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Feng X, Zhang D, Wang G, Lu L, Feng F, Wang X, Yu C, Chai Y, Zhang J, Li W, Liu J, Sun H, Yao L. Mechanisms and Therapeutic Strategies for Minority Cell-Induced Paclitaxel Resistance and Tumor Progression Mediated by Mechanical Forces. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2417805. [PMID: 40270447 DOI: 10.1002/advs.202417805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 04/02/2025] [Indexed: 04/25/2025]
Abstract
Chemotherapy remains a prevalent strategy in cancer therapy; however, the emergence of drug resistance poses a considerable challenge to its efficacy. Most drug resistance arises from the accumulation of genetic mutations in a minority of resistant cells. The mechanisms underlying the emergence and progression of cancer resistance from these minority-resistant cells (MRCs) remain poorly understood. This study employs force-induced remnant magnetization spectroscopy (FIRMS) alongside various biological investigations to reveal the mechanical pathways for MRCs fostering drug resistance and tumor progression. The findings show that minority Paclitaxel-resistant cancer cells have enhanced mechanical properties. These cells can transmit high-intensity forces to surrounding sensitive cells (SCs) through the force transducer, Merlin. This force transmission facilitates the assimilation of surrounding SCs, subsequently strengthening the contraction and adhesion of tumor cells. This process is termed "mechano-assimilation," which accelerates the development of drug resistance and tumor progression. Interestingly, disturbances and reductions of mechano-assimilation within tumors can restore sensitivity to Paclitaxel both in vitro and in vivo. This study provides preliminary evidence highlighting the contribution of MRCs to the development of drug resistance and malignancy, mediated through mechanical interactions. It also establishes a foundation for future research focused on integrating mechanical factors into innovative cancer therapies.
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Affiliation(s)
- Xueyan Feng
- State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Chinese Academy of Science, Beijing, 100190, P. R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Di Zhang
- State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Chinese Academy of Science, Beijing, 100190, P. R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
- University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Guoxun Wang
- University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Liwei Lu
- State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Chinese Academy of Science, Beijing, 100190, P. R. China
| | - Feng Feng
- State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Chinese Academy of Science, Beijing, 100190, P. R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Xiuyu Wang
- State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Chinese Academy of Science, Beijing, 100190, P. R. China
| | - Chanchan Yu
- State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Chinese Academy of Science, Beijing, 100190, P. R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Yahong Chai
- State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Chinese Academy of Science, Beijing, 100190, P. R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Jin Zhang
- Department of Thoracic Surgery, China-Japan Friendship Hospital, Beijing, 100029, P. R. China
| | - Wenchao Li
- Senior Department of Pediatrics, The Seventh Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100007, P. R. China
| | - Jing Liu
- Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China
| | - Hongxia Sun
- State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Chinese Academy of Science, Beijing, 100190, P. R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Li Yao
- State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Chinese Academy of Science, Beijing, 100190, P. R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
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2
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Gantert B, Karakaya E, Hofmann F, Jungst T, Meinel L, Bosserhoff AK, Detsch R, Lühmann T. Alginate-Dialdehyde-Based Reporter Ink Enabling Online Detection of Matrix Metalloproteinase Activity of Encapsulated Cells. ACS Biomater Sci Eng 2025; 11:2435-2447. [PMID: 40052617 DOI: 10.1021/acsbiomaterials.4c02399] [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] [Indexed: 04/15/2025]
Abstract
Biofabrication and three-dimensional (3D) bioprinting enable precise spatial arrangement of cells within biomaterial scaffolds. We developed an alginate-based and Förster resonance energy transfer (FRET)-responsive "turn-on" reporter ink platform to enable real-time monitoring of matrix metalloproteinase (MMP) activity. Three distinct MMP-cleavable turn-on peptide reporters were synthesized and characterized for their cell-specific cleavage profiles using recombinant MMPs, cell-derived media, and different cell cultures (NIH3T3, HEK293, and MelHo). All turn-on reporters were covalently and site-specifically incorporated into alginate dialdehyde (ADA) to yield an MMP reporter ink. The ADA reporter ink with an MMP 13 turn-on reporter was responsive to all tested cell types over time within the cast bulk constructs. The ADA reporter ink material blended with gelatin had comparable print resolution and structural fidelity as observed for ADA. The extrusion-based bioprinted MelHo cell grids, measuring 2 × 2 cm2 and containing 1 × 106 cells/mL, exhibited MMP activity responses comparable to those of the casted reporter ink system, with a 3-fold increase observed at 24 h. This study introduces a versatile, FRET-based alginate bioink platform for the real-time monitoring of MMP activities, expanding the toolkit to understand cellular performance in bioprinted 3D constructs.
