|
1
|
Vadibeler S, Clarke S, Phyu SM, Parkes EE. Interactions between cancer-associated fibroblasts and the extracellular matrix in oesophageal cancer. Matrix Biol 2025:S0945-053X(25)00049-6. [PMID: 40379112 DOI: 10.1016/j.matbio.2025.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Revised: 05/13/2025] [Accepted: 05/13/2025] [Indexed: 05/19/2025]
Abstract
Stromal components of the tumour microenvironment, such as cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM), are actively involved in tumorigenesis. CAFs and the ECM co-evolve with resultant molecular and mechanical pressure on tumour cells mediated by CAFs via the ECM. Meanwhile, ECM fibers determine CAF differentiation and activity, establishing a protumorigenic feed-forward loop. Oesophageal cancer carries a high morbidity and mortality, and curative surgical resection is only an option for a limited number of patients while early lymphatic spread and poor therapeutic responses are common. Although studies report marked heterogeneity in investigation of the stromal density of gastrointestinal cancers, it is generally accepted that oesophageal cancer is highly fibrotic, and stromal components like CAFs may outnumber cancer cells. Therefore, a comprehensive understanding of the reciprocal interaction between CAFs and the ECM in oesophageal cancer is essential to improving diagnostics and prognostication, as well as designing innovative anti-cancer strategies. Here, we summarise current understanding of oesophageal cancer from a stromal perspective. Then, we discuss that CAFs and the ECM in oesophageal cancer can independently and synergistically contribute to tumour progression and therapeutic resistance. We also summarise potential stromal targets that have been described in transcriptomic analyses, highlighting those validated in downstream experimental studies. Importantly, clinical translation of stromal-targeting strategies in oesophageal cancer is still in its infancy but holds significant promise for future therapeutic combinations.
Collapse
Affiliation(s)
- Subashan Vadibeler
- Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford; Department of Oncology, University of Oxford
| | - Shannique Clarke
- Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford; Department of Oncology, University of Oxford
| | - Su M Phyu
- Department of Oncology, University of Oxford
| | - Eileen E Parkes
- Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford; Department of Oncology, University of Oxford
| |
Collapse
|
|
2
|
Ahuja S, Sureka N, Zaheer S. Unraveling the intricacies of cancer-associated fibroblasts: a comprehensive review on metabolic reprogramming and tumor microenvironment crosstalk. APMIS 2024. [PMID: 38873945 DOI: 10.1111/apm.13447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 05/30/2024] [Indexed: 06/15/2024]
Abstract
Cancer-associated fibroblasts (CAFs) are crucial component of tumor microenvironment (TME) which undergo significant phenotypic changes and metabolic reprogramming, profoundly impacting tumor growth. This review delves into CAF plasticity, diverse origins, and the molecular mechanisms driving their continuous activation. Emphasis is placed on the intricate bidirectional crosstalk between CAFs and tumor cells, promoting cancer cell survival, proliferation, invasion, and immune evasion. Metabolic reprogramming, a cancer hallmark, extends beyond cancer cells to CAFs, contributing to the complex metabolic interplay within the TME. The 'reverse Warburg effect' in CAFs mirrors the Warburg effect, involving the export of high-energy substrates to fuel cancer cells, supporting their rapid proliferation. Molecular regulations by key players like p53, Myc, and K-RAS orchestrate this metabolic adaptation. Understanding the metabolic symbiosis between CAFs and tumor cells opens avenues for targeted therapeutic strategies to disrupt this dynamic crosstalk. Unraveling CAF-mediated metabolic reprogramming provides valuable insights for developing novel anticancer therapies. This comprehensive review consolidates current knowledge, shedding light on CAFs' multifaceted roles in the TME and offering potential targets for future therapies.
Collapse
Affiliation(s)
- Sana Ahuja
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Niti Sureka
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| |
Collapse
|
|
3
|
Miyako S, Koma YI, Nakanishi T, Tsukamoto S, Yamanaka K, Ishihara N, Azumi Y, Urakami S, Shimizu M, Kodama T, Nishio M, Shigeoka M, Kakeji Y, Yokozaki H. Periostin in Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression by Enhancing Cancer and Stromal Cell Migration. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:828-848. [PMID: 38320632 DOI: 10.1016/j.ajpath.2023.12.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 12/15/2023] [Accepted: 12/27/2023] [Indexed: 02/08/2024]
Abstract
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are involved in the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). CAF-like cells were generated through direct co-culture of human bone marrow-derived mesenchymal stem cells, one of CAF origins, with ESCC cells. Periostin (POSTN) was found to be highly expressed in CAF-like cells. After direct co-culture, ESCC cells showed increased malignant phenotypes, such as survival, growth, and migration, as well as increased phosphorylation of Akt and extracellular signal-regulated kinase (Erk). Recombinant human POSTN activated Akt and Erk signaling pathways in ESCC cells, enhancing survival and migration. The suppression of POSTN in CAF-like cells by siRNA during direct co-culture also suppressed enhanced survival and migration in ESCC cells. In ESCC cells, knockdown of POSTN receptor integrin β4 inhibited Akt and Erk phosphorylation, and survival and migration increased by POSTN. POSTN also enhanced mesenchymal stem cell and macrophage migration and endowed macrophages with tumor-associated macrophage-like properties. Immunohistochemistry showed that high POSTN expression in the cancer stroma was significantly associated with tumor invasion depth, lymphatic and blood vessel invasion, higher pathologic stage, CAF marker expression, and infiltrating tumor-associated macrophage numbers. Moreover, patients with ESCC with high POSTN expression exhibited poor postoperative outcomes. Thus, CAF-secreted POSTN contributed to tumor microenvironment development. These results indicate that POSTN may be a novel therapeutic target for ESCC.
