, Shandong, 261053, People's Republic of China.
| |
Collapse
|
|
10
|
Zhang P, Xu M, Ding J, Chen J, Zhang T, Huo L, Liu Z. Fatty acid-conjugated radiopharmaceuticals for fibroblast activation protein-targeted radiotherapy. Eur J Nucl Med Mol Imaging 2021; 49:1985-1996. [PMID: 34746969 DOI: 10.1007/s00259-021-05591-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 10/11/2021] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Radiopharmaceuticals that target cancer-associated fibroblasts (CAFs) have become an increasingly attractive strategy for cancer theranostics. Recently, a series of fibroblast activation protein inhibitor (FAPI)-based radiopharmaceuticals have been successfully applied to the diagnosis of a variety of cancers and exhibited excellent tumor selectivity. Nevertheless, CAF-targeted radionuclide therapy encounters difficulties in cancer treatment, as the tumor uptake and retention of FAPIs are insufficient. To meet this challenge, we tried to conjugate albumin-binding moiety to FAPI molecule for prolonged circulation that may increase the accumulation and retention of radiopharmaceuticals in tumor. METHODS Two fatty acids, lauric acid (C12) and palmitic acid (C16), were conjugated to FAPI-04 to give two albumin-binding FAPI radiopharmaceuticals, denoted as FAPI-C12 and FAPI-C16, respectively. They had been radiolabeled with gallium-68, yttrium-86, and lutecium-177 for stability study, binding affinity assay, PET and SPECT imaging, biodistribution, and radionuclide therapy study to systematically evaluate their potential for CAF-targeted radionuclide therapy. RESULTS FAPI-C12 and FAPI-C16 showed high binding affinity to FAP with the IC50 of 6.80 ± 0.58 nM and 5.06 ± 0.69 nM, respectively. They were stable in both saline and plasma. The tumor uptake of [68Ga]Ga-FAPI-04 decreased by 56.9% until 30 h after treated with FAPI-C16 before, and the uptakes of [86Y]Y-FAPI-C12 and [86Y]Y-FAPI-C16 in HT-1080-FAP tumor were both much higher than that of HT-1080-Vehicle tumor which identified the high FAP specific of these two radiopharmaceuticals. Both FAPI-C12 and FAPI-C16 showed notably longer circulation and significantly enhanced tumor uptake than those of FAPI-04. [177Lu]Lu-FAPI-C16 had the higher tumor uptake at both 24 h (11.22 ± 1.18%IA/g) and 72 h (6.50 ± 1.19%IA/g) than that of [177Lu]Lu-FAPI-C12 (24 h, 7.54 ± 0.97%IA/g; 72 h, 2.62 ± 0.65%IA/g); both of them were much higher than [177Lu]Lu-FAPI-04 with the value of 1.24 ± 0.54%IA/g at 24 h after injection. Significant tumor volume inhibition of [177Lu]Lu-FAPI-C16 at the high activity of 29.6 MBq was observed, and the median survival was 28 days which was much longer than that of the [177Lu]Lu-FAPI-04 treated group of which the median survival was only 10 days. CONCLUSION This proof-of-concept study validates the hypothesis that conjugation of albumin binders may shift the pharmacokinetics and enhance the tumor uptake of FAPI-based radiopharmaceuticals. This could be a general strategy to transform the diagnostic FAP-targeted radiopharmaceuticals into their therapeutic pairs.
Collapse
Affiliation(s)
- Pu Zhang
- Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, 100871, Beijing, China
| | - Mengxin Xu
- Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, 100871, Beijing, China
| | - Jie Ding
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Junyi Chen
- Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, 100871, Beijing, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Li Huo
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China.
| | - Zhibo Liu
- Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, 100871, Beijing, China.
- Peking University-Tsinghua University Center for Life Sciences, Beijing, 100871, China.
| |
Collapse
|
|
11
|
Oh HJ, Kim J, Kim H, Choi N, Chung S. Microfluidic Reconstitution of Tumor Microenvironment for Nanomedical Applications. Adv Healthc Mater 2021; 10:e2002122. [PMID: 33576178 DOI: 10.1002/adhm.202002122] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Indexed: 12/17/2022]
Abstract
Nanoparticles have an extensive range of diagnostic and therapeutic applications in cancer treatment. However, their current clinical translation is slow, mainly due to the failure to develop preclinical evaluation techniques that can draw similar conclusions to clinical outcomes by adequately mimicking nanoparticle behavior in complicated tumor microenvironments (TMEs). Microfluidic methods offer significant advantages over conventional in vitro methods to resolve these challenges by recapitulating physiological cues of the TME such as the extracellular matrix, shear stress, interstitial flow, soluble factors, oxygen, and nutrient gradients. The methods are capable of de-coupling microenvironmental features, spatiotemporal controlling of experimental sequences, and high throughput readouts in situ. This progress report highlights the recent achievements of microfluidic models to reconstitute the physiological microenvironment, especially for nanomedical tools for cancer treatment.
Collapse
Affiliation(s)
- Hyun Jeong Oh
- School of Mechanical Engineering Korea University Seoul 02841 Republic of Korea
| | - Jaehoon Kim
- School of Mechanical Engineering Korea University Seoul 02841 Republic of Korea
| | - Hyunho Kim
- School of Mechanical Engineering Korea University Seoul 02841 Republic of Korea
| | - Nakwon Choi
- Center for BioMicrosystems Brain Science Institute Korea Institute of Science and Technology (KIST) Seoul 02792 Republic of Korea
- Division of Bio‐Medical Science & Technology KIST School Korea University of Science and Technology (UST) Seoul 34113 Republic of Korea
- KU‐KIST Graduate School of Converging Science and Technology Korea University Seoul 02841 Republic of Korea
| | - Seok Chung
- School of Mechanical Engineering Korea University Seoul 02841 Republic of Korea
- KU‐KIST Graduate School of Converging Science and Technology Korea University Seoul 02841 Republic of Korea
| |
Collapse
|
|
12
|
Feng Y, Zhao Y, Li Y, Peng T, Kuang Y, Shi X, Wang G, Peng F, Yu C. Inhibition of Fibroblast Activation in Uterine Leiomyoma by Components of Rhizoma Curcumae and Rhizoma Sparganii. Front Public Health 2021; 9:650022. [PMID: 33732680 PMCID: PMC7957009 DOI: 10.3389/fpubh.2021.650022] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Background: The herbs Rhizoma Curcumae and Rhizoma Sparganii (RCRS) are often used in traditional Chinese medicine for the treatment of uterine leiomyoma (UL). The effectiveness of RCRS for the treatment of UL has been confirmed in our previous studies. Purpose: This study aimed to investigate the molecular mechanism by which RCRS inhibits the activation of fibroblast activation protein (FAP) and prevents UL in rats. Study Design and Methods: A Sprague Dawley (SD) rat model of UL was established via estrogen and progesterone load combined with external stimulation. Histological analyses, enzyme-linked immunosorbent assays, and western blotting were performed to evaluate the effect of RCRS on UL and elucidate its mechanism of action. Results: Our data showed that the treatment of SD rats with RCRS significantly reduced the expression of extracellular matrix component collagen, FAP, and transforming growth factor beta (a FAP-activating factor) and the phosphorylation of the cell proliferation pathway-related signaling factors AKT/MEK/ERK. Conclusion: Our results suggest that RCRS is effective in the prevention and treatment of UL in rats, and RCRS may exert its functions by inhibiting the activation of tumor-associated fibroblasts and cell proliferation and by improving the tumor extracellular matrix.
Collapse
Affiliation(s)
- Yewen Feng
- Basic Medicine College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yumin Zhao
- Basic Medicine College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yao Li
- Department of Pediatrics, The Second Hospital Affiliated Shaanxi University of Chinese Medicine, Shaanxi, China
| | - Teng Peng
- Basic Medicine College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu Kuang
- Suining Traditional Chinese Medicine Hospital, Sichuan, China
| | - Xingming Shi
- Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Gang Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Sichuan, China
| | - Fu Peng
- West China School of Pharmacy, Sichuan University, Sichuan, China
| | - Chenghao Yu
- Basic Medicine College, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,State Key Laboratory of Southwestern Chinese Medicine Resources, Sichuan, China
| |
Collapse
|
|
13
|
Sazeides C, Le A. Metabolic Relationship Between Cancer-Associated Fibroblasts and Cancer Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1311:189-204. [PMID: 34014544 DOI: 10.1007/978-3-030-65768-0_14] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME), play an important role in cancer initiation, progression, and metastasis. Recent findings have demonstrated that the TME not only provides physical support for cancer cells but also directs cell-to-cell interactions (in this case, the interaction between cancer cells and CAFs). As cancer progresses, the CAFs also coevolve, transitioning from an inactivated state to an activated state. The elucidation and understanding of the interaction between cancer cells and CAFs will pave the way for new cancer therapies [1-3].
Collapse
Affiliation(s)
| | - Anne Le
- Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. .,Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, USA.
| |
Collapse
|
|
14
|
Anchan A, Martin O, Hucklesby JJW, Finlay G, Johnson RH, Robilliard LD, O’Carroll SJ, Angel CE, Graham ES. Analysis of Melanoma Secretome for Factors That Directly Disrupt the Barrier Integrity of Brain Endothelial Cells. Int J Mol Sci 2020; 21:ijms21218193. [PMID: 33139674 PMCID: PMC7663570 DOI: 10.3390/ijms21218193] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 10/28/2020] [Accepted: 10/28/2020] [Indexed: 12/19/2022] Open
Abstract
We have recently demonstrated that invasive melanoma cells are capable of disrupting the brain endothelial barrier integrity. This was shown using ECIS biosensor technology, which revealed rapid disruption via the paracellular junctions. In this paper, we demonstrate that melanoma cells secrete factors (e.g., cytokines) that weaken the endothelial barrier integrity. Through proteome profiling, we attempt to identify the barrier-disrupting cytokines. Melanoma conditioned media were collected from three New Zealand melanoma lines. ECIS technology was used to assess if the conditioned media disrupted the endothelial barrier independent of the melanoma cells. The melanoma cell secretome was assessed using cytometric bead array (CBA), Luminex immunoassay and multiplex Proteome Profilers, to detect the expression of secretory proteins, which may facilitate metastasis. Finally, ECIS technology was used to assess the direct effects of secreted proteins identified as candidates from the proteome screens. We show that melanoma-conditioned media significantly disrupted the brain endothelial barrier, however, to a much lesser extent than the cells from which they were collected. Cytokine and proteome profiling of the conditioned media showed evidence of high concentrations of approximately 15 secreted proteins (including osteopontin, IL-8, GDF-15, MIF and VEGF). These 15 secreted proteins were expressed variably across the melanoma lines. Surprisingly, the addition of these individually to the brain endothelial cells did not substantially affect the barrier integrity. ANGPTL-4 and TGFβ were also produced by the melanoma cells. Whilst TGFβ-1 had a pronounced effect on the barrier integrity, surprisingly ANGPTL-4 did not. However, its C-terminal fragment did and within a very similar period to the conditioned media, albeit not to the same extent. Herein we show that melanoma cells produce a wide-range of soluble factors at high concentrations, which most likely favour support or survival of the cancer cells. Most of these, except for TGFβ-1 and the C-terminal fragment of ANGPTL-4, did not have an impact on the integrity of the brain endothelial cells.