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Affiliation(s)
- Benedikt Gantert
- Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
| | - Emine Karakaya
- Institute of Biomaterials, Department of Materials Science and Engineering, University of Erlangen-Nuremberg, Ulrich-Schalk-Str. 3, 91056 Erlangen, Germany
| | - Florian Hofmann
- Department for Functional Materials in Medicine and Dentistry, Institute of Functional Materials and Biofabrication, University of Würzburg and KeyLab Polymers for Medicine of the Bavarian Polymer Institute (BPI), 97070 Würzburg, Germany
| | - Tomasz Jungst
- Department for Functional Materials in Medicine and Dentistry, Institute of Functional Materials and Biofabrication, University of Würzburg and KeyLab Polymers for Medicine of the Bavarian Polymer Institute (BPI), 97070 Würzburg, Germany
| | - Lorenz Meinel
- Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
- Helmholtz Institute for RNA-Based Infection Research (HIRI), Helmholtz Center for Infection Research (HZI), 97080 Würzburg, Germany
| | - Anja K Bosserhoff
- Institute of Biochemistry, Emil-Fischer-Zentrum, University of Erlangen-Nuremberg, Fahrstrasse 17, 91054 Erlangen, Germany
| | - Rainer Detsch
- Institute of Biomaterials, Department of Materials Science and Engineering, University of Erlangen-Nuremberg, Ulrich-Schalk-Str. 3, 91056 Erlangen, Germany
| | - Tessa Lühmann
- Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
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Shamul JG, Wang Z, Gong H, Ou W, White AM, Moniz-Garcia DP, Gu S, Clyne AM, Quiñones-Hinojosa A, He X. Meta-analysis of the make-up and properties of in vitro models of the healthy and diseased blood-brain barrier. Nat Biomed Eng 2025; 9:566-598. [PMID: 39304761 PMCID: PMC11922799 DOI: 10.1038/s41551-024-01250-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/08/2024] [Indexed: 09/22/2024]
Abstract
In vitro models of the human blood-brain barrier (BBB) are increasingly used to develop therapeutics that can cross the BBB for treating diseases of the central nervous system. Here we report a meta-analysis of the make-up and properties of transwell and microfluidic models of the healthy BBB and of BBBs in glioblastoma, Alzheimer's disease, Parkinson's disease and inflammatory diseases. We found that the type of model, the culture method (static or dynamic), the cell types and cell ratios, and the biomaterials employed as extracellular matrix are all crucial to recapitulate the low permeability and high expression of tight-junction proteins of the BBB, and to obtain high trans-endothelial electrical resistance. Specifically, for models of the healthy BBB, the inclusion of endothelial cells and pericytes as well as physiological shear stresses (~10-20 dyne cm-2) are necessary, and when astrocytes are added, astrocytes or pericytes should outnumber endothelial cells. We expect this meta-analysis to facilitate the design of increasingly physiological models of the BBB.
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Affiliation(s)
- James G Shamul
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
- RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Zhiyuan Wang
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | - Hyeyeon Gong
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | - Wenquan Ou
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | - Alisa M White
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | | | - Shuo Gu
- RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Alisa Morss Clyne
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
- Robert E. Fischell Institute for Biomedical Devices, University of Maryland, College Park, MD, USA
- Brain and Behavior Institute, University of Maryland, College Park, MD, USA
| | | | - Xiaoming He
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
- Robert E. Fischell Institute for Biomedical Devices, University of Maryland, College Park, MD, USA.