Collapse
Affiliation(s)
- Shoji Miyako
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yu-Ichiro Koma
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
| | - Takashi Nakanishi
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shuichi Tsukamoto
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Keitaro Yamanaka
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Obstetrics and Gynecology, Department of Surgery Related, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Nobuaki Ishihara
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuki Azumi
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Satoshi Urakami
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masaki Shimizu
- Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takayuki Kodama
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Mari Nishio
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Manabu Shigeoka
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshihiro Kakeji
- Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroshi Yokozaki
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| |
Collapse
|
|
4
|
Lai SW, Cheng YC, Kiu KT, Yen MH, Chen YW, Yadav VK, Yeh CT, Kuo KT, Chang TC. PROX1 interaction with α-SMA-rich cancer-associated fibroblasts facilitates colorectal cancer progression and correlates with poor clinical outcomes and therapeutic resistance. Aging (Albany NY) 2024; 16:1620-1639. [PMID: 38244581 PMCID: PMC10866434 DOI: 10.18632/aging.205447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 11/30/2023] [Indexed: 01/22/2024]
Abstract
BACKGROUND The tumor microenvironment (TME) plays a vital role in tumor progression through intricate molecular interactions. Cancer-associated fibroblasts (CAFs), notably those expressing alpha-smooth muscle actin (α-SMA) or myofibroblasts, are instrumental in this context and correlate with unfavorable outcomes in colorectal cancer (CRC). While several transcription factors influence TME, the exact regulator causing CAF dysregulation in CRC remains elusive. Prospero Homeobox 1 (PROX1) stands out, as its inhibition reduces α-SMA-rich CAF activity. However, the therapeutic role of PROX1 is debated due to inconsistent study findings. METHODS Using the ULCAN portal, we noted an elevated PROX1 level in advanced colon adenocarcinoma, linking to a poor prognosis. Assays determined the impact of PROX1 overexpression on CRC cell properties, while co-culture experiments spotlighted the PROX1-CAF relationship. Molecular expressions were validated by qRT-PCR and Western blots, with in vivo studies further solidifying the observations. RESULTS Our study emphasized the connection between PROX1 and α-SMA in CAFs. Elevated PROX1 in CRC samples correlated with increased α-SMA in tumors. PROX1 modulation influenced the behavior of specific CRC cells, with its overexpression fostering invasiveness. Kaplan-Meier evaluations demonstrated a link between PROX1 or α-SMA and survival outcomes. Consequently, PROX1, alone or with α-SMA, emerges as a CRC prognostic marker. Co-culture and animal experiments further highlighted this relationship. CONCLUSION PROX1 appears crucial in modulating CRC behavior and therapeutic resistance within the TME by influencing CAFs, signifying the combined PROX1/α-SMA gene as a potential CRC prognostic marker. The concept of developing inhibitors targeting this gene set emerges as a prospective therapeutic strategy. However, this study is bound by limitations, including potential challenges in clinical translation, a focused exploration on PROX1/α-SMA potentially overlooking other significant molecular contributors, and the preliminary nature of the inhibitor development proposition.
Collapse
Affiliation(s)
- Shiue-Wei Lai
- Department of Internal Medicine, Division of Hematology and Oncology, Tri-service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Chiao Cheng
- Department of Surgery, Division of Colon and Rectal Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Kee-Thai Kiu
- Department of Surgery, Division of Colorectal Surgery, Taipei Medical University Shuang-Ho Hospital, Taipei, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Min-Hsuan Yen
- Department of Surgery, Division of Colorectal Surgery, Taipei Medical University Shuang-Ho Hospital, Taipei, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Ying-Wei Chen
- Department of Surgery, Division of Colorectal Surgery, Taipei Medical University Shuang-Ho Hospital, Taipei, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Vijesh Kumar Yadav
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shuang-Ho Hospital, New Taipei City, Taiwan
- Department of Medical Research and Education, Taipei Medical University Shuang-Ho Hospital, New Taipei City 23561, Taiwan
| | - Chi-Tai Yeh
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shuang-Ho Hospital, New Taipei City, Taiwan
- Department of Medical Research and Education, Taipei Medical University Shuang-Ho Hospital, New Taipei City 23561, Taiwan
- Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung 95092, Taiwan
| | - Kuang-Tai Kuo
- Department of Surgery, Division of Thoracic Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Surgery, Division of Thoracic Surgery, Taipei Medical University Shuang-Ho Hospital, New Taipei City 23561, Taiwan
| | - Tung-Cheng Chang
- Department of Surgery, Division of Colorectal Surgery, Taipei Medical University Shuang-Ho Hospital, Taipei, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| |
Collapse
|
|
5
|
Melchionna R, Trono P, Di Carlo A, Di Modugno F, Nisticò P. Transcription factors in fibroblast plasticity and CAF heterogeneity. J Exp Clin Cancer Res 2023; 42:347. [PMID: 38124183 PMCID: PMC10731891 DOI: 10.1186/s13046-023-02934-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 12/13/2023] [Indexed: 12/23/2023] Open
Abstract
In recent years, research focused on the multifaceted landscape and functions of cancer-associated fibroblasts (CAFs) aimed to reveal their heterogeneity and identify commonalities across diverse tumors for more effective therapeutic targeting of pro-tumoral stromal microenvironment. However, a unified functional categorization of CAF subsets remains elusive, posing challenges for the development of targeted CAF therapies in clinical settings.The CAF phenotype arises from a complex interplay of signals within the tumor microenvironment, where transcription factors serve as central mediators of various cellular pathways. Recent advances in single-cell RNA sequencing technology have emphasized the role of transcription factors in the conversion of normal fibroblasts to distinct CAF subtypes across various cancer types.This review provides a comprehensive overview of the specific roles of transcription factor networks in shaping CAF heterogeneity, plasticity, and functionality. Beginning with their influence on fibroblast homeostasis and reprogramming during wound healing and fibrosis, it delves into the emerging insights into transcription factor regulatory networks. Understanding these mechanisms not only enables a more precise characterization of CAF subsets but also sheds light on the early regulatory processes governing CAF heterogeneity and functionality. Ultimately, this knowledge may unveil novel therapeutic targets for cancer treatment, addressing the existing challenges of stromal-targeted therapies.
Collapse
Affiliation(s)
- Roberta Melchionna
- Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy.
| | - Paola Trono
- Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Rome, Italy
| | - Anna Di Carlo
- Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | - Francesca Di Modugno
- Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | - Paola Nisticò
- Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| |
Collapse
|
|
6
|
Xue M, Tong Y, Xiong Y, Yu C. Role of cancer-associated fibroblasts in the progression, therapeutic resistance and targeted therapy of oesophageal squamous cell carcinoma. Front Oncol 2023; 13:1257266. [PMID: 37927475 PMCID: PMC10623436 DOI: 10.3389/fonc.2023.1257266] [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: 07/12/2023] [Accepted: 09/11/2023] [Indexed: 11/07/2023] Open
Abstract
Oesophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumours with high morbidity and mortality. Although surgery, radiotherapy and chemotherapy are common treatment options available for oesophageal cancer, the 5-year survival rate remains low after treatment. On the one hand, many oesophageal cancers are are discovered at an advanced stage and, on the other hand, treatment resistance is a major obstacle to treating locally advanced ESCC. Cancer-associated fibroblasts (CAFs), the main type of stromal cell in the tumour microenvironment, enhance tumour progression and treatment resistance and have emerged as a major focus of study on targeted therapy of oesophageal cancer.With the aim of providing potential, prospective targets for improving therapeutic efficacy, this review summarises the origin and activation of CAFs and their specific role in regulating tumour progression and treatment resistance in ESCC. We also emphasize the clinical potential and emerging trends of ESCC CAFs-targeted treatments.