Collapse
Affiliation(s)
- Akshata Anchan
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (A.A.); (O.M.); (J.J.W.H.); (G.F.); (L.D.R.)
- Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (R.H.J.); (S.J.O.)
| | - Olivia Martin
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (A.A.); (O.M.); (J.J.W.H.); (G.F.); (L.D.R.)
- Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (R.H.J.); (S.J.O.)
| | - James J. W. Hucklesby
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (A.A.); (O.M.); (J.J.W.H.); (G.F.); (L.D.R.)
- Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (R.H.J.); (S.J.O.)
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland 1010, New Zealand;
| | - Graeme Finlay
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (A.A.); (O.M.); (J.J.W.H.); (G.F.); (L.D.R.)
- Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Rebecca H. Johnson
- Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (R.H.J.); (S.J.O.)
- Department of Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Laverne D. Robilliard
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (A.A.); (O.M.); (J.J.W.H.); (G.F.); (L.D.R.)
- Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (R.H.J.); (S.J.O.)
| | - Simon J. O’Carroll
- Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (R.H.J.); (S.J.O.)
- Department of Anatomy and Medical Imaging, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Catherine E. Angel
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland 1010, New Zealand;
| | - E Scott Graham
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (A.A.); (O.M.); (J.J.W.H.); (G.F.); (L.D.R.)
- Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; (R.H.J.); (S.J.O.)
- Correspondence:
| |
Collapse
|
|
15
|
Ba P, Xu M, Yu M, Li L, Duan X, Lv S, Fu G, Yang J, Yang P, Yang C, Sun Q. Curcumin suppresses the proliferation and tumorigenicity of Cal27 by modulating cancer‐associated fibroblasts of TSCC. Oral Dis 2020; 26:1375-1383. [PMID: 32060973 DOI: 10.1111/odi.13306] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 02/08/2020] [Accepted: 02/10/2020] [Indexed: 12/26/2022]
Affiliation(s)
- Pengfei Ba
- Department of Periodontology School of Stomatology Shandong University Jinan China
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration Shandong University Jinan China
- Department of Periodontology Weihai Stomatological Hospital Weihai China
| | - Mingcai Xu
- Department of Reproductive Medicine Weihai second municipal hospital Affiliated to Qingdao University Weihai China
| | - Miao Yu
- Department of Stomatology Weifang People’s Hospital Weifang China
| | - Linxia Li
- Department of Stomatology Affiliated Hospital of Jining Medical University Jining China
| | - Xiaoyu Duan
- National Engineering Laboratory WeGo Group Co., Ltd Weihai China
| | - Shuyan Lv
- Department of Periodontology Weihai Stomatological Hospital Weihai China
| | - Guo Fu
- Department of Periodontology Weihai Stomatological Hospital Weihai China
| | - Jianbo Yang
- Department of Periodontology Weihai Stomatological Hospital Weihai China
| | - Pishan Yang
- Department of Periodontology School of Stomatology Shandong University Jinan China
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration Shandong University Jinan China
| | - Chengzhe Yang
- Department of Oral and Maxillofacial Surgery Institute of Stomatology Qilu Hospital Shandong University Jinan China
| | - Qinfeng Sun
- Department of Periodontology School of Stomatology Shandong University Jinan China
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration Shandong University Jinan China
| |
Collapse
|
|
16
|
Huang F, Cao Y, Wu G, Chen J, CaihongWang, Lin W, Lan R, Wu B, Xie X, Hong J, Fu L. BMP2 signalling activation enhances bone metastases of non-small cell lung cancer. J Cell Mol Med 2020; 24:10768-10784. [PMID: 32750747 PMCID: PMC7521321 DOI: 10.1111/jcmm.15702] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 07/10/2020] [Accepted: 07/14/2020] [Indexed: 12/13/2022] Open
Abstract
Distant metastases occur when non‐small cell lung cancer (NSCLC) is at late stages. Bone metastasis is one of the most frequent metastases of NSCLC and leads to poor prognosis. It has been reported that high expression of BMP2 in NSCLC correlates with poor survival, but whether BMP2 contributes to NSCLC bone metastasis remains largely unknown. The activation of BMP signalling is found in metastatic bone tumours of mice Lewis lung carcinoma and predicts poor survival in human NSCLC. BMP2 signalling activation can enhance bone metastasis of Lewis lung carcinoma. Moreover, BMP2 secreted by stroma fibroblasts can promote the migration and invasion of NSCLC cells. Besides, in combination with pre‐osteoblast and LLCs, BMP2 could enhance the differentiation of macrophages into osteoclasts to play roles in the osteolytic mechanism of NSCLC bone metastasis. Interestingly, NSCLC cells can also enrich BMP2 to pre‐osteoblasts to function in the osteoblastic mechanism. Our results firstly demonstrate the detailed mechanisms about what roles BMP2 signalling play in enhancing NSCLC bone metastases. These findings provide a new potential therapy choice for preventing bone metastases of NSCLC via the inhibition of BMP2 signalling.
Collapse
Affiliation(s)
- Fei Huang
- Central Laboratory, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Platform for Medical Research at First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Individualized Active Immunotherapy, Fuzhou, China.,Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou, China
| | - Yaqiang Cao
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Gui Wu
- Department of Orthopedics, First Affiliated hospital, Fujian Medical University, Fuzhou, China
| | - Junying Chen
- Central Laboratory, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Platform for Medical Research at First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Individualized Active Immunotherapy, Fuzhou, China.,Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou, China
| | - CaihongWang
- Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou, China.,Department of Radiation Oncology, First Affiliated hospital, Fujian Medical University, Fuzhou, China
| | - Wanzun Lin
- Department of Chemotherapy, First Affiliated hospital, Fujian Medical University, Fuzhou, China
| | - Ruilong Lan
- Central Laboratory, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Platform for Medical Research at First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Individualized Active Immunotherapy, Fuzhou, China.,Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou, China
| | - Bing Wu
- Central Laboratory, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Platform for Medical Research at First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Individualized Active Immunotherapy, Fuzhou, China.,Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou, China
| | - Xianhe Xie
- Department of Chemotherapy, First Affiliated hospital, Fujian Medical University, Fuzhou, China
| | - Jinsheng Hong
- Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou, China.,Department of Radiation Oncology, First Affiliated hospital, Fujian Medical University, Fuzhou, China
| | - Lengxi Fu
- Central Laboratory, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Platform for Medical Research at First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Individualized Active Immunotherapy, Fuzhou, China.,Key Laboratory of Radiation Biology of Fujian Province Universities, Fuzhou, China
| |
Collapse
|
|
17
|
Microenvironment remodeled by tumor and stromal cells elevates fibroblast-derived COL1A1 and facilitates ovarian cancer metastasis. Exp Cell Res 2020; 394:112153. [PMID: 32589888 DOI: 10.1016/j.yexcr.2020.112153] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 06/08/2020] [Accepted: 06/21/2020] [Indexed: 01/25/2023]
Abstract
Wide peritoneal metastasis is the cause of the highest lethality of ovarian cancer in gynecologic malignancies. Ascites play a key role in ovarian cancer metastasis, but involved mechanism is uncertain. Here, we performed a quantitative proteomics of ascites, and found that collagen type I alpha 1 (COL1A1) was notably elevated in ascites from epithelial ovarian cancer patients compared to normal peritoneal fluids, and verified that elevated COL1A1 was mainly originated from fibroblasts. COL1A1 promoted migration and invasion of ovarian cancer cells, but such effects were partially eliminated by COL1A1 antibodies. Intraperitoneally injected COL1A1 accelerated intraperitoneal metastasis of ovarian cancer xenograft in NOD/SCID mice. Further, COL1A1 activated downstream AKT phosphorylation by binding to membrane surface receptor integrin β1 (ITGB1). Knockdown or blockage of ITGB1 reversed COL1A1 enhanced migration and invasion in ovarian cancer cells. Conversely, ovarian cancer ascites and fibrinogen promoted fibroblasts to secrete COL1A1. Elevated fibrinogen in ascites might be associated with increased vascular permeability induced by ovarian cancer. Our findings suggest that microenvironment remodeled by tumor cells and stromal cells promotes fibroblasts to secrete COL1A1 and facilitates the metastasis of ovarian cancer, which may provide a new approach for ovarian cancer therapeutics.
Collapse
|
|
18
|
Rousselle P, Scoazec JY. Laminin 332 in cancer: When the extracellular matrix turns signals from cell anchorage to cell movement. Semin Cancer Biol 2020; 62:149-165. [PMID: 31639412 DOI: 10.1016/j.semcancer.2019.09.026] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Revised: 08/22/2019] [Accepted: 09/29/2019] [Indexed: 02/07/2023]
Abstract
Laminin 332 is crucial in the biology of epithelia. This large extracellular matrix protein consists of the heterotrimeric assembly of three subunits - α3, β3, and γ2 - and its multifunctionality relies on a number of extracellular proteolytic processing events. Laminin 332 is central to normal epithelium homeostasis by sustaining cell adhesion, polarity, proliferation, and differentiation. It also supports a major function in epithelial tissue formation, repair, and regeneration by buttressing cell migration and survival and basement membrane assembly. Interest in this protein increased after the discovery that its expression is perturbed in tumor cells, cancer-associated fibroblasts, and the tumor microenvironment. This review summarizes current knowledge regarding the established involvement of the laminin 332 γ2 chain in tumor invasiveness and discusses the role of its α3 and β3 subunits.