- Brain and Behavior Institute, University of Maryland, College Park, MD, USA.
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA.
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4
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Wang H, Liu H, Tang X, Lu G, Luo S, Du M, Christiani DC, Wei Q. Potentially functional variants of PARK7 and DDR2 in ferroptosis-related genes predict survival of non-small cell lung cancer patients. Int J Cancer 2025; 156:744-755. [PMID: 39319523 DOI: 10.1002/ijc.35197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 06/29/2024] [Accepted: 07/09/2024] [Indexed: 09/26/2024]
Abstract
Ferroptosis, a form of regulated cell death, is characterized by iron-dependent lipid peroxidation. It is recognized increasingly for its pivotal role in both cancer development and the response to cancer treatments. We assessed associations between 370,027 single-nucleotide polymorphisms (SNPs) within 467 ferroptosis-related genes and survival of non-small cell lung cancer (NSCLC) patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial served as our discovery dataset, while the Harvard Lung Cancer Susceptibility Study used as our validation dataset. For SNPs that remained statistically significantly associated with overall survival (OS) in both datasets, we employed a multivariable stepwise Cox proportional hazards regression model with the PLCO dataset. Ultimately, two independent SNPs, PARK7 rs225120 C>T and DDR2 rs881127 T>C, were identified with adjusted hazard ratios of 1.32 (95% confidence interval = 1.15-1.52, p = .0001) and 1.34 (95% confidence interval = 1.09-1.64, p = .006) for OS, respectively. We aggregated these two SNPs into a genetic score reflecting the number of unfavorable genotypes (NUG) in further multivariable analysis, revealing a noteworthy association between increased NUG and diminished OS (ptrend = .001). Additionally, an expression quantitative trait loci analysis indicated that PARK7 rs225120T genotypes were significantly associated with higher PARK7 mRNA expression levels in both whole blood and normal lung tissue. Conversely, DDR2 rs881127C genotypes were significantly associated with lower DDR2 mRNA expression levels in normal lung tissue. Our findings suggest that genetic variants in the ferroptosis-related genes PARK7 and DDR2 are associated with NSCLC survival, potentially through their influence on gene expression levels.
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Affiliation(s)
- Huilin Wang
- Department of Respiratory Oncology, Guangxi Cancer Hospital, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina, USA
| | - Hongliang Liu
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina, USA
| | - Xiaozhun Tang
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina, USA
- Department of Head and Neck Surgery, Guangxi Cancer Hospital, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Guojun Lu
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina, USA
- Department of Respiratory Medicine, Nanjing Chest Hospital, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Sheng Luo
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina, USA
| | - Mulong Du
- Department of Environmental Health, Harvard TH Chan School of Public Health, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts, USA
| | - David C Christiani
- Department of Environmental Health, Harvard TH Chan School of Public Health, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts, USA
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina, USA
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
- Duke Global Health Institute, Duke University Medical Center, Durham, North Carolina, USA
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5
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Liu M, Liu X, Zhang J, Liang S, Gong Y, Shi S, Yuan X. Single-cell RNA sequencing reveals the heterogeneity of myofibroblasts in wound repair. Genomics 2025; 117:110982. [PMID: 39706310 DOI: 10.1016/j.ygeno.2024.110982] [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: 03/20/2024] [Revised: 12/09/2024] [Accepted: 12/15/2024] [Indexed: 12/23/2024]
Abstract
Skin wound repair involves myofibroblasts crucial for tissue integrity. This study utilized single-cell RNA sequencing to explore myofibroblast diversity in various wound healing scenarios. Analysis of 89,148 cells from skin ulcers, keloids, and normal scars identified 13 cell clusters. Myofibroblast subcluster analysis unveiled 11 subsets, with subclusters 1 and 9 predominant in ulcers. Subcluster 1 exhibited heightened matrix metalloproteinase expression and involvement in bacterial response and angiogenesis, crucial in inflammation. Tissue validation confirmed subcluster 1 significance., while animal models supported upregulated CA12, TDO2, and IL-7R in chronic ulcers. These findings illuminate myofibroblast heterogeneity and their impact on wound healing, offering insights into potential therapeutic targets.