Collapse
Affiliation(s)
| | | | | | - Changhua Yu
- Department of Radiotherapy, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, China
| |
Collapse
|
|
7
|
Raudenska M, Balvan J, Hanelova K, Bugajova M, Masarik M. Cancer-associated fibroblasts: Mediators of head and neck tumor microenvironment remodeling. Biochim Biophys Acta Rev Cancer 2023; 1878:188940. [PMID: 37331641 DOI: 10.1016/j.bbcan.2023.188940] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/05/2023] [Accepted: 06/12/2023] [Indexed: 06/20/2023]
Abstract
Cancer-associated fibroblasts (CAFs) are involved in critical aspects of head and neck squamous cell carcinoma (HNSCC) pathogenesis, such as the formation of a tumor-permissive extracellular matrix structure, angiogenesis, or immune and metabolic reprogramming of the tumor microenvironment (TME), with implications for metastasis and resistance to radiotherapy and chemotherapy. The pleiotropic effect of CAFs in TME is likely to reflect the heterogeneity and plasticity of their population, with context-dependent effects on carcinogenesis. The specific properties of CAFs provide many targetable molecules that could play an important role in the future therapy of HNSCC. In this review article, we will focus on the role of CAFs in the TME of HNSCC tumors. We will also discuss clinically relevant agents targeting CAFs, their signals, and signaling pathways, which are activated by CAFs in cancer cells, with the potential for repurposing for HNSCC therapy.
Collapse
Affiliation(s)
- Martina Raudenska
- Department of Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Jan Balvan
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Klara Hanelova
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Maria Bugajova
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Michal Masarik
- Department of Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Institute of Pathophysiology, First Faculty of Medicine, Charles University, / U Nemocnice 5, CZ-128 53 Prague, Czech Republic.
| |
Collapse
|
|
8
|
Zhao D, Zhang J, Zhang L, Wu Q, Wang Y, Zhang W, Xiao Y, Chen J, Zhan Q. PAFR/Stat3 axis maintains the symbiotic ecosystem between tumor and stroma to facilitate tumor malignancy. Acta Pharm Sin B 2023; 13:694-708. [PMID: 36873192 PMCID: PMC9978919 DOI: 10.1016/j.apsb.2022.08.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 06/17/2022] [Accepted: 08/07/2022] [Indexed: 11/18/2022] Open
Abstract
Stroma surrounding the tumor cells plays crucial roles for tumor progression. However, little is known about the factors that maintain the symbiosis between stroma and tumor cells. In this study, we found that the transcriptional regulator-signal transducer and activator of transcription 3 (Stat3) was frequently activated in cancer-associated fibroblasts (CAFs), which was a potent facilitator of tumor malignancy, and formed forward feedback loop with platelet-activating factor receptor (PAFR) both in CAFs and tumor cells. Importantly, PAFR/Stat3 axis connected intercellular signaling crosstalk between CAFs and cancer cells and drove mutual transcriptional programming of these two types of cells. Two central Stat3-related cytokine signaling molecules-interleukin 6 (IL-6) and IL-11 played the critical role in the process of PAFR/Stat3 axis-mediated communication between tumor and CAFs. Pharmacological inhibition of PAFR and Stat3 activities effectively reduced tumor progression using CAFs/tumor co-culture xenograft model. Our study reveals that PAFR/Stat3 axis enhances the interaction between tumor and its associated stroma and suggests that targeting this axis can be an effective therapeutic strategy against tumor malignancy.
Collapse
Affiliation(s)
- Di Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China
| | - Jing Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Lingyuan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Qingnan Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China
- Peking University International Cancer Institute, Beijing 100191, China
| | - Yan Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China
- Peking University International Cancer Institute, Beijing 100191, China
| | - Weimin Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China
- Shenzhen Bay Laboratory, Shenzhen 518132, China
| | - Yuanfan Xiao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Jie Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China
- Peking University International Cancer Institute, Beijing 100191, China
- Corresponding authors.
| | - Qimin Zhan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China
- Peking University International Cancer Institute, Beijing 100191, China
- Shenzhen Bay Laboratory, Shenzhen 518132, China
- Corresponding authors.
| |
Collapse
|
|
9
|
Song WP, Wang SY, Zhou SC, Wu DS, Xie JY, Liu TT, Wu XZ, Che GW. Prognostic and clinicopathological value of Twist expression in esophageal cancer: A meta-analysis. World J Gastrointest Oncol 2022; 14:1874-1886. [PMID: 36187399 PMCID: PMC9516646 DOI: 10.4251/wjgo.v14.i9.1874] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/30/2022] [Accepted: 07/31/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Twist is a repressor of E-cadherin transcription that induces epithelial-mesenchymal transition and cancer metastasis. However, the prognostic value of Twist expression in patients with esophageal cancer remains controversial. AIM To investigate the prognostic and clinicopathological value of Twist expression in esophageal cancer. METHODS Published literature in databases such as EMBASE, Web of Science, PubMed, China National Knowledge Infrastructure, Wanfang, and VIP databases was searched for eligible articles. Participants with esophageal cancer whose tumor tissues underwent immunohistochemistry to detect the expression of Twist were considered. Our meta-analysis was conducted using Stata version 12.0. The hazard ratio (HR) and relative ratio (RR) with their 95%CI were pooled. Heterogeneity was estimated by I 2 statistics. RESULTS Eleven articles published between 2009 and 2021 fulfilled the selection criteria. The pooled HR for overall survival was 1.88 (95%CI: 1.32-2.69, I 2 = 68.6%), and the pooled HR for disease-free survival/relapse-free survival/progression-free survival was 1.84 (95%CI: 1.12-3.02, I 2 = 67.1%), suggesting that high Twist expression is associated with poor prognosis in esophageal cancer patients. In addition, overexpression of Twist was correlated with T stage (T3 + T4 vs T1 + T2, RR = 1.38, 95%CI: 1.14-1.67), lymph node metastasis (yes vs no, RR = 1.34, 95%CI: 1.11-1.60), distant metastasis (yes vs no, RR = 1.18, 95%CI: 1.02-1.35), tumor, node and metastasis (TNM) stage (III + IV vs I + II, RR = 1.35, 95%CI: 1.14-1.60), and clinical stage (III + IV vs I + II, RR = 1.58, 95%CI: 1.34-1.87). However, no correlation between Twist expression and age, gender, tumor location, differentiation, or venous invasion was observed. CONCLUSION High expression of Twist is associated with poor esophageal cancer prognosis. Moreover, Twist overexpression is correlated with T stage, lymph node metastasis, distant metastasis, TNM stage, and clinical stage, which indicates that Twist might accelerate esophageal cancer progression and metastasis.