Collapse
Affiliation(s)
- Patricia Rousselle
- Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique, UMR 5305, CNRS - Université Lyon 1, Institut de Biologie et Chimie des Protéines, SFR BioSciences Gerland-Lyon Sud, 7 passage du Vercors, F-69367, France.
| | - Jean Yves Scoazec
- Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, 94805 Villejuif cedex, France; Université Paris Sud, Faculté de Médecine de Bicêtre, 94270 Le Kremlin Bicêtre, France
| |
Collapse
|
|
19
|
Li Z, Zheng Z, Li C, Li Z, Wu J, Zhang B. Therapeutic drugs and drug delivery systems targeting stromal cells for cancer therapy: a review. J Drug Target 2020; 28:714-726. [DOI: 10.1080/1061186x.2020.1744157] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Zhaohuan Li
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Zengjuan Zheng
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Chenglei Li
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Zhipeng Li
- School of Bioscience and Technology, Weifang Medical University, Weifang, China
| | - Jingliang Wu
- School of Bioscience and Technology, Weifang Medical University, Weifang, China
| | - Bo Zhang
- School of Pharmacy, Weifang Medical University, Weifang, China
| |
Collapse
|
|
20
|
An Y, Liu F, Chen Y, Yang Q. Crosstalk between cancer-associated fibroblasts and immune cells in cancer. J Cell Mol Med 2019; 24:13-24. [PMID: 31642585 PMCID: PMC6933413 DOI: 10.1111/jcmm.14745] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 08/12/2019] [Accepted: 08/25/2019] [Indexed: 12/21/2022] Open
Abstract
Multiple studies have shown that cancer‐associated fibroblasts (CAFs) play an important role in tumour progression, including carcinogenesis, invasion, metastasis and the chemoresistance of cancer cells. Immune cells, including macrophages, natural killer cells, dendritic cells and T cells, play a dual role in the tumour microenvironment. Although increasing research has focused on studying interactions between distinct cells in the tumour microenvironment, the complex relationships between CAFs and immune cells remain unclear and need further study. Here, we summarize our current understanding of crosstalk between CAFs and immune cells, which may help clarify their diagnostic and therapeutic value in tumour progression.
Collapse
Affiliation(s)
- Yuanyuan An
- Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Fengtian Liu
- Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Ying Chen
- Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Qing Yang
- Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| |
Collapse
|
|
21
|
Sandri BJ, Masvidal L, Murie C, Bartish M, Avdulov S, Higgins L, Markowski T, Peterson M, Bergh J, Yang P, Rolny C, Limper AH, Griffin TJ, Bitterman PB, Wendt CH, Larsson O. Distinct Cancer-Promoting Stromal Gene Expression Depending on Lung Function. Am J Respir Crit Care Med 2019; 200:348-358. [PMID: 30742544 PMCID: PMC6680296 DOI: 10.1164/rccm.201801-0080oc] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 02/08/2019] [Indexed: 12/31/2022] Open
Abstract
Rationale: Chronic obstructive pulmonary disease is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that lung stromal cells activate pathological gene expression programs that support oncogenesis.Objectives: To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer.Methods: The study included subjects with and without lung cancer across a spectrum of lung-function values. We conducted a multiomics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome.Measurements and Main Results: Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation modulating protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms that drove these cancer-associated translation programs differed based on lung function. In subjects with normal to mildly impaired lung function, the mammalian target of rapamycin (mTOR) pathway served as an upstream driver, whereas in subjects with severe airflow obstruction, pathways downstream of pathological extracellular matrix emerged. Consistent with a role during cancer initiation, both the mTOR and extracellular matrix gene expression programs paralleled the activation of previously identified procancer secretomes. Furthermore, an in situ examination of lung tissue showed that stromal fibroblasts expressed cancer-associated proteins from two procancer secretomes: one that included IL-6 (in cases of mild or no airflow obstruction), and one that included BMP1 (in cases of severe airflow obstruction).Conclusions: Two distinct stromal gene expression programs that promote cancer initiation are activated in patients with lung cancer depending on lung function. Our work has implications both for screening strategies and for personalized approaches to cancer treatment.
Collapse
Affiliation(s)
- Brian J. Sandri
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Laia Masvidal
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Carl Murie
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Margarita Bartish
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Svetlana Avdulov
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota
| | - LeeAnn Higgins
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota
| | - Todd Markowski
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota
| | - Mark Peterson
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Jonas Bergh
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | | | - Charlotte Rolny
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Andrew H. Limper
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota; and
| | - Timothy J. Griffin
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota
| | - Peter B. Bitterman
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Chris H. Wendt
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota
- Pulmonary, Allergy, Critical Care, and Sleep Medicine, Veterans Affairs Medical Center, Minneapolis, Minnesota
| | - Ola Larsson
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| |
Collapse
|
|
22
|
Ba P, Zhang X, Yu M, Li L, Duan X, Wang M, Lv S, Fu G, Yang P, Yang C, Sun Q. Cancer associated fibroblasts are distinguishable from peri-tumor fibroblasts by biological characteristics in TSCC. Oncol Lett 2019; 18:2484-2490. [PMID: 31404347 PMCID: PMC6676749 DOI: 10.3892/ol.2019.10556] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 05/22/2019] [Indexed: 12/14/2022] Open
Abstract
The aim of the present study was to investigate the differential biological characteristics between cancer-associated fibroblasts (CAFs) and peri-tumor fibroblasts (PTFs) in tongue squamous cell carcinoma (TSCC). The primary CAFs and PTFs from TSCC were obtained and purified. Cell morphology was observed, and the expression of α-smooth muscle actin (α-SMA), vimentin and cytokeratin 19 (CK19) was detected by immunohistochemistry (IHC). The percentage of α-SMA positive cells in CAFs and PTFs was calculated separately, and α-SMA expression was further confirmed by western blot analysis. Cell viability and the expression of matrix metalloproteinase 2 (MMP2), stromal cell derived factor1 (SDF-1) and transforming growth factor β1 (TGFβ1) in the purified fibroblasts was detected separately. CAFs and PTFs were attained and purified. Compared with PTFs, CAFs were long-fusiform shaped cells with reduced cytoplasm and variable size. CAFs crowded together in a disorderly manner when the cell density was increased, but this phenomenon did not occur with PTFs. IHC results verified that there was no significant difference between CAFs and PTFs in the percentage of cells staining positive for CK19 and vimentin (P>0.05); the percentage of positive staining cells for α-SMA in CAFs was significantly higher compared with that in PTFs (P<0.001) Western blot analysis showed that α-SMA expression in CAFs was 4.3-fold higher compared with that in PTFs (P<0.001). A Cell Counting Kit-8 assay indicated that the viability of CAFs increased significantly compared with that in the PTFs (P<0.05). Reverse transcription-quantitative polymerase chain reaction and ELISA analysis showed that the expression of MMP2, SDF-1 and TGF β1 in CAFs was higher compared with that in PTFs (P<0.05). CAFs are distinguishable from PTFs with respect to their morphology, cellular phenotype, cell viability and pro-carcinogenic cytokine expression.
Collapse
Affiliation(s)
- Pengfei Ba
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, Shandong 250012, P.R. China.,Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, Shandong 250012, P.R. China.,Department of Periodontology, Weihai Stomatological Hospital, Weihai, Shandong 264200, P.R. China
| | - Xiaojuan Zhang
- Department of Stomatology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing 101149, P.R. China
| | - Miao Yu
- Department of Stomatology, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Linxia Li
- Department of Stomatology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Xiaoyu Duan
- National Engineering Laboratory, WeGo Group Co., Ltd., Weihai, Shandong 264200, P.R. China
| | - Mingying Wang
- Department of Periodontology, Weihai Stomatological Hospital, Weihai, Shandong 264200, P.R. China
| | - Shuyan Lv
- Department of Periodontology, Weihai Stomatological Hospital, Weihai, Shandong 264200, P.R. China
| | - Guo Fu
- Department of Periodontology, Weihai Stomatological Hospital, Weihai, Shandong 264200, P.R. China
| | - Pishan Yang
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, Shandong 250012, P.R. China.,Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Chengzhe Yang
- Department of Oral and Maxillofacial Surgery, Qilu Hospital, Institute of Stomatology, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Qinfeng Sun
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, Shandong 250012, P.R. China.,Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, Shandong 250012, P.R. China
| |
Collapse
|
|
23
|
Pang N, Li J, Sun A, Yang Z, Cheng S, Qi XR. Prior anti-CAFs break down the CAFs barrier and improve accumulation of docetaxel micelles in tumor. Int J Nanomedicine 2018; 13:5971-5990. [PMID: 30323586 PMCID: PMC6178342 DOI: 10.2147/ijn.s171224] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Abnormal expression of stromal cells and extracellular matrix in tumor stroma creates a tight barrier, leading to insufficient extravasation and penetration of therapeutic agents. Cancer-associated fibroblasts (CAFs) take on pivotal roles encouraging tumor progression. METHOD To surmount the refractoriness of stroma, we constructed a multi-targeting combined scenario of anti-CAFs agent tranilast and antitumor agent docetaxel micelles (DTX-Ms). Tranilast cut down crosstalk between tumor cells and stromal cells, ameliorated the tumor microenvironment, and enhanced the antiproliferation efficacy of DTX-Ms on cancer cells. RESULTS Diverse experiments demonstrated that tranilast enhanced DTX-Ms' antitumor effect in a two-stage pattern by CAFs ablation, tumor cell migration blocking, and metastasis inhibition. Along with activated CAFs decreasing in vivo, the two-stage therapy succeeded in reducing interstitial fluid pressure, normalizing microvessels, improving micelles penetration and retention, and inhibiting tumor growth and metastasis. Interestingly, tranilast alone failed to inhibit tumor growth in vivo, and it could only be used as an adjuvant medicine together with an antitumor agent. CONCLUSION Our proposed two-stage therapy offers a promising strategy to enhance antitumor effects by breaking down CAFs barrier and increasing micellar delivery efficiency.