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Affiliation(s)
- Miaonan Liu
- Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoxuan Liu
- Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jingchi Zhang
- Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Shaocong Liang
- Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yan Gong
- Department of Burns and Wound Repairing, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Shengjun Shi
- Department of Burns and Wound Repairing, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
| | - Xiaopeng Yuan
- Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Department of Laboratory Medicine, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University; Shenzhen 518020, Guangdong China..
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6
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Sabeh F, Li XY, Olson AW, Botvinick E, Kurup A, Gimenez LE, Cho JS, Weiss SJ. Mmp14-dependent remodeling of the pericellular-dermal collagen interface governs fibroblast survival. J Cell Biol 2024; 223:e202312091. [PMID: 38990714 PMCID: PMC11244150 DOI: 10.1083/jcb.202312091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 05/10/2024] [Accepted: 05/30/2024] [Indexed: 07/13/2024] Open
Abstract
Dermal fibroblasts deposit type I collagen, the dominant extracellular matrix molecule found in skin, during early postnatal development. Coincident with this biosynthetic program, fibroblasts proteolytically remodel pericellular collagen fibrils by mobilizing the membrane-anchored matrix metalloproteinase, Mmp14. Unexpectedly, dermal fibroblasts in Mmp14-/- mice commit to a large-scale apoptotic program that leaves skin tissues replete with dying cells. A requirement for Mmp14 in dermal fibroblast survival is recapitulated in vitro when cells are embedded within, but not cultured atop, three-dimensional hydrogels of crosslinked type I collagen. In the absence of Mmp14-dependent pericellular proteolysis, dermal fibroblasts fail to trigger β1 integrin activation and instead actuate a TGF-β1/phospho-JNK stress response that leads to apoptotic cell death in vitro as well as in vivo. Taken together, these studies identify Mmp14 as a requisite cell survival factor that maintains dermal fibroblast viability in postnatal dermal tissues.
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Affiliation(s)
- Farideh Sabeh
- Division of Genetic Medicine, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Xiao-Yan Li
- Division of Genetic Medicine, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Adam W. Olson
- Division of Genetic Medicine, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Elliot Botvinick
- The Henry Samueli School of Engineering, University of California, Irvine, CA, USA
| | - Abhishek Kurup
- The Henry Samueli School of Engineering, University of California, Irvine, CA, USA
| | - Luis E. Gimenez
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Jung-Sun Cho
- Division of Genetic Medicine, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Stephen J. Weiss
- Division of Genetic Medicine, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
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Tamura K, Tomita Y, Kanazawa T, Shinohara H, Sakano M, Ishibashi S, Ikeda M, Kinoshita M, Minami J, Yamamoto K, Kato Y, Furukawa A, Haruki S, Tokunaga M, Kinugasa Y, Kurata M, Kitagawa M, Ohashi K, Yamamoto K. Lipid Peroxidation Regulators GPX4 and FSP1 as Prognostic Markers and Therapeutic Targets in Advanced Gastric Cancer. Int J Mol Sci 2024; 25:9203. [PMID: 39273151 PMCID: PMC11395505 DOI: 10.3390/ijms25179203] [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: 07/31/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Gastric cancer is one of the most common cancers worldwide, and new therapeutic strategies are urgently needed. Ferroptosis is an intracellular iron-dependent cell death induced by the accumulation of lipid peroxidation, a mechanism different from conventional apoptosis and necrosis. Therefore, induction of ferroptosis is expected to be a new therapeutic strategy. Glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) have been identified as the major inhibitors of ferroptosis. Herein, we performed immunohistochemistry for GPX4, FSP1, and 4-HNE using tissues from patients with gastric cancer and investigated the relationship between these factors and prognosis. Patients with high GPX4 expression or high GPX4 expression and low 4-HNE accumulation tended to have a poor prognosis (p = 0.036, 0.023), whereas those with low FSP1 expression and high 4-HNE accumulation had a good prognosis (p = 0.033). The synergistic induction of cell death by inhibiting GPX4 and FSP1 in vitro was also observed, indicating that the cell death was non-apoptotic. Our results indicate that the expression and accumulation of lipid peroxidation-related factors play an important role in the clinicopathological significance of gastric cancer and that novel therapeutic strategies targeting GPX4 and FSP1 may be effective in treating patients with gastric cancer who have poor prognosis.