Collapse
Affiliation(s)
- Wen-Peng Song
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Su-Yan Wang
- Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Si-Cheng Zhou
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Dong-Sheng Wu
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Yu Xie
- Laboratory Experiments in Microbiology, Shuang Liu Center for Disease Control and Prevention, Chengdu 610041, Sichuan Province, China
| | - Tong-Tong Liu
- West China School of Public Health & West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiu-Zhu Wu
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Guo-Wei Che
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| |
Collapse
|
|
10
|
Qiu L, Yue J, Ding L, Yin Z, Zhang K, Zhang H. Cancer-associated fibroblasts: An emerging target against esophageal squamous cell carcinoma. Cancer Lett 2022; 546:215860. [DOI: 10.1016/j.canlet.2022.215860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/18/2022] [Accepted: 08/01/2022] [Indexed: 11/02/2022]
|
|
11
|
PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression. Nat Commun 2022; 13:2793. [PMID: 35589735 PMCID: PMC9120014 DOI: 10.1038/s41467-022-30484-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 05/04/2022] [Indexed: 12/01/2022] Open
Abstract
Although stromal fibroblasts play a critical role in cancer progression, their identities remain unclear as they exhibit high heterogeneity and plasticity. Here, a master transcription factor (mTF) constructing core-regulatory circuitry, PRRX1, which determines the fibroblast lineage with a myofibroblastic phenotype, is identified for the fibroblast subgroup. PRRX1 orchestrates the functional drift of fibroblasts into myofibroblastic phenotype via TGF-β signaling by remodeling a super-enhancer landscape. Such reprogrammed fibroblasts have myofibroblastic functions resulting in markedly enhanced tumorigenicity and aggressiveness of cancer. PRRX1 expression in cancer-associated fibroblast (CAF) has an unfavorable prognosis in multiple cancer types. Fibroblast-specific PRRX1 depletion induces long-term and sustained complete remission of chemotherapy-resistant cancer in genetically engineered mice models. This study reveals CAF subpopulations based on super-enhancer profiles including PRRX1. Therefore, mTFs, including PRRX1, provide another opportunity for establishing a hierarchical classification system of fibroblasts and cancer treatment by targeting fibroblasts. Cancer associated fibroblasts are an important and highly heterogeneous component of the tumor microenvironment. Here the authors identify PRRX1 as a master transcription factor determining a fibroblast lineage with myofibroblastic phenotype, associated with unfavourable prognosis in several cancer types.
Collapse
|
|
12
|
Dinh HQ, Pan F, Wang G, Huang QF, Olingy CE, Wu ZY, Wang SH, Xu X, Xu XE, He JZ, Yang Q, Orsulic S, Haro M, Li LY, Huang GW, Breunig JJ, Koeffler HP, Hedrick CC, Xu LY, Lin DC, Li EM. Integrated single-cell transcriptome analysis reveals heterogeneity of esophageal squamous cell carcinoma microenvironment. Nat Commun 2021; 12:7335. [PMID: 34921160 PMCID: PMC8683407 DOI: 10.1038/s41467-021-27599-5] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 11/29/2021] [Indexed: 02/05/2023] Open
Abstract
The tumor microenvironment is a highly complex ecosystem of diverse cell types, which shape cancer biology and impact the responsiveness to therapy. Here, we analyze the microenvironment of esophageal squamous cell carcinoma (ESCC) using single-cell transcriptome sequencing in 62,161 cells from blood, adjacent nonmalignant and matched tumor samples from 11 ESCC patients. We uncover heterogeneity in most cell types of the ESCC stroma, particularly in the fibroblast and immune cell compartments. We identify a tumor-specific subset of CST1+ myofibroblasts with prognostic values and potential biological significance. CST1+ myofibroblasts are also highly tumor-specific in other cancer types. Additionally, a subset of antigen-presenting fibroblasts is revealed and validated. Analyses of myeloid and T lymphoid lineages highlight the immunosuppressive nature of the ESCC microenvironment, and identify cancer-specific expression of immune checkpoint inhibitors. This work establishes a rich resource of stromal cell types of the ESCC microenvironment for further understanding of ESCC biology.
Collapse
Affiliation(s)
- Huy Q Dinh
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
- Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA, USA.
| | - Feng Pan
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
- Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Shantou, China
| | - Geng Wang
- Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Shantou, China
- Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Qing-Feng Huang
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
- Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Shantou, China
| | - Claire E Olingy
- Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA, USA
| | | | | | - Xin Xu
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
- Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Shantou, China
| | - Xiu-E Xu
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
- Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Shantou, China
| | - Jian-Zhong He
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
- Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Shantou, China
| | - Qian Yang
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Sandra Orsulic
- Department of Obstetrics and Gynecology and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Marcela Haro
- Department of Obstetrics and Gynecology and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Li-Yan Li
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - Guo-Wei Huang
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - Joshua J Breunig
- Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - H Phillip Koeffler
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Catherine C Hedrick
- Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA, USA
| | - Li-Yan Xu
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
- Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Shantou, China.
| | - De-Chen Lin
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - En-Min Li
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
- Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Shantou, China.
| |
Collapse
|
|
13
|
Exacerbation of Liver Tumor Metastasis in twist1a+/ xmrk+ Double Transgenic Zebrafish following Lipopolysaccharide or Dextran Sulphate Sodium Exposure. Pharmaceuticals (Basel) 2021; 14:ph14090867. [PMID: 34577566 PMCID: PMC8468836 DOI: 10.3390/ph14090867] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 12/20/2022] Open
Abstract
The poor prognosis for patients with hepatocellular carcinoma (HCC) is related directly to metastasis. The Twist1 gene encodes for a transcription factor essential to embryogenesis. It has also been shown to promote epithelial-to-mesenchymal transition (EMT), invasion, and metastasis; however, there is currently no in vivo evidence that Twist1 plays a role in the metastasis of liver tumors. Zebrafish are increasingly being used as an alternative cancer model. In the current study, an adult-stage zebrafish HCC model was used to examine the synergistic effects of twist1a and xmrk, a well characterized oncogene, during HCC metastasis. We also examined the effects of two inflammatory agents, lipopolysaccharides (LPS) and dextran sulfate sodium (DSS), on the hepatocyte-specific expression of transgenic twist1a and xmrk. The conditional overexpression of twist1a and xmrk was shown to promote liver tumor metastasis in zebrafish, resulting in increased apoptosis and cell proliferation as well as tumor maintenance and propagation independent of the inherent EMT-inducing activity of xmrk. Exposing twist1a+/xmrk+ transgenic zebrafish to LPS or DSS was shown to promote metastasis, indicating that the overexpression of twist1a and xmrk led to crosstalk between the signaling pathways involved in EMT. This study provides important evidence pertaining to the largely overlooked effects of signaling crosstalk between twist1a and xmrk in regulating HCC metastasis. Our results also suggest that the co-expression of twist1a/xmrk in conjunction with exposure to LPS or DSS enhances HCC metastasis, and provides a valuable in vivo platform by which to investigate tumor initiation and metastasis in the study of liver cancer.