Collapse
Affiliation(s)
- Ning Pang
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China,
| | - Ji Li
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China,
| | - Aning Sun
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China,
| | - Zhenzhen Yang
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China,
| | - Shixuan Cheng
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China,
| | - Xian-Rong Qi
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China,
| |
Collapse
|
|
24
|
Soundararajan M, Kannan S. Fibroblasts and mesenchymal stem cells: Two sides of the same coin? J Cell Physiol 2018; 233:9099-9109. [DOI: 10.1002/jcp.26860] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 05/23/2018] [Indexed: 12/13/2022]
Affiliation(s)
| | - Suresh Kannan
- Department of Biomedical Sciences Sri Ramachandra University Chennai Tamil Nadu India
| |
Collapse
|
|
25
|
Schmidt VM, Isachenko V, Rappl G, Rahimi G, Hanstein B, Morgenstern B, Mallmann P, Isachenko E. Comparison of the enzymatic efficiency of Liberase TM and tumor dissociation enzyme: effect on the viability of cells digested from fresh and cryopreserved human ovarian cortex. Reprod Biol Endocrinol 2018; 16:57. [PMID: 29859539 PMCID: PMC5985056 DOI: 10.1186/s12958-018-0374-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 05/23/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The aim of this study was to examine the effectiveness of Tumor Dissociation Enzyme (TDE) on the viability of follicles after digestion of fresh and cryopreserved ovarian cortex fragments (OCFs). METHODS Fresh and thawed OCF from 14 patients (29 ± 6 years), sized 20 to 210 mm3 were randomly distributed into four treatment groups and digested with 16% TDE or 0.05 mg/ml Liberase TM: Group 1, frozen OCF digested with TDE; Group 2, frozen OCF digested with LiberaseTM; Group 3, fresh OCF digested with TDE; and Group 4, fresh OCF digested with Liberase TM. Evaluation of follicle viability was performed under light microscope after staining with Neutral red. For visualization of viable and dead cells under a confocal laser scanning microscope, the follicles were stained with Calcein AM and ethidium homodimer-1. RESULTS The results showed that the number of retrieved follicles was significantly higher (990 vs 487; P < 0.01) in the TDE-treatment group compared to the Liberase TM-group. The presence of intense neutral red stained follicles was significantly higher in Group 1 and Group 3 compared to Group 2 and Group 4 (70.3% ± +/- 6.22 vs 53,1% ± 2.03 and 94.2% ± 6.6 vs 79.1% ± 2.1; P < 0.01). The percentage of Calcein AM stained follicles of class V1 was significantly higher in Group 1 and Group 3 compared to Group 2 and Group 4 (95.97% ± 7.8 vs 87.87% ± 2.4; 97.1% ± 6.8 vs 91.3% ± 2.3; P < 0.01). CONCLUSION The enzymatic digestion of ovarian cortex with TDE provides recovery of a higher number of healthy preantral follicles in contrast to earlier described Liberase TM procedure.
Collapse
Affiliation(s)
- Viola Maria Schmidt
- Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Gynaecology, University Maternal Hospital, Cologne University, Kerpener Str. 34, 50931, Cologne, Germany
| | - Vladimir Isachenko
- Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Gynaecology, University Maternal Hospital, Cologne University, Kerpener Str. 34, 50931, Cologne, Germany
| | - Gunter Rappl
- Cell Sort Service Department, Center for Molecular Medicine Cologne University (CMMC), Robert Koch Str. 21, 50931, Cologne, Germany
| | - Gohar Rahimi
- Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Gynaecology, University Maternal Hospital, Cologne University, Kerpener Str. 34, 50931, Cologne, Germany
| | - Bettina Hanstein
- Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Gynaecology, University Maternal Hospital, Cologne University, Kerpener Str. 34, 50931, Cologne, Germany
| | - Bernd Morgenstern
- Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Gynaecology, University Maternal Hospital, Cologne University, Kerpener Str. 34, 50931, Cologne, Germany
| | - Peter Mallmann
- Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Gynaecology, University Maternal Hospital, Cologne University, Kerpener Str. 34, 50931, Cologne, Germany
| | - Evgenia Isachenko
- Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Gynaecology, University Maternal Hospital, Cologne University, Kerpener Str. 34, 50931, Cologne, Germany.
| |
Collapse
|
|
26
|
Sleeboom JJF, Eslami Amirabadi H, Nair P, Sahlgren CM, den Toonder JMJ. Metastasis in context: modeling the tumor microenvironment with cancer-on-a-chip approaches. Dis Model Mech 2018; 11:11/3/dmm033100. [PMID: 29555848 PMCID: PMC5897732 DOI: 10.1242/dmm.033100] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Most cancer deaths are not caused by the primary tumor, but by secondary tumors formed through metastasis, a complex and poorly understood process. Cues from the tumor microenvironment, such as the biochemical composition, cellular population, extracellular matrix, and tissue (fluid) mechanics, have been indicated to play a pivotal role in the onset of metastasis. Dissecting the role of these cues from the tumor microenvironment in a controlled manner is challenging, but essential to understanding metastasis. Recently, cancer-on-a-chip models have emerged as a tool to study the tumor microenvironment and its role in metastasis. These models are based on microfluidic chips and contain small chambers for cell culture, enabling control over local gradients, fluid flow, tissue mechanics, and composition of the local environment. Here, we review the recent contributions of cancer-on-a-chip models to our understanding of the role of the tumor microenvironment in the onset of metastasis, and provide an outlook for future applications of this emerging technology. Summary: This Review evaluates the recent contributions of cancer-on-a-chip models to our understanding of the tumor microenvironment and its role in the onset of metastasis. The authors also provide an outlook for future applications of this emerging technology.
Collapse
Affiliation(s)
- Jelle J F Sleeboom
- Microsystems Group, Department of Mechanical Engineering, Eindhoven University of Technology, Gemini-Zuid, Groene Loper 15, 5612AZ, Eindhoven, The Netherlands.,Soft Tissue Engineering & Mechanobiology, Eindhoven University of Technology, Gemini-Zuid, Groene Loper 15, 5612AZ, Eindhoven, The Netherlands.,Institute for Complex Molecular Systems, Eindhoven University of Technology, Gemini-Zuid, Groene Loper 15, 5612AZ, Eindhoven, The Netherlands
| | - Hossein Eslami Amirabadi
- Microsystems Group, Department of Mechanical Engineering, Eindhoven University of Technology, Gemini-Zuid, Groene Loper 15, 5612AZ, Eindhoven, The Netherlands.,Institute for Complex Molecular Systems, Eindhoven University of Technology, Gemini-Zuid, Groene Loper 15, 5612AZ, Eindhoven, The Netherlands
| | - Poornima Nair
- Microsystems Group, Department of Mechanical Engineering, Eindhoven University of Technology, Gemini-Zuid, Groene Loper 15, 5612AZ, Eindhoven, The Netherlands.,Institute for Complex Molecular Systems, Eindhoven University of Technology, Gemini-Zuid, Groene Loper 15, 5612AZ, Eindhoven, The Netherlands
| | - Cecilia M Sahlgren
- Soft Tissue Engineering & Mechanobiology, Eindhoven University of Technology, Gemini-Zuid, Groene Loper 15, 5612AZ, Eindhoven, The Netherlands.,Institute for Complex Molecular Systems, Eindhoven University of Technology, Gemini-Zuid, Groene Loper 15, 5612AZ, Eindhoven, The Netherlands.,Turku Centre for Biotechnology, Åbo Akademi University, Domkyrkotorget 3, FI-20500, Turku, Finland
| | - Jaap M J den Toonder
- Microsystems Group, Department of Mechanical Engineering, Eindhoven University of Technology, Gemini-Zuid, Groene Loper 15, 5612AZ, Eindhoven, The Netherlands .,Institute for Complex Molecular Systems, Eindhoven University of Technology, Gemini-Zuid, Groene Loper 15, 5612AZ, Eindhoven, The Netherlands
| |
Collapse
|
|
27
|
Wang L, Yang D, Tian J, Gao A, Shen Y, Ren X, Li X, Jiang G, Dong T. Tumor necrosis factor receptor 2/AKT and ERK signaling pathways contribute to the switch from fibroblasts to CAFs by progranulin in microenvironment of colorectal cancer. Oncotarget 2018; 8:26323-26333. [PMID: 28412748 PMCID: PMC5432260 DOI: 10.18632/oncotarget.15461] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 02/06/2017] [Indexed: 12/01/2022] Open
Abstract
Cancer associated fibroblasts (CAFs) are a crucial cellular component in tumor microenvironment and could promote tumor progression. CAFs are usually derived from resident fibroblasts, which undergoing an activated process stimulated by tumor cells. However, the agents and mechanism driving this switch have not yet been elucidated. Progranulin (PGRN), a well acknowledged secreted glycoprotein, could promote proliferation and angiogenesis of colorectal cancer (CRC) cells, and high expression of PGRN correlated with patient poor prognosis. Whether PGRN has effects on the function of stromal fibroblasts is unknown. Herein we found that there was a positive correlation between PGRN expression of CRC cells and expressions of smooth muscle actin α (α-SMA) on CAFs in CRC patient tissues. PGRN/α-SMA co-expression was positively correlated with CRC patient poor prognosis. Co-cultured with CRC cells or human recombinant PGRN (rPGRN), the expression of Ki67, fibroblast activation protein (FAP) and α-SMA in fibroblasts were all up-regulated significantly, accompanying with elevated cellular proliferation, migration and contraction. Whilst co-cultured with PGRN-silenced CRC cells, these functions were down-regulated. Studies of the underlying molecular mechanism demonstrated that either tumor necrosis factor receptor 2 (TNFR2)/Akt or the extracellular regulated kinase (ERK) signaling pathway contributed to modulate of Ki67, FAP, and α-SMA expression, and correlated to abilities of proliferation, migration and contraction in fibroblasts. In conclusion, PGRN plays an important role in activation of CRC fibroblasts, which may be taken as a prospective target of CRC therapy.