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Affiliation(s)
- Kazuhiro Tamura
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Yoshinobu Tomita
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Takumi Kanazawa
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
- Department of Clinical Laboratory Medicine, Faculty of Health Science Technology, Bunkyo Gakuin University, Tokyo 113-8668, Japan
| | - Hajime Shinohara
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Masayoshi Sakano
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Sachiko Ishibashi
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Masumi Ikeda
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Mayumi Kinoshita
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
- Department of Clinical Laboratory Medicine, Faculty of Health Science Technology, Bunkyo Gakuin University, Tokyo 113-8668, Japan
| | - Junko Minami
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Kurara Yamamoto
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Yuki Kato
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Asuka Furukawa
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Shigeo Haruki
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Masanori Tokunaga
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Yusuke Kinugasa
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Morito Kurata
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Masanobu Kitagawa
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Kenichi Ohashi
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Kouhei Yamamoto
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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8
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Corsetti G, Romano C, Codenotti S, Giugno L, Pasini E, Fanzani A, Scarabelli T, Dioguardi FS. Intake of Special Amino Acids Mixture Leads to Blunted Murine Colon Cancer Growth In Vitro and In Vivo. Cells 2024; 13:1210. [PMID: 39056792 PMCID: PMC11274386 DOI: 10.3390/cells13141210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 07/13/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Cancer cells require substantial amounts of energy and substrates for their metabolic hyperactivity, enabling the synthesis of new cells at the expense of healthy ones. Preliminary in vitro data suggest that a mix of free essential amino acids (EAA-mix) can promote cancer cell apoptosis by enhancing autophagy. This study aimed to confirm, both in vitro and in vivo, whether EAA intake could influence the development of colon cancer in mice. We investigated changes in cancer proliferation in CT26 cells treated with EAA-mix and in mice fed with EAA-rich modified diets (EAARD) as compared to those on a standard laboratory diet (StD). CT26 cells were injected subcutaneously (s.c.) or intraperitoneally (i.p.). After 21 days, tumors were removed and measured. In vitro data corroborated that EAA-mix impairs cancer growth by inducing apoptosis. In vivo data revealed that mice on StD developed significantly larger (s.c.) and more numerous (i.p.) cancers than those on EAARD. EAA administration appears to influence cancer cell survival with notable antiproliferative properties.
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Affiliation(s)
- Giovanni Corsetti
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (C.R.); (L.G.); (E.P.)
| | - Claudia Romano
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (C.R.); (L.G.); (E.P.)
| | - Silvia Codenotti
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (S.C.); (A.F.)
| | - Lorena Giugno
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (C.R.); (L.G.); (E.P.)
| | - Evasio Pasini
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (C.R.); (L.G.); (E.P.)
- Italian Association of Functional Medicine, 20855 Lesmo, Italy
| | - Alessandro Fanzani
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (S.C.); (A.F.)