Collapse
|
|
14
|
Galbo PM, Zang X, Zheng D. Molecular Features of Cancer-associated Fibroblast Subtypes and their Implication on Cancer Pathogenesis, Prognosis, and Immunotherapy Resistance. Clin Cancer Res 2021; 27:2636-2647. [PMID: 33622705 DOI: 10.1158/1078-0432.ccr-20-4226] [Citation(s) in RCA: 208] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/05/2021] [Accepted: 02/18/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment, but a systematic investigation of their molecular characteristics and clinical relevance are lacking. Here, we sought to compare CAFs across multiple cancer types to identify critical molecular pathways activated in CAF subtypes, which may contribute to clinical outcome, disease progression, and immunotherapy resistance. EXPERIMENTAL DESIGN We performed integrated analysis of CAFs from melanoma, head and neck squamous cell carcinoma, and lung cancer, and identified the molecular characteristics that are distinctly active in each CAF subtype. Gene signatures for individual CAF subtypes were identified and used to study the association of subtype abundance with clinical outcome and immunotherapy resistance. RESULTS We identified six CAF subtypes (pan-CAF) shared across cancer types and uncovered the molecular characteristics and genetic pathways distinguishing them. Interestingly, these CAF subtypes express distinct immunosuppressive factors, such as CXCL12 and CXLC14, and stem cell-promoting factor IL6. In addition, we identified novel transcriptional drivers (MEF2C, TWIST1, NR1H3, RELB, and FOXM1) key to CAF heterogeneity. Furthermore, we showed that CAF subtypes were associated with different clinical outcomes and uncovered key molecular pathways that could activate or suppress cancer progression or were involved in resistance to anti-PD1 or anti-PD-L1 immunotherapy. CONCLUSIONS Our study identifies the molecular characteristics of CAF subtypes shared across several cancer types, implicates cancer types that may benefit from CAF subtype targeted therapies, and identifies specific CAF subtypes associated with immunotherapy resistance.
Collapse
Affiliation(s)
- Phillip M Galbo
- Department of Genetics, Albert Einstein College of Medicine, Bronx, New York.,Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York
| | - Xingxing Zang
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York. .,Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
| | - Deyou Zheng
- Department of Genetics, Albert Einstein College of Medicine, Bronx, New York. .,Departments of Neurology and Neuroscience, Albert Einstein College of Medicine, Bronx, New York
| |
Collapse
|
|
15
|
Han P, Cao P, Hu S, Kong K, Deng Y, Zhao B, Li F. Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche. Cancer Manag Res 2020; 12:5857-5879. [PMID: 32765088 PMCID: PMC7371556 DOI: 10.2147/cmar.s258215] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 06/29/2020] [Indexed: 12/15/2022] Open
Abstract
Esophageal cancer (EC) is the sixth most deadly cancer, and its incidence is still increasing year by year. Although the researches on the molecular mechanisms of EC have been widely carried out and incremental progress has been made, its overall survival rate is still low. There is cumulative evidence showing that the esophageal microenvironment plays a vital role in the development of EC. In precancerous lesions of the esophagus, high-risk environmental factors can promote the development of precancerous lesions by inducing the production of inflammatory factors and the recruitment of immune cells. In the tumor microenvironment, tumor-promoting cells can inhibit anti-tumor immunity and promote tumor progression through a variety of pathways, such as bone marrow-derived suppressor cells (MDSCs), tumor-associated fibroblasts (CAFs), and regulatory T cells (Tregs). The formation of extracellular hypoxia and acidic microenvironment and the change of extracellular matrix stiffness are also important factors affecting tumor progression and metastasis. Simultaneously, primary tumor-derived cytokines and bone marrow-derived immune cells can also promote the formation of pre-metastasis niche of EC lymph nodes, which are beneficial to EC lymph node metastasis. Further research on the specific mechanism of these processes in the occurrence, development, and metastasis of each EC subtype will support us to grasp the overall pre-cancerous prevention, targeted treatment, and metastatic assessment of EC.
Collapse
Affiliation(s)
- Peng Han
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Peng Cao
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Shan Hu
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Kangle Kong
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Yu Deng
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Bo Zhao
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Fan Li
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| |
Collapse
|
|
16
|
Nurmik M, Ullmann P, Rodriguez F, Haan S, Letellier E. In search of definitions: Cancer-associated fibroblasts and their markers. Int J Cancer 2020; 146:895-905. [PMID: 30734283 PMCID: PMC6972582 DOI: 10.1002/ijc.32193] [Citation(s) in RCA: 458] [Impact Index Per Article: 91.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 12/14/2018] [Accepted: 01/28/2019] [Indexed: 12/12/2022]
Abstract
The tumor microenvironment has been identified as one of the driving factors of tumor progression and invasion. Inside this microenvironment, cancer-associated fibroblasts (CAFs), a type of perpetually activated fibroblasts, have been implicated to have a strong tumor-modulating effect and play a key role in areas such as drug resistance. Identification of CAFs has typically been carried based on the expression of various "CAF markers", such as fibroblast activation protein alpha (FAP) and alpha smooth muscle actin (αSMA), which separates them from the larger pool of fibroblasts present in the body. However, as outlined in this Review, the expression of various commonly used fibroblast markers is extremely heterogeneous and varies strongly between different CAF subpopulations. As such, novel selection methods based on cellular function, as well as further characterizing research, are vital for the standardization of CAF identification in order to improve the cross-applicability of different research studies in the field. The aim of this review is to give a thorough overview of the commonly used fibroblast markers in the field and their various strengths and, more importantly, their weaknesses, as well as to highlight potential future avenues for CAF identification and targeting.