Collapse
Affiliation(s)
- Linlin Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, Shandong 250117, P. R. China.,Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R.China
| | - Dong Yang
- Department of Oncology, Affiliated hospital of Jining Medical College, Jining, Shandong 272129, P. R. China
| | - Jing Tian
- Department of Oncology, People's Hospital of Zhangqiu City, Zhangqiu, Shandong 250200, P. R. China
| | - Aiqin Gao
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R.China
| | - Yihang Shen
- Programs of Cancer Biology, University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA
| | - Xia Ren
- Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology, Key Laboratory for Rare and Uncommon Diseases of Shandong, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250012, P. R. China
| | - Xia Li
- Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology, Key Laboratory for Rare and Uncommon Diseases of Shandong, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250012, P. R. China
| | - Guosheng Jiang
- Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology, Key Laboratory for Rare and Uncommon Diseases of Shandong, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250012, P. R. China
| | - Taotao Dong
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P. R. China
| |
Collapse
|
|
28
|
Challenges of Oncoimmunology for Ovarian and Breast Cancers. Oncoimmunology 2018. [DOI: 10.1007/978-3-319-62431-0_36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
|
|
29
|
Sazeides C, Le A. Metabolic Relationship between Cancer-Associated Fibroblasts and Cancer Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1063:149-165. [PMID: 29946782 DOI: 10.1007/978-3-319-77736-8_11] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME), play an important role in cancer initiation, progression, and metastasis. Recent findings have demonstrated that the TME not only provides physical support for cancer cells, but also directs cell-to-cell interactions (in this case the interaction between cancer cells and CAFs). As cancer progresses, the CAFs also co evolve—transitioning from an inactivated state to an activated state. The elucidation and understanding of the interaction between cancer cells and CAFs will pave the way for new cancer therapies [1–3]. The TME is a heterogeneous environment consisting of fibroblasts, tumor-associated macrophages, adipocytes, an extracellular matrix, and mesenchymal stem cells [4]. The exact composition of each stroma varies depending on cancer and tissue type. To add to this variation, there is heterogeneity even within the CAF population itself. Different CAFs express different markers and influence stromal pro-tumorigenic capacity and cancer progression in diverse ways [5, 6].
Collapse
Affiliation(s)
- Christos Sazeides
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Anne Le
- Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| |
Collapse
|
|
30
|
Gandhi P, Prasad UC. Evaluation of myofibroblasts in oral submucous fibrosis and oral squamous cell carcinoma: The pathogenesis and correlation. Dent Res J (Isfahan) 2017; 14:314-320. [PMID: 29109745 PMCID: PMC5654225 DOI: 10.4103/1735-3327.215960] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background: Oral submucous fibrosis (OSMF) is a chronic debilitating disease of the oral cavity having premalignant potential and unclear pathogenesis. Recently, myofibroblast has been postulated to play an important role in its pathogenesis and in the process of carcinogenesis. The purpose of this study was to evaluate and compare the presence of myofibroblasts in normal mucosa, different grades of OSMF, and oral squamous cell carcinoma (OSCC). Materials and Methods: The present in vitro cross-sectional descriptive study sample consisted of three groups, including 40 OSCCs, 40 OSMF, and 10 sections of normal oral epithelium taken as control group. Alpha-smooth muscle actin was used to identify myofibroblasts using immunohistochemical technique. P < 0.05 was taken as statistically significant. Results: The presence of myofibroblasts was significantly higher in OSMF cases when compared with normal epithelium specimens. The presence of myofibroblasts was significantly higher in OSCC compared to OSMF cases. A significant difference was not observed between the different grades of OSCC. Conclusion: These findings favor the possibility that OSMF actually represents an abnormal healing process in response irritation caused by areca nut. A significant increase in myofibroblasts in OSCC as compared to OSMF also highlights the possible role it may play in the malignant transformation of OSMF.
Collapse
Affiliation(s)
- Piyush Gandhi
- Department of Oral Pathology, Dasmesh Institute of Research and Dental Sciences, Faridkot, Punjab, India
| | - Umesh Chandra Prasad
- Department of Oral Pathology, Kanti Devi Dental College, Mathura, Uttar Pradesh, India
| |
Collapse
|
|
31
|
Thuwajit C, Ferraresi A, Titone R, Thuwajit P, Isidoro C. The metabolic cross-talk between epithelial cancer cells and stromal fibroblasts in ovarian cancer progression: Autophagy plays a role. Med Res Rev 2017; 38:1235-1254. [PMID: 28926101 PMCID: PMC6032948 DOI: 10.1002/med.21473] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 08/16/2017] [Accepted: 08/23/2017] [Indexed: 12/17/2022]
Abstract
Cancer and stromal cells, which include (cancer‐associated) fibroblasts, adipocytes, and immune cells, constitute a mixed cellular ecosystem that dynamically influences the behavior of each component, creating conditions that ultimately favor the emergence of malignant clones. Ovarian cancer cells release cytokines that recruit and activate stromal fibroblasts and immune cells, so perpetuating a state of inflammation in the stroma that hampers the immune response and facilitates cancer survival and propagation. Further, the stroma vasculature impacts the metabolism of the cells by providing or limiting the availability of oxygen and nutrients. Autophagy, a lysosomal catabolic process with homeostatic and prosurvival functions, influences the behavior of cancer cells, affecting a variety of processes such as the survival in metabolic harsh conditions, the invasive growth, the development of immune and chemo resistance, the maintenance of stem‐like properties, and dormancy. Further, autophagy is involved in the secretion and the signaling of promigratory cytokines. Cancer‐associated fibroblasts can influence the actual level of autophagy in ovarian cancer cells through the secretion of pro‐inflammatory cytokines and the release of autophagy‐derived metabolites and substrates. Interrupting the metabolic cross‐talk between cancer cells and cancer‐associated fibroblasts could be an effective therapeutic strategy to arrest the progression and prevent the relapse of ovarian cancer.
Collapse
Affiliation(s)
- Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Alessandra Ferraresi
- Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Rossella Titone
- Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Peti Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ciro Isidoro
- Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.,Visiting Professor at Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| |
Collapse
|
|
32
|
Potential Therapeutic Strategy of Targeting Pulp Fibroblasts in Dentin-Pulp Regeneration. J Endod 2017; 43:S17-S24. [DOI: 10.1016/j.joen.2017.06.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
|
|
33
|
Ji X, Zhu X, Lu X. Effect of cancer-associated fibroblasts on radiosensitivity of cancer cells. Future Oncol 2017; 13:1537-1550. [PMID: 28685611 DOI: 10.2217/fon-2017-0054] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Solid tumors are composed of tumor epithelial cells and the stroma, which are seemingly separate but actually related through cell-cell and cell-matrix interactions. These interactions can promote tumor evolution. Cancer-associated fibroblasts (CAFs) are the most abundant non-neoplastic cells in the stroma and also among the most important cell types interacting with cancer cells. Particularly, cancer cells promote the formation and maintenance of CAFs by secreting various cytokines. The activated CAFs then synthesize a series of growth factors to promote tumor cell growth, invasion and metastasis. More importantly, the presence of CAFs also interferes with therapeutic efficacy, bringing severe challenges to radiotherapy. This review summarizes the effect of CAFs on the radiosensitivity of tumor cells and underscores the need for further studies on CAFs in order to improve the efficacy of antitumor therapy.
Collapse
Affiliation(s)
- Xiaoqin Ji
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China
| | - Xixu Zhu
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China
| | - Xueguan Lu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| |
Collapse
|
|
34
|
Wu JS, Sheng SR, Liang XH, Tang YL. The role of tumor microenvironment in collective tumor cell invasion. Future Oncol 2017; 13:991-1002. [PMID: 28075171 DOI: 10.2217/fon-2016-0501] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
For many cancer types, cancer cells invade into surrounding tissues by collective movement of cell groups that remain connected via cell-cell junctions. This migration is completely distinguished from single-cell migration, in which cancer cells disrupt the tight intercellular junctions and gain a mesenchymal phenotype. Recently, emerging evidence has revealed that collective cell invasion depends on not only cell-intrinsic mechanisms but also on extracellular mechanisms by bidirectional interplay between the tumor cell and the tumor environment. Herein, in this review we discuss the role and underline mechanisms of tumor microenvironment in collective tumor cell invasion, particularly focusing on extracellular matrix remodeling and cross-talk between tumor and stromal cells.
Collapse
Affiliation(s)
- Jia-Shun Wu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), No. 14, Sec. 3, Renminnan Road, Chengdu Sichuan 610041, PR China.,Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), No. 14, Sec. 3, Renminnan Road, Chengdu Sichuan 610041, PR China
| | - Su-Rui Sheng
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), No. 14, Sec. 3, Renminnan Road, Chengdu Sichuan 610041, PR China.,Department of Oral & Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), No. 14, Sec. 3, Renminnan Road, Chengdu Sichuan 610041, PR China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), No. 14, Sec. 3, Renminnan Road, Chengdu Sichuan 610041, PR China.,Department of Oral & Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), No. 14, Sec. 3, Renminnan Road, Chengdu Sichuan 610041, PR China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), No. 14, Sec. 3, Renminnan Road, Chengdu Sichuan 610041, PR China.,Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), No. 14, Sec. 3, Renminnan Road, Chengdu Sichuan 610041, PR China
| |
Collapse
|
|
35
|
Kanehira M, Fujiwara T, Nakajima S, Okitsu Y, Onishi Y, Fukuhara N, Ichinohasama R, Okada Y, Harigae H. An Lysophosphatidic Acid Receptors 1 and 3 Axis Governs Cellular Senescence of Mesenchymal Stromal Cells and Promotes Growth and Vascularization of Multiple Myeloma. Stem Cells 2016; 35:739-753. [PMID: 27641212 DOI: 10.1002/stem.2499] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 08/24/2016] [Indexed: 12/16/2022]
Abstract
Mesenchymal stromal cells (MSCs) are multipotent progenitor cells and there is much interest in how MSCs contribute to the regulation of the tumor microenvironment. Whether MSCs exert a supportive or suppressive effect on tumor progression is still controversial, but is likely dependent on a variety of factors that are tumor-type dependent. Multiple myeloma (MM) is characterized by growth of malignant plasma cells in the bone marrow. It has been shown that the progression of MM is governed by MSCs, which act as a stroma of the myeloma cells. Although stroma is created via mutual communication between myeloma cells and MSCs, the mechanism is poorly understood. Here we explored the role of lysophosphatidic acid (LPA) signaling in cellular events where MSCs were converted into either MM-supportive or MM-suppressive stroma. We found that myeloma cells stimulate MSCs to produce autotaxin, an indispensable enzyme for the biosynthesis of LPA, and LPA receptor 1 (LPA1) and 3 (LPA3) transduce opposite signals to MSCs to determine the fate of MSCs. LPA3-silenced MSCs (siLPA3-MSCs) exhibited cellular senescence-related phenotypes in vitro, and significantly promoted progression of MM and tumor-related angiogenesis in vivo. In contrast, siLPA1-MSCs showed resistance to cellular senescence in vitro, and efficiently delayed progression of MM and tumor-related angiogenesis in vivo. Consistently, anti-MM effects obtained by LPA1-silencing in MSCs were completely reproduced by systemic administration of Ki6425, an LPA1 antagonist. Collectively, our results indicate that LPA signaling determines the fate of MSCs and has potential as a therapeutic target in MM. Stem Cells 2017;35:739-753.