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Radisky ES. Extracellular proteolysis in cancer: Proteases, substrates, and mechanisms in tumor progression and metastasis. J Biol Chem 2024; 300:107347. [PMID: 38718867 PMCID: PMC11170211 DOI: 10.1016/j.jbc.2024.107347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/08/2024] [Accepted: 04/25/2024] [Indexed: 06/02/2024] Open
Abstract
A vast ensemble of extracellular proteins influences the development and progression of cancer, shaped and reshaped by a complex network of extracellular proteases. These proteases, belonging to the distinct classes of metalloproteases, serine proteases, cysteine proteases, and aspartic proteases, play a critical role in cancer. They often become dysregulated in cancer, with increases in pathological protease activity frequently driven by the loss of normal latency controls, diminished regulation by endogenous protease inhibitors, and changes in localization. Dysregulated proteases accelerate tumor progression and metastasis by degrading protein barriers within the extracellular matrix (ECM), stimulating tumor growth, reactivating dormant tumor cells, facilitating tumor cell escape from immune surveillance, and shifting stromal cells toward cancer-promoting behaviors through the precise proteolysis of specific substrates to alter their functions. These crucial substrates include ECM proteins and proteoglycans, soluble proteins secreted by tumor and stromal cells, and extracellular domains of cell surface proteins, including membrane receptors and adhesion proteins. The complexity of the extracellular protease web presents a significant challenge to untangle. Nevertheless, technological strides in proteomics, chemical biology, and the development of new probes and reagents are enabling progress and advancing our understanding of the pivotal importance of extracellular proteolysis in cancer.
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Affiliation(s)
- Evette S Radisky
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA.
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10
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Scianna M. Selected aspects of avascular tumor growth reproduced by a hybrid model of cell dynamics and chemical kinetics. Math Biosci 2024; 370:109168. [PMID: 38408698 DOI: 10.1016/j.mbs.2024.109168] [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: 09/04/2023] [Revised: 02/10/2024] [Accepted: 02/23/2024] [Indexed: 02/28/2024]
Abstract
We here propose a hybrid computational framework to reproduce and analyze aspects of the avascular progression of a generic solid tumor. Our method first employs an individual-based approach to represent the population of tumor cells, which are distinguished in viable and necrotic agents. The active part of the disease is in turn differentiated according to a set of metabolic states. We then describe the spatio-temporal evolution of the concentration of oxygen and of tumor-secreted proteolytic enzymes using partial differential equations (PDEs). A differential equation finally governs the local degradation of the extracellular matrix (ECM) by the malignant mass. Numerical realizations of the model are run to reproduce tumor growth and invasion in a number scenarios that differ for cell properties (adhesiveness, duplication potential, proteolytic activity) and/or environmental conditions (level of tissue oxygenation and matrix density pattern). In particular, our simulations suggest that tumor aggressiveness, in terms of invasive depth and extension of necrotic tissue, can be reduced by (i) stable cell-cell contact interactions, (ii) poor tendency of malignant agents to chemotactically move upon oxygen gradients, and (iii) presence of an overdense matrix, if coupled by a disrupted proteolytic activity of the disease.
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Affiliation(s)
- Marco Scianna
- Department of Mathematical Sciences, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy.
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11
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Gonzalez‐Molina J, Hahn P, Falcão RM, Gultekin O, Kokaraki G, Zanfagnin V, Braz Petta T, Lehti K, Carlson JW. MMP14 expression and collagen remodelling support uterine leiomyosarcoma aggressiveness. Mol Oncol 2024; 18:850-865. [PMID: 37078535 PMCID: PMC10994236 DOI: 10.1002/1878-0261.13440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 03/14/2023] [Accepted: 04/18/2023] [Indexed: 04/21/2023] Open
Abstract
Fibrillar collagen deposition, stiffness and downstream signalling support the development of leiomyomas (LMs), common benign mesenchymal tumours of the uterus, and are associated with aggressiveness in multiple carcinomas. Compared with epithelial carcinomas, however, the impact of fibrillar collagens on malignant mesenchymal tumours, including uterine leiomyosarcoma (uLMS), remains elusive. In this study, we analyse the network morphology and density of fibrillar collagens combined with the gene expression within uLMS, LM and normal myometrium (MM). We find that, in contrast to LM, uLMS tumours present low collagen density and increased expression of collagen-remodelling genes, features associated with tumour aggressiveness. Using collagen-based 3D matrices, we show that matrix metalloproteinase-14 (MMP14), a central protein with collagen-remodelling functions that is particularly overexpressed in uLMS, supports uLMS cell proliferation. In addition, we find that, unlike MM and LM cells, uLMS proliferation and migration are less sensitive to changes in collagen substrate stiffness. We demonstrate that uLMS cell growth in low-stiffness substrates is sustained by an enhanced basal yes-associated protein 1 (YAP) activity. Altogether, our results indicate that uLMS cells acquire increased collagen remodelling capabilities and are adapted to grow and migrate in low collagen and soft microenvironments. These results further suggest that matrix remodelling and YAP are potential therapeutic targets for this deadly disease.