Collapse
Affiliation(s)
- Martin Nurmik
- Molecular Disease Mechanisms Group, Life Sciences Research UnitUniversity of LuxembourgBelvauxLuxembourg
| | - Pit Ullmann
- Molecular Disease Mechanisms Group, Life Sciences Research UnitUniversity of LuxembourgBelvauxLuxembourg
| | - Fabien Rodriguez
- Molecular Disease Mechanisms Group, Life Sciences Research UnitUniversity of LuxembourgBelvauxLuxembourg
| | - Serge Haan
- Molecular Disease Mechanisms Group, Life Sciences Research UnitUniversity of LuxembourgBelvauxLuxembourg
| | - Elisabeth Letellier
- Molecular Disease Mechanisms Group, Life Sciences Research UnitUniversity of LuxembourgBelvauxLuxembourg
| |
Collapse
|
|
17
|
Ai X, Zhu X, Zuo J. Prolactin (PRL), placenta growth factor (PIGF) and nerve growth factor receptor (NGFR) as biomarkers for early diagnosis and prognosis in patients with esophageal squamous cell carcinoma (ESCC). Transl Cancer Res 2020; 9:647-656. [PMID: 35117410 PMCID: PMC8798035 DOI: 10.21037/tcr.2019.12.31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 10/25/2019] [Indexed: 11/12/2022]
Abstract
BACKGROUND The purpose of this study was to investigate the expression and clinical significance of prolactin (PRL), placenta growth factor (PIGF) and nerve growth factor receptor (NGFR) in esophageal squamous cell carcinoma (ESCC). METHODS PRL, PIGF and NGFR were selected through being screened normal human and esophageal cancer (EC) plasma by high-throughput protein chips. Subsequently, enzyme linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were used to detect the expression in ESCC and control group. Then, its clinical significance was statistically evaluated. RESULTS The expression of PRL, PIGF and NGFR in plasma and tissue of patients with EC was higher than healthy controls and adjacent tissue, respectively. Among the clinical parameters, the expression of PRL and NGFR protein was correlated with the tumor classification of ESCC (P<0.05), while PIGF protein was correlated with the clinical stage of ESCC (P<0.05). The area under the ROC (AUC) of PRL, PIGF, and NGFR in plasma was 0.69, 0.72, and 0.66 in separately. Furthermore, the combined detection of three proteins had a better AUC of 0.74 with a sensitivity of 66.7% and a specificity of 72.4%. Kaplan-Meier survival analysis revealed that positive expression of PRL, PIGF and NGFR in histological predicted significantly worse overall survival (OS) than negative expression (P<0.05). CONCLUSIONS PRL, PIGF and NGFR are promising biomarkers for diagnosis and prognosis prediction of ESCC.
Collapse
Affiliation(s)
- Xiaohong Ai
- Department of Radiotherapy, The First Affiliated Hospital, University of South China, Hengyang 421900, China
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, School of Medicine, University of South China, Hengyang 421900, China
| | - Xiaoxi Zhu
- Department of Radiotherapy, The First Affiliated Hospital, University of South China, Hengyang 421900, China
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, School of Medicine, University of South China, Hengyang 421900, China
| | - Jianhong Zuo
- Department of Radiotherapy, The First Affiliated Hospital, University of South China, Hengyang 421900, China
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, School of Medicine, University of South China, Hengyang 421900, China
- The Translational Medicine Laboratory, Hengyang Medical College, University of South China, Hengyang 421900, China
- The Third Affiliated Hospital, University of South China, Hengyang 421900, China
| |
Collapse
|
|
18
|
Sun H, Zhang Z, Zhang T, Geng H, Xie D, Wang Y, Ding D, Zhang T, Yu D. Resveratrol Reverses Cigarette Smoke-Induced Urocystic Epithelial-Mesenchymal Transition via Suppression of STAT3 Phosphorylation in SV-HUC-1-Immortalized Human Urothelial Cells. Onco Targets Ther 2019; 12:10227-10237. [PMID: 32063715 PMCID: PMC6884977 DOI: 10.2147/ott.s226580] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 11/06/2019] [Indexed: 01/08/2023] Open
Abstract
Purpose Bladder cancer is a malignant tumor of the urinary tract, and cigarette smoke (CS) is closely related to tumorigenesis. Resveratrol, a plant-derived bioactive nutrient, possesses multiple anticancer effects. However, the mechanism of CS-induced tumorigenesis is still not clear. The role of resveratrol in CS-meditated bladder cancer development has not been reported. Methods MTT assay showed the toxicity of cigarette smoke extract (CSE) on the cell viability of SV-HUC-1 cells. Western blotting detected the expression levels of related proteins. Transwell migration or invasion assay evaluated the capacity of cell migration or invasion after treatment. Wound-healing assay revealed the effect of cell migratory capacity. The cell cycle was detected by flow cytometry. Results Our study demonstrated that CSE-triggered epithelial–mesenchymal transition (EMT) in SV-HUC-1-immortalized human urothelial cells via the STAT3/TWIST1 pathway. Furthermore, the results showed resveratrol effectively inhibited STAT3 phosphorylation, thus reversed EMT triggered by CSE. Meanwhile, the cell proliferation was also suppressed. Conclusion In conclusion, inhibition of the STAT3 in CSE-induced EMT on bladder cancer may be a promising cancer treatment target for suppression by resveratrol.
Collapse
Affiliation(s)
- Hongliang Sun
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
| | - Zhiqiang Zhang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
| | - Taotao Zhang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
| | - Hao Geng
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
| | - Dongdong Xie
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
| | - Yi Wang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
| | - Demao Ding
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
| | - Tao Zhang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
| | - Dexin Yu
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, People's Republic of China
| |
Collapse
|
|
19
|
Akin Telli T, Bregni G, Camera S, Deleporte A, Hendlisz A, Sclafani F. PD-1 and PD-L1 inhibitors in oesophago-gastric cancers. Cancer Lett 2019; 469:142-150. [PMID: 31669518 DOI: 10.1016/j.canlet.2019.10.036] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/18/2019] [Accepted: 10/22/2019] [Indexed: 12/25/2022]
Abstract
Oesophago-gastric cancers (OGCs) are aggressive tumours. While better peri-operative strategies, increased number of cytotoxic agents and availability of targeted therapies have improved survival, there remains an unmet need for novel treatment approaches. Immune checkpoint inhibitors (ICIs) have marked a new era in cancer management with unprecedented results in several malignancies. Although OGC lagged behind other solid tumours, evidence has increasingly accumulated supporting the contention that modulation of the anti-cancer host immune response may be beneficial for at least some patients. Many trials have been completed in Eastern and Western countries, some of these leading to the approval of ICIs in the refractory setting, and favorable opinion from regulatory agencies is expected also in treatment-naïve, advanced OGC. Furthermore, studies are evaluating ICIs in the early stage setting and exploring the potential of combination treatments. In this article we discuss the biological bases underlying the successful development of ICIs in OGC and review the available data on PD-1 and PD-L1 monoclonal antibodies in this disease. Also, we present ongoing clinical trials of these ICIs that could shape the future treatment landscape of OGC.