Collapse
Affiliation(s)
- Masahiko Kanehira
- Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Tohru Fujiwara
- Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Miyagi, Japan.,Molecular Hematology/Oncology, Hebita, Ishinomaki, Japan
| | - Shinji Nakajima
- Japanese Red Cross Ishinomaki Hospital, Hebita, Ishinomaki, Japan
| | - Yoko Okitsu
- Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Yasushi Onishi
- Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Noriko Fukuhara
- Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Ryo Ichinohasama
- Division of Hematopathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yoshinori Okada
- Department of Thoracic surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan
| | - Hideo Harigae
- Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Miyagi, Japan.,Molecular Hematology/Oncology, Hebita, Ishinomaki, Japan
| |
Collapse
|
|
36
|
CXCL1-Mediated Interaction of Cancer Cells with Tumor-Associated Macrophages and Cancer-Associated Fibroblasts Promotes Tumor Progression in Human Bladder Cancer. Neoplasia 2016; 18:636-646. [PMID: 27690238 PMCID: PMC5043399 DOI: 10.1016/j.neo.2016.08.002] [Citation(s) in RCA: 151] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 08/05/2016] [Accepted: 08/11/2016] [Indexed: 01/13/2023] Open
Abstract
Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are reported to be associated with poor prognosis, depending on their pro-tumoral roles. Current knowledge of TAMs and CAFs in the tumor microenvironment of urothelial cancer of the bladder (UCB) is limited. Therefore, we investigated the paracrine effect induced by TAMs and CAFs in the tumor microenvironment of human UCB. For this, we first carried out immunohistochemical analysis for CXCL1, CD204 (TAM marker), αSMA (CAF marker), E-cadherin, and MMP2 using 155 UBC tissue samples. Next, CXCL1-overexpressing clones of THP-1-derived TAMs and NIH3T3-derived CAFs were developed by lentiviral vector infection. The immunohistochemical study showed high CXCL1 levels in UCB cells to be associated with enhanced recruitment of TAMs/CAFs, higher metastatic potential, and poor prognosis. Three-dimensional (3D) co-culture of UCB cells and TAMs/CAFs suggested that CXCL1 production in TAMs/CAFs play an important role in cell-to-cell adhesion and interaction among cancer cells and these stromal cells. CXCL1-expressing TAMs/CAFs enhanced tumor growth of subcutaneous UCB tumors in nude mice when injected together. In addition, an experiment using the orthotopic bladder cancer model revealed that CXCL1 production in TAMs/CAFs supported tumor implantation into the murine bladder wall and UCB growth when injected together, which was confirmed by clinical data of patients with bladder cancer. Thus, CXCL1 signaling in the tumor microenvironment is highly responsible for repeated intravesical recurrence, disease progression, and drug resistance through enhanced invasion ability. In conclusion, disrupting CXCL1 signaling to dysregulate this chemokine is a promising therapeutic approach for human UCB.
Collapse
|
|
37
|
Fu H, Yang H, Zhang X, Xu W. The emerging roles of exosomes in tumor-stroma interaction. J Cancer Res Clin Oncol 2016; 142:1897-907. [PMID: 26987524 DOI: 10.1007/s00432-016-2145-0] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 03/09/2016] [Indexed: 12/13/2022]
Abstract
PURPOSE The tumor-stroma interaction is critical for the development and progression of cancer. Cancer-associated fibroblasts (CAFs), one of the major components of the tumor stroma, can promote tumor growth and metastasis. Exosomes are secreted microvesicles that mediate cell-to-cell communication. Exosomal contents, including proteins, nucleic acids, and lipids, can be shuttled from donor cells to target cells. Recent studies suggest that exosomes play important roles in the tumor-stroma interaction. Herein, we review the multifaceted roles of exosomes in the tumor-stroma interaction and the underlying molecular mechanisms. METHODS Literature search for all relevant publications was performed on PubMed databases. The keywords of exosomes, tumor, stroma, CAFs, mesenchymal stem cells (MSCs) and other closely related terms were used for searching. RESULTS Tumor cell-derived exosomes induce the differentiation of fibroblasts and MSCs into CAFs. In turn, exosomes secreted by CAFs promote tumor growth, metastasis, and drug resistance through distinct mechanisms. Moreover, exosomes from stromal cells can be used as therapeutic vehicles for the delivery of anticancer drugs. CONCLUSIONS Tumor cells communicate with CAFs through exosomes, which establishes a bidirectional cross talk to promote tumor growth, metastasis, and drug resistance. Targeting exosomes in tumor-stroma interaction may have important implications for anticancer therapy.
Collapse
Affiliation(s)
- Hailong Fu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Huan Yang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Xu Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.
| | - Wenrong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.
- The Affiliated Hospital, Jiangsu University, Zhenjiang, 212013, Jiangsu, China.
| |
Collapse
|
|
38
|
Al-Rakan MA, Hendrayani SF, Aboussekhra A. CHEK2 represses breast stromal fibroblasts and their paracrine tumor-promoting effects through suppressing SDF-1 and IL-6. BMC Cancer 2016; 16:575. [PMID: 27484185 PMCID: PMC4970236 DOI: 10.1186/s12885-016-2614-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2016] [Accepted: 07/25/2016] [Indexed: 11/21/2022] Open
Abstract
Background Active fibroblasts, the predominant and the most active cells of breast cancer stroma, are responsible for tumor growth and spread. However, the molecular mediators and pathways responsible for stromal fibroblast activation, and their paracrine pro-carcinogenic effects are still not well defined. The CHEK2 tumor suppressor gene codes for a protein kinase, which plays important roles in the cellular response to various genotoxic stresses. Methods Immunoblotting, quantitative RT-PCR and Immunofluorescence were used to assess the expression of CHEK2 in different primary breast fibroblasts and in tissues. The effect of CHEK2 on the expression and secretion of SDF-1 and IL-6 was evaluated by immunoblotting and ELISA. The WST-1 colorimetric assay was used to assess cell proliferation, while the BD BioCoat Matrigel invasion chambers were utilized to determine the effects of CHEK2 on the migratory and the invasiveness capacities of breast stromal fibroblasts as well as breast cancer cells. Results We have shown that CHEK2 is down-regulated in most cancer-associated fibroblasts (CAFs) as compared to their corresponding tumor counterpart fibroblasts (TCFs) at both the mRNA and protein levels. Interestingly, CHEK2 down-regulation using specific siRNA increased the expression/secretion of both cancer-promoting cytokines SDF-1 and IL-6, and transdifferentiated stromal fibroblasts to myofibroblasts. These cells were able to enhance the proliferation of non-cancerous epithelial cells, and also boosted the migration/invasion abilities of breast cancer cells in a paracrine manner. The later effect was SDF-1/IL-6-dependent. Importantly, ectopic expression of CHEK2 in active CAFs converted these cells to a normal state, with lower migration/invasion capacities and reduced paracrine pro-carcinogenic effects. Conclusion These results indicate that CHEK2 possesses non-cell-autonomous tumor suppressor functions, and present the Chk2 protein as an important mediator in the functional interplay between breast carcinomas and their stromal fibroblasts.
Collapse
Affiliation(s)
- Maha A Al-Rakan
- Present address: Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11211, Kingdom of Saudi Arabia.,Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, MBC# 03, PO BOX 3354, Riyadh, 11211, Kingdom of Saudi Arabia
| | - Siti-Faujiah Hendrayani
- Present address: Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11211, Kingdom of Saudi Arabia.,Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, MBC# 03, PO BOX 3354, Riyadh, 11211, Kingdom of Saudi Arabia
| | - Abdelilah Aboussekhra
- Present address: Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11211, Kingdom of Saudi Arabia. .,Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, MBC# 03, PO BOX 3354, Riyadh, 11211, Kingdom of Saudi Arabia.
| |
Collapse
|
|
39
|
Labovsky V, Martinez LM, Calcagno MDL, Davies KM, García-Rivello H, Wernicke A, Feldman L, Giorello MB, Matas A, Borzone FR, Howard SC, Chasseing NA. Interleukin-6 receptor in spindle-shaped stromal cells, a prognostic determinant of early breast cancer. Tumour Biol 2016; 37:13377-13384. [PMID: 27460086 DOI: 10.1007/s13277-016-5268-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 07/15/2016] [Indexed: 02/06/2023] Open
Abstract
Spindle-shaped stromal cells, like carcinoma-associated fibroblasts and mesenchymal stem cells, influence tumor behavior and can serve as parameters in the clinical diagnosis, therapy, and prognosis of early breast cancer. Therefore, the aim of this study is to explore the clinicopathological significance of tumor necrosis factor-related apoptosis-induced ligand (TRAIL) receptors (Rs) 2 and 4 (TRAIL-R2 and R4), and interleukin-6 R (IL-6R) in spindle-shaped stromal cells, not associated with the vasculature, as prognostic determinants of early breast cancer patients. Receptors are able to trigger the migratory activity, among other functions, of these stromal cells. We conducted immunohistochemical analysis for the expression of these receptors in spindle-shaped stromal cells, not associated with the vasculature, of primary tumors from early invasive breast cancer patients, and analyzed their association with clinicopathological characteristics. Here, we demonstrate that the elevated levels of TRAIL-R2, TRAIL-R4, and IL-6R in these stromal cells were significantly associated with a higher risk of metastatic occurrence (p = 0.034, 0.026, and 0.006; respectively). Moreover, high expression of TRAIL-R4 was associated with shorter disease-free survival and metastasis-free survival (p = 0.013 and 0.019; respectively). Also, high expression of IL-6R was associated with shorter disease-free survival, metastasis-free survival, and overall survival (p = 0.003, 0.001, and 0.003; respectively). Multivariate analysis showed that IL-6R expression was an independent prognostic factor for disease-free survival and metastasis-free survival (p = 0.035). This study is the first to demonstrate that high levels of IL-6R expression in spindle-shaped stromal cells, not associated with the vasculature, could be used to identify early breast cancer patients with poor outcomes.