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Affiliation(s)
- Jordi Gonzalez‐Molina
- Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
- Department of Oncology‐PathologyKarolinska InstitutetStockholmSweden
| | - Paula Hahn
- Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
| | - Raul Maia Falcão
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
- Department of Cellular Biology and GeneticsFederal University of Rio Grande do NorteNatalBrazil
| | - Okan Gultekin
- Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
| | - Georgia Kokaraki
- Department of Oncology‐PathologyKarolinska InstitutetStockholmSweden
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
| | | | - Tirzah Braz Petta
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
- Department of Cellular Biology and GeneticsFederal University of Rio Grande do NorteNatalBrazil
| | - Kaisa Lehti
- Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
- Department of Biomedical Laboratory ScienceNorwegian University of Science and TechnologyTrondheimNorway
| | - Joseph W. Carlson
- Department of Oncology‐PathologyKarolinska InstitutetStockholmSweden
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
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12
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Baral B, Kandpal M, Ray A, Jana A, Yadav DS, Sachin K, Mishra A, Baig MS, Jha HC. Helicobacter pylori and Epstein-Barr virus infection in cell polarity alterations. Folia Microbiol (Praha) 2024; 69:41-57. [PMID: 37672163 DOI: 10.1007/s12223-023-01091-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 08/28/2023] [Indexed: 09/07/2023]
Abstract
The asymmetrical distribution of the cellular organelles inside the cell is maintained by a group of cell polarity proteins. The maintenance of polarity is one of the vital host defense mechanisms against pathogens, and the loss of it contributes to infection facilitation and cancer progression. Studies have suggested that infection of viruses and bacteria alters cell polarity. Helicobacter pylori and Epstein-Barr virus are group I carcinogens involved in the progression of multiple clinical conditions besides gastric cancer (GC) and Burkitt's lymphoma, respectively. Moreover, the coinfection of both these pathogens contributes to a highly aggressive form of GC. H. pylori and EBV target the host cell polarity complexes for their pathogenesis. H. pylori-associated proteins like CagA, VacA OipA, and urease were shown to imbalance the cellular homeostasis by altering the cell polarity. Similarly, EBV-associated genes LMP1, LMP2A, LMP2B, EBNA3C, and EBNA1 also contribute to altered cell asymmetry. This review summarized all the possible mechanisms involved in cell polarity deformation in H. pylori and EBV-infected epithelial cells. We have also discussed deregulated molecular pathways like NF-κB, TGF-β/SMAD, and β-catenin in H. pylori, EBV, and their coinfection that further modulate PAR, SCRIB, or CRB polarity complexes in epithelial cells.
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Affiliation(s)
- Budhadev Baral
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India
| | - Meenakshi Kandpal
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India
| | - Anushka Ray
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India
| | - Ankit Jana
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India
| | - Dhirendra Singh Yadav
- Central Forensic Science Laboratory, Pune, DFSS, Ministry of Home Affairs, Govt. of India, Talegaon MIDC Phase-1, Near JCB Factory, Pune, Maharashtra, 410506, India
| | - Kumar Sachin
- Himalayan School of Biosciences, Swami Rama Himalayan University, Swami Ram Nagar, Jolly Grant, Dehradun, Uttarakhand, 248 016, India
| | - Amit Mishra
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, NH 