Collapse
Affiliation(s)
- Tugba Akin Telli
- Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Giacomo Bregni
- Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Silvia Camera
- Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Amelie Deleporte
- Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Alain Hendlisz
- Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Francesco Sclafani
- Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet - Université Libre de Bruxelles (ULB), Brussels, Belgium.
| |
Collapse
|
|
20
|
Son SW, Chau GC, Kim ST, Um SH. Vacuolar H +-ATPase Subunit V0C Regulates Aerobic Glycolysis of Esophageal Cancer Cells via PKM2 Signaling. Cells 2019; 8:E1137. [PMID: 31554233 PMCID: PMC6830105 DOI: 10.3390/cells8101137] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/16/2019] [Accepted: 09/20/2019] [Indexed: 12/16/2022] Open
Abstract
The vacuolar H+-adenosine triphosphatase (ATPase) subunit V0C (ATP6V0C), a proton-conducting, pore-forming subunit of vacuolar ATPase, maintains pH homeostasis and induces organelle acidification. The intracellular and extracellular pH of cancer cells affects their growth; however, the role of ATP6V0C in highly invasive esophageal cancer cells (ECCs) remains unclear. In this study, we examined the role of ATP6V0C in glucose metabolism in ECCs. The ATP6V0C depletion attenuated ECC proliferation, invasion, and suppressed glucose metabolism, as indicated by reduced glucose uptake and decreased lactate and adenosine triphosphate (ATP) production in cells. Consistent with this, expression of glycolytic enzyme and the extracellular acidification rate (ECAR) were also decreased by ATP6V0C knockdown. Mechanistically, ATP6V0C interacted with pyruvate kinase isoform M2 (PKM2), a key regulator of glycolysis in ECCs. The ATP6V0C depletion reduced PKM2 phosphorylation at tyrosine residue 105 (Tyr105), leading to inhibition of nuclear translocation of PKM2. In addition, ATP6V0C was recruited at hypoxia response element (HRE) sites in the lactate dehydrogenase A (LDHA) gene for glycolysis. Thus, our data suggest that ATP6V0C enhances aerobic glycolysis and motility in ECCs.
Collapse
Affiliation(s)
- Sung Wook Son
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 16419, Korea.
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, Korea.
| | - Gia Cac Chau
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 16419, Korea.
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, Korea.
| | - Seong-Tae Kim
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 16419, Korea.
| | - Sung Hee Um
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 16419, Korea.
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, Korea.
- Biomedical Institute Convergence at Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Korea.
| |
Collapse
|
|
21
|
Abbaszadegan MR, Keyvani V, Moghbeli M. Genetic and molecular bases of esophageal Cancer among Iranians: an update. Diagn Pathol 2019; 14:97. [PMID: 31470870 PMCID: PMC6717340 DOI: 10.1186/s13000-019-0875-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 08/22/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Esophageal cancer is one of the leading causes of cancer related deaths among the Iranians. There is still a high ratio of mortality and low 5 years survival which are related to the late onset and diagnosis. Majority of patients refer for the treatment in advanced stages of tumor progression. MAIN BODY It is required to define an efficient local panel of diagnostic and prognostic markers for the Iranians. Indeed such efficient specific panel of markers will pave the way to decrease the mortality rate and increase the 5 years survival among the Iranian patients via the early diagnosis and targeted therapy. CONCLUSION in present review we have reported all of the molecular markers in different signaling pathways and cellular processes which have been assessed among the Iranian esophageal cancer patients until now.
Collapse
Affiliation(s)
| | - Vahideh Keyvani
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
22
|
Dual role of twist1 in cancer-associated fibroblasts and tumor cells promoted epithelial-mesenchymal transition of esophageal cancer. Exp Cell Res 2019; 375:41-50. [PMID: 30611739 DOI: 10.1016/j.yexcr.2019.01.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 12/26/2018] [Accepted: 01/02/2019] [Indexed: 02/07/2023]
Abstract
Cancer-associated fibroblasts (CAFs) play critical roles in tumor progression. However, the role and mechanism underlying CAFs in esophageal cancer (EC) remain unclear. In this study, primary CAFs and normal esophageal fibroblasts (NOFs) were isolated and characterized by immunofluorescence, qRT-PCR and western blot. Clinical significance of twist1 in CAFs were evaluated by immunohistochemistry assay. Conditioned medium (CM) was collected from CAFs to evaluate the influence on epithelial-mesenchymal transition (EMT) of EC cells. EC cells were mixed with CAFs and subcutaneously injected into nude mice to assess the in vivo tumor growth. As the result, twist1 was overexpressed in CAFs compared with NOFs and exhibited adverse prognostic significance. In CAFs, twist1 promoted the expression and secretion of CXCL12. In EC cells, activated CXCL12/CXCR4 signaling promoted the EMT process through ERK/AKT - twist1 - MMP1/E-cadherin pathway. In addition, knockdown of twist1 in CAFs also suppressed in vivo tumor growth. In conclusion, our results revealed a dual role of twist1 in CAFs and EC cells to promote the EMT process.
Collapse
|
|
23
|
Nilendu P, Sarode SC, Jahagirdar D, Tandon I, Patil S, Sarode GS, Pal JK, Sharma NK. Mutual concessions and compromises between stromal cells and cancer cells: driving tumor development and drug resistance. Cell Oncol (Dordr) 2018; 41:353-367. [PMID: 30027403 DOI: 10.1007/s13402-018-0388-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/08/2018] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Various cancers have been found to be associated with heterogeneous and adaptive tumor microenvironments (TMEs) and to be driven by the local TMEs in which they thrive. Cancer heterogeneity plays an important role in tumor cell survival, progression and drug resistance. The diverse cellular components of the TME may include cancer-associated fibroblasts, adipocytes, pericytes, mesenchymal stem cells, endothelial cells, lymphocytes and other immune cells. These components may support tumor development through the secretion of growth factors, evasion from immune checkpoints, metabolic adaptations, modulations of the extracellular matrix, activation of oncogenes and the acquisition of drug resistance. Here, we will address recent advances in our understanding of the molecular mechanisms underlying stromal-tumor cell interactions, with special emphasis on basic and pre-clinical information that may facilitate the design of novel personalized cancer therapies. CONCLUSIONS This review presents a holistic view on the translational potential of the interplay between stromal cells and cancer cells. This interplay is currently being employed for the development of promising preclinical and clinical biomarkers, and the design of small molecule inhibitors, antibodies and small RNAs for (combinatorial) cancer treatment options. In addition, nano-carriers, tissue scaffolds and 3-D based matrices are being developed to precisely and safely deliver these compounds.