Collapse
Affiliation(s)
- Vivian Labovsky
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Leandro Marcelo Martinez
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - María de Luján Calcagno
- Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 954, CP 1113, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Kevin Mauro Davies
- Departamento de Anatomía Patológica, Hospital Italiano, Juan Domingo Perón 4190, CP 1181, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Hernán García-Rivello
- Departamento de Anatomía Patológica, Hospital Italiano, Juan Domingo Perón 4190, CP 1181, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Alejandra Wernicke
- Departamento de Anatomía Patológica, Hospital Italiano, Juan Domingo Perón 4190, CP 1181, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Leonardo Feldman
- Departamento de Trasplante de Medula Ósea, Fundación Favaloro, Solís 443, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - María Belén Giorello
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Ayelén Matas
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Francisco Raúl Borzone
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Scott C Howard
- University of Memphis, 3720 Alumni Ave, 38152, Memphis, TN, USA
| | - Norma Alejandra Chasseing
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
| |
Collapse
|
|
40
|
Wang J, Zhang G, Wang J, Wang L, Huang X, Cheng Y. The role of cancer-associated fibroblasts in esophageal cancer. J Transl Med 2016; 14:30. [PMID: 26822225 PMCID: PMC4732002 DOI: 10.1186/s12967-016-0788-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 01/17/2016] [Indexed: 01/04/2023] Open
Abstract
Fibroblasts are known as critical stromal cells in wound healing by synthesizing extracellular matrix and collagen. A subpopulation of them is called cancer-associated fibroblasts (CAFs), because their production of proteins participated in various biological activities including tumor cell proliferation, invasion and metastasis. Currently some studies shed light on their role in esophageal cancer which was an aggressive cancer with a dismal survival and high rate of metastasis. Thus, to find cures for it relies on elucidating the epithelial-fibroblasts crosstalk. Herein, we reviewed the present knowledge of the CAFs’ role in esophageal premalignant condition, cancer initiation, progression, metastasis and prognosis prediction and further provided some insights into its clinical application.
Collapse
Affiliation(s)
- Jiangfeng Wang
- Department of Radiation Oncology, Qilu Hospital of Shandong University, No 107 West Wenhua Road, Jinan, 250012, People's Republic of China.
| | - Guangyu Zhang
- Department of Radiation Oncology, Qilu Hospital of Shandong University, No 107 West Wenhua Road, Jinan, 250012, People's Republic of China.
| | - Jianbo Wang
- Department of Radiation Oncology, Qilu Hospital of Shandong University, No 107 West Wenhua Road, Jinan, 250012, People's Republic of China.
| | - Lu Wang
- Department of Radiation Oncology, Qilu Hospital of Shandong University, No 107 West Wenhua Road, Jinan, 250012, People's Republic of China.
| | - Xiaochen Huang
- Department of Radiation Oncology, Qilu Hospital of Shandong University, No 107 West Wenhua Road, Jinan, 250012, People's Republic of China.
| | - Yufeng Cheng
- Department of Radiation Oncology, Qilu Hospital of Shandong University, No 107 West Wenhua Road, Jinan, 250012, People's Republic of China.
| |
Collapse
|
|
41
|
Qiao A, Gu F, Guo X, Zhang X, Fu L. Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications. Front Med 2016; 10:33-40. [DOI: 10.1007/s11684-016-0431-5] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023]
|
|
42
|
Herrera A, Herrera M, Peña C. The emerging role of Snail1 in the tumor stroma. Clin Transl Oncol 2015; 18:872-7. [PMID: 26687368 DOI: 10.1007/s12094-015-1474-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 12/08/2015] [Indexed: 01/11/2023]
Abstract
The transcription factor Snail1 leads to the epithelial-mesenchymal transition by repressing the adherent and tight junctions in epithelial cells. This process is related to an increase of cell migratory and mesenchymal properties during both embryonic development and tumor progression. Although Snail1 expression is very limited in adult animals, emerging evidence has placed Snail at the forefront of medical science. As a transcriptional repressor, Snail1 confers cancer stem cell-like traits on tumor cells and promotes drug resistance, tumor recurrence and metastasis. In this review, we summarize recent reports that suggest the pro-tumorigenic roles of Snail1 expression in tumor stroma. The crosstalk between tumor and stromal cells mediated by Snail1 regulates paracrine communication, pro-tumorigenic abilities of cancer cells, extracellular matrix characteristics and mesenchymal differentiation in cancer stem cells and cancer-associated fibroblasts. Therefore, understanding the regulation and functional roles of Snail1 in the tumor microenvironment will provide us with new therapies for treating metastatic disease.
Collapse
Affiliation(s)
- A Herrera
- "Cancer Cell Signaling" Research Group, Hospital Universitario Puerta de Hierro de Majadahonda, Majadahonda, Madrid, Spain
| | - M Herrera
- "Cancer Cell Signaling" Research Group, Hospital Universitario Puerta de Hierro de Majadahonda, Majadahonda, Madrid, Spain
| | - C Peña
- "Cancer Cell Signaling" Research Group, Hospital Universitario Puerta de Hierro de Majadahonda, Majadahonda, Madrid, Spain.
| |
Collapse
|
|
43
|
Singh SP, Schwartz MP, Tokuda EY, Luo Y, Rogers RE, Fujita M, Ahn NG, Anseth KS. A synthetic modular approach for modeling the role of the 3D microenvironment in tumor progression. Sci Rep 2015; 5:17814. [PMID: 26638791 PMCID: PMC4671067 DOI: 10.1038/srep17814] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 10/22/2015] [Indexed: 11/09/2022] Open
Abstract
Here, we demonstrate the flexibility of peptide-functionalized poly(ethylene glycol) (PEG) hydrogels for modeling tumor progression. The PEG hydrogels were formed using thiol-ene chemistry to incorporate a matrix metalloproteinase-degradable peptide crosslinker (KKCGGPQG↓IWGQGCKK) permissive to proteolytic remodeling and the adhesive CRGDS peptide ligand. Tumor cell function was investigated by culturing WM239A melanoma cells on PEG hydrogel surfaces or encapsulating cells within the hydrogels, and either as monocultures or indirect (non-contact) cocultures with primary human dermal fibroblasts (hDFs). WM239A cluster size and proliferation rate depended on the shear elastic modulus for cells cultured on PEG hydrogels, while growth was inhibited by coculture with hDFs regardless of hydrogel stiffness. Cluster size was also suppressed by hDFs for WM239A cells encapsulated in PEG hydrogels, which is consistent with cells seeded on top of hydrogels. Notably, encapsulated WM239A clusters and single cells adopted invasive phenotypes in the hDF coculture model, which included single cell and collective migration modes that resembled invasion from human melanoma patient-derived xenograft tumors encapsulated in equivalent PEG hydrogels. Our combined results demonstrate that peptide-functionalized PEG hydrogels provide a useful platform for investigating aspects of tumor progression in 2D and 3D microenvironments, including single cell migration, cluster growth and invasion.
Collapse
Affiliation(s)
- S P Singh
- Department of Chemical and Biological Engineering and the BioFrontiers Institute, University of Colorado at Boulder, Boulder, Colorado, United States of America
| | - M P Schwartz
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - E Y Tokuda
- Department of Chemical and Biological Engineering and the BioFrontiers Institute, University of Colorado at Boulder, Boulder, Colorado, United States of America
| | - Y Luo
- Department of Dermatology, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - R E Rogers
- College of Medicine, Texas A&M Health Science Center, Bryan, Texas, United States of America
| | - M Fujita
- Department of Dermatology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.,Denver Veterans Affairs Medical Center, Denver, Colorado, United States of America
| | - N G Ahn
- Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado, United States of America
| | - K S Anseth
- Department of Chemical and Biological Engineering and the BioFrontiers Institute, University of Colorado at Boulder, Boulder, Colorado, United States of America.,Howard Hughes Medical Institute, University of Colorado at Boulder, Boulder, Colorado, United States of America
| |
Collapse
|
|
44
|
Pang W, Su J, Wang Y, Feng H, Dai X, Yuan Y, Chen X, Yao W. Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts. Cancer Sci 2015. [PMID: 26195069 PMCID: PMC4638007 DOI: 10.1111/cas.12747] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Cancer-associated fibroblasts (CAF) are a major constituent of the pancreatic cancer microenvironment and that the meaning is as intended. Pancreatic cancer cells can induce normal fibroblasts to convert into CAF and, reciprocally, CAF promote tumor invasions and proliferations. The mechanism of the conversion from normal fibroblasts (NF) to CAF remains unclear. MicroRNA are short non-coding RNA involved in the post-transcription gene regulation, which have been defined as an imperative controller in tumor invasions, proliferations and colony formations. Microvesicles (MV) have been proved to be an important mediator of intercellular communication and can selectively transport secreted microRNA from a donor cell into a recipient cell. In this study, we isolated primary pancreatic fibroblasts from wild type C57 mice and co-cultured them with pancreatic cancer cell lines, BxPC-3 and SW1990, and observed the conversion from NF to CAF, or at least CAF-like cells. This phenomenon could also be replicated in primary fibroblasts treated with MV separated from a cancer cell media. We identified that miR-155 was upregulated in PaC-derived MV and we confirmed that normal fibroblasts could convert into CAF after MV containing miR-155 had been taken up. TP53INP1 is a target of miR-155 in fibroblasts and a downregulation of TP53INP1 protein levels could contribute to the fibroblasts' activation. These results indicated that pancreatic cancer cells might reprogram normal adjacent fibroblasts into CAF by means of secreted MV containing miR-155. Targeting the circulating microRNA might be a potential therapy for malignant tumors.
Collapse
Affiliation(s)
- Wenjing Pang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Jiaojiao Su
- Department of Gastroenterology, First-affiliated Hospital, Anhui Medical School, Hefei, China.,Department of Gastroenterology, Lúan People's Hospital, Lúan Affiliated Hospital of Anhui Medical University, 21, Wanxi Road, 237000, Lúan, China
| | - Yalei Wang
- Department of Gastroenterology, First-affiliated Hospital, Anhui Medical School, Hefei, China
| | - Hui Feng
- Department of Gastroenterology, First-affiliated Hospital, Anhui Medical School, Hefei, China
| | - Xin Dai
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Yaozong Yuan
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Xi Chen
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical, Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Weiyan Yao
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, China
| |
Collapse
|
|
45
|
Specific upregulation of RHOA and RAC1 in cancer-associated fibroblasts found at primary tumor and lymph node metastatic sites in breast cancer. Tumour Biol 2015; 36:9589-97. [PMID: 26142737 DOI: 10.1007/s13277-015-3727-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 06/28/2015] [Indexed: 12/21/2022] Open
Abstract
The importance of tumor-stromal cell interactions in breast tumor progression and invasion is well established. Here, an evaluation of differential genomic profiles of carcinoma-associated fibroblasts (CAFs) compared to fibroblasts derived from tissues adjacent to fibroadenomas (NAFs) revealed altered focal adhesion pathways. These data were validated through confocal assays. To verify the possible role of fibroblasts in lymph node invasion, we constructed a tissue microarray consisting of primary breast cancer samples and corresponding lymph node metastasis and compared the expression of adhesion markers RhoA and Rac1 in fibroblasts located at these different locations. Two distinct tissue microarrays were constructed from the stromal component of 43 primary tumors and matched lymph node samples, respectively. Fibroblasts were characterized for their expression of α-smooth muscle actin (α-SMA) and vimentin. Moreover, we verified the level of these proteins in the stromal compartment from normal adjacent tissue and in non-compromised lymph nodes. Our immunohistochemistry revealed that 59 % of fibroblasts associated with primary tumors and 41 % of the respective metastatic lymph nodes (p = 0.271) displayed positive staining for RhoA. In line with this, 57.1 % of fibroblasts associated with primary tumors presented Rac1-positive staining, and the frequency of co-positivity within the lymph nodes was 42.9 % (p = 0.16). Expression of RhoA and Rac1 was absent in fibroblasts of adjacent normal tissue and in compromised lymph nodes. Based on our findings that no significant changes were observed between primary and metastatic lymph nodes, we suggest that fibroblasts are active participants in the invasion of cancer cells to lymph nodes and support the hypothesis that metastatic tumor cells continue to depend on their microenvironment.
Collapse
|
|
46
|
Spina A, De Pasquale V, Cerulo G, Cocchiaro P, Della Morte R, Avallone L, Pavone LM. HGF/c-MET Axis in Tumor Microenvironment and Metastasis Formation. Biomedicines 2015; 3:71-88. [PMID: 28536400 PMCID: PMC5344235 DOI: 10.3390/biomedicines3010071] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 12/09/2014] [Indexed: 02/07/2023] Open
Abstract
Tumor metastases are responsible for approximately 90% of all cancer-related deaths. Metastasis formation is a multistep process that requires acquisition by tumor cells of a malignant phenotype that allows them to escape from the primary tumor site and invade other organs. Each step of this mechanism involves a deep crosstalk between tumor cells and their microenvironment where the host cells play a key role in influencing metastatic behavior through the release of many secreted factors. Among these signaling molecules, Hepatocyte Growth Factor (HGF) is released by many cell types of the tumor microenvironment to target its receptor c-MET within the cells of the primary tumor. Many studies reveal that HGF/c-MET axis is implicated in various human cancers, and genetic and epigenetic gain of functions of this signaling contributes to cancer development through a variety of mechanisms. In this review, we describe the specific types of cells in the tumor microenvironment that release HGF in order to promote the metastatic outgrowth through the activation of extracellular matrix remodeling, inflammation, migration, angiogenesis, and invasion. We dissect the potential use of new molecules that interfere with the HGF/c-MET axis as therapeutic targets for future clinical trials in cancer disease.
Collapse
Affiliation(s)
- Anna Spina
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
| | - Valeria De Pasquale
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
| | - Giuliana Cerulo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy.
| | - Pasquale Cocchiaro
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy.
| | - Rossella Della Morte
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy.
| | - Luigi Avallone
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy.
| | - Luigi Michele Pavone
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
| |
Collapse
|
|
47
|
Kucerova L, Zmajkovic J, Toro L, Skolekova S, Demkova L, Matuskova M. Tumor-driven Molecular Changes in Human Mesenchymal Stromal Cells. CANCER MICROENVIRONMENT 2014; 8:1-14. [PMID: 25169041 DOI: 10.1007/s12307-014-0151-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 08/07/2014] [Indexed: 12/23/2022]
Abstract
Mesenchymal stromal cells (MSC) exert either tumor-stimulatory or tumor-inhibitory effect. The outcome of the tumor-MSC interaction is dictated by the tumor-specific activating signals. We analyzed the alterations in MSC phenotype in response to stimulation by tumor-secreted paracrine factors. Paracrine factors from human melanoma A375 and glioblastoma 8MGBA cells were used for prolonged culture of MSC to produce derived cells designated DIFF(A)-MSC or DIFF(G)-MSC, respectively. Derived cells were analyzed for the specific surface markers, the expression pattern of MSC markers and fibroblast-specific proteins. Changes in the cell phenotype were evaluated using scratch wound assay and tube formation in vitro; and xenotransplant growth in vivo. Our data show induced expression of vascular endothelial growth factor 2, CD146, fibroblast-specific protein, vimentin and endosialin in DIFF(A)-MSC cells. This indicates their differentiation towards the cells with features of tumor-associated fibroblasts upon stimulation with melanoma-secreted cytokines. Paracrine stimulation in DIFF(G)-MSC led to up-regulation of the genes involved in the MSC differentiation. MSC-specific surface marker characteristics were preserved in derived DIFF(A)-MSC and DIFF(G)-MSC cells. However, we observed increased proportion of CD146 and GD2 (neural ganglioside) positive cells and decreased expression of marker NG2 in the MSC exposed to tumor-conditioned medium. Melanoma-CM increased MSC migration, glioblastoma-CM compromised angiogenic capacity of MSC in vitro and the protumorigenic effect in vivo. Our data directly compare the pleiotropic effects mediated by the malignant cells on the MSC. Secreted paracrine factors from melanoma or glioblastoma differently changed molecular traits in MSC, which explains the dual role of MSC in tumor growth.
Collapse
Affiliation(s)
- Lucia Kucerova
- Laboratory of Molecular Oncology, Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 833 91, Bratislava, Slovakia,
| | | | | | | | | | | |
Collapse
|
|
48
|
Mariani F, Sena P, Roncucci L. Inflammatory pathways in the early steps of colorectal cancer development. World J Gastroenterol 2014; 20:9716-9731. [PMID: 25110410 PMCID: PMC4123361 DOI: 10.3748/wjg.v20.i29.9716] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 12/05/2013] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is a major cause of cancer-related death in many countries. Colorectal carcinogenesis is a stepwise process which, from normal mucosa leads to malignancy. Many factors have been shown to influence this process, however, at present, several points remain obscure. In recent years some hypotheses have been considered on the mechanisms involved in cancer development, expecially in its early stages. Tissue injury resulting from infectious, mechanical, or chemical agents may elicit a chronic immune response resulting in cellular proliferation and regeneration. Chronic inflammation of the large bowel (as in inflammatory bowel diseases), has been associated with the subsequent development of colorectal cancer. In this review we examine the inflammatory pathways involved in the early steps of carcinogenesis, with particular emphasis on colorectal. Firstly, we describe cells and proteins recently suggested as central in the mechanism leading to tumor development. Macrophages and neutrophils are among the cells mostly involved in these processes and proteins, as cyclooxygenases and resolvins, are crucial in these inflammatory pathways. Indeed, the activation of these pathways establishes an oxidative and anaerobic microenvironment with DNA damage to epithelial cells, and shifting from an aerobic to an anaerobic metabolism. Many cellular mechanisms, such as proliferation, apoptosis, and autophagy are altered causing failure to control normal mucosa repair and renewal.
Collapse
|
|
49
|
Hyaluronan and RHAMM in wound repair and the "cancerization" of stromal tissues. BIOMED RESEARCH INTERNATIONAL 2014; 2014:103923. [PMID: 25157350 PMCID: PMC4137499 DOI: 10.1155/2014/103923] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 07/04/2014] [Indexed: 12/12/2022]
Abstract
Tumors and wounds share many similarities including loss of tissue architecture, cell polarity and cell differentiation, aberrant extracellular matrix (ECM) remodeling (Ballard et al., 2006) increased inflammation, angiogenesis, and elevated cell migration and proliferation. Whereas these changes are transient in repairing wounds, tumors do not regain tissue architecture but rather their continued progression is fueled in part by loss of normal tissue structure. As a result tumors are often described as wounds that do not heal. The ECM component hyaluronan (HA) and its receptor RHAMM have both been implicated in wound repair and tumor progression. This review highlights the similarities and differences in their roles during these processes and proposes that RHAMM-regulated wound repair functions may contribute to “cancerization” of the tumor microenvironment.
Collapse
|
|
50
|
Simultaneous expression of cancer stem cell-like properties and cancer-associated fibroblast-like properties in a primary culture of breast cancer cells. Cancers (Basel) 2014; 6:1570-8. [PMID: 25089665 PMCID: PMC4190556 DOI: 10.3390/cancers6031570] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Revised: 06/16/2014] [Accepted: 07/22/2014] [Indexed: 02/06/2023] Open
Abstract
The importance of cancer-associated fibroblasts (CAFs) in cancer biology has been recently highlighted owing to their critical roles in cancer growth, progression, metastasis, and therapeutic resistance. We have previously established a primary culture of breast cancer cells, which showed epithelial-mesenchymal transition and cancer stem cell-like properties. In this study, we found that the primary culture also showed CAF-like properties. For example, hypoxia inducible factor 1α (HIF1A) and its downstream genes, nuclear factor-kappa B2 (NF-κB2) and BCL2/adenovirus E1B 19 kd-interacting protein 3 (BNIP3), and many enzymes involved in glycolysis, such as GAPDH, LDH, PGAM1, and PKM2, were highly overexpressed in the primary culture. Moreover, media conditioned with the primary culture cells enhanced the growth of breast cancer cells. Similar to previous CAF studies, this enhancement suggested to be occurred through fibroblast growth factor signaling. This MCKH primary culture cell, which showed simultaneous expression of tumorigenic and CAF properties, offers a unique experimental system for studying the biology of CAFs.
Collapse
|