Collapse
Affiliation(s)
- Pritish Nilendu
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
| | - Sachin C Sarode
- Department of Oral Pathology and Microbiology, Dr. D Y Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India.
| | - Devashree Jahagirdar
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
| | - Ishita Tandon
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, Saudi Arabia
| | - Gargi S Sarode
- Department of Oral Pathology and Microbiology, Dr. D Y Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India
| | - Jayanta K Pal
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
| | - Nilesh Kumar Sharma
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India.
| |
Collapse
|
|
24
|
Yeo SY, Lee KW, Shin D, An S, Cho KH, Kim SH. A positive feedback loop bi-stably activates fibroblasts. Nat Commun 2018; 9:3016. [PMID: 30069061 PMCID: PMC6070563 DOI: 10.1038/s41467-018-05274-6] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 06/18/2018] [Indexed: 01/12/2023] Open
Abstract
Although fibroblasts are dormant in normal tissue, they exhibit explosive activation during wound healing and perpetual activation in pathologic fibrosis and cancer stroma. The key regulatory network controlling these fibroblast dynamics is still unknown. Here, we report that Twist1, a key regulator of cancer-associated fibroblasts, directly upregulates Prrx1, which, in turn, increases the expression of Tenascin-C (TNC). TNC also increases Twist1 expression, consequently forming a Twist1-Prrx1-TNC positive feedback loop (PFL). Systems biology studies reveal that the Twist1-Prrx1-TNC PFL can function as a bistable ON/OFF switch and regulates fibroblast activation. This PFL can be irreversibly activated under pathologic conditions, leading to perpetual fibroblast activation. Sustained activation of the Twist1-Prrx1-TNC PFL reproduces fibrotic nodules similar to idiopathic pulmonary fibrosis in vivo and is implicated in fibrotic disease and cancer stroma. Considering that this PFL is specific to activated fibroblasts, Twist1-Prrx1-TNC PFL may be a fibroblast-specific therapeutic target to deprogram perpetually activated fibroblasts.
Collapse
Affiliation(s)
- So-Young Yeo
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, 06351, Republic of Korea
| | - Keun-Woo Lee
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, 06351, Republic of Korea
| | - Dongkwan Shin
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Sugyun An
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Kwang-Hyun Cho
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
| | - Seok-Hyung Kim
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, 06351, Republic of Korea. .,Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea. .,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwona, Gyeonggi-do, 16419, Republic of Korea.
| |
Collapse
|
|
25
|
Liu L, Yang Z, Ni W, Xuan Y. ADAMTS-6 is a predictor of poor prognosis in patients with esophageal squamous cell carcinoma. Exp Mol Pathol 2018; 104:134-139. [PMID: 29475036 DOI: 10.1016/j.yexmp.2018.02.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Revised: 01/14/2018] [Accepted: 02/20/2018] [Indexed: 11/19/2022]
Abstract
BACKGROUND A disintegrin and metalloprotease with thrombospondin motif (ADAMTS) enzymes play important roles in cell functions including adhesion, invasion, migration, and proliferation. ADAMTS-6 is a member of the ADAMTS family; reports of its relationship with esophageal squamous cell carcinoma (ESCC) progression are rare. It is unclear whether ADAMTS-6 could be an independent ESCC biomarker. METHODS ADAMTS-6 expression was detected by immunohistochemistry (IHC) in 171 paraffin-embedded ESCC specimens; relationships with patients' clinicopathological features and Twist-1 expression were analyzed by the Pearson Chi-square method, respectively. Overall survival (OS) and disease-free survival (DFS) were determined using the Kaplan-Meier method and compared using the long-rank test. RESULTS ADAMTS-6 was expressed mainly in the cytoplasm and nucleus; the expression was significantly higher in tumor tissues. Increased expression of ADAMTS-6 correlated with clinical stage (P = 0.009), pT stage (P = 0.042), lymph node metastasis (P = 0.014) and recurrence (P = 0.033). There were no significant correlations between ADAMTS-6 expression and other clinicopathological parameters including age, sex, tumor size, distant metastasis, differentiation, …chemotherapy, radiotherapy, CD68 expression and epithelial mesenchymal transition (EMT) status. Kaplan-Meier survival curves revealed that upregulated expression of ADAMTS-6 indicated short OS (P = 0.001) and DFS (P = 0.002). Multivariate analysis confirmed that high ADAMTS-6 expression was an independent factor for ESCC prognosis. ADAMTS-6 expression was significantly correlated with Twist-1 expression in ESCC cancer cells (P = 0.007) and stromal cells (P < 0.001). Patients with ESCC revealing expression of both ADAMTS-6 and Twist-1 exhibited significantly reduced OS and DFS rates than other patients. CONCLUSIONS High ADAMTS-6 expression is a useful marker of poor prognosis in patients with ESCC.
Collapse
Affiliation(s)
- Lan Liu
- Key Laboratory of Natural Resources of the Changbai Mountain and Functional Molecules, Ministry of Education, Yanbian University College of Medicine, Yanji 13302, China; Department of Pathology, Affiliated Hospital of Yanbian University, Yanji 133002, China
| | - Zhaoting Yang
- Key Laboratory of Natural Resources of the Changbai Mountain and Functional Molecules, Ministry of Education, Yanbian University College of Medicine, Yanji 13302, China; Department of Pathology, Yanbian University College of Medicine, Yanji 13302, China
| | - Weidong Ni
- Key Laboratory of Natural Resources of the Changbai Mountain and Functional Molecules, Ministry of Education, Yanbian University College of Medicine, Yanji 13302, China; Department of Pathology, Yanbian University College of Medicine, Yanji 13302, China
| | - Yanhua Xuan
- Key Laboratory of Natural Resources of the Changbai Mountain and Functional Molecules, Ministry of Education, Yanbian University College of Medicine, Yanji 13302, China; Department of Pathology, Yanbian University College of Medicine, Yanji 13302, China.
| |
Collapse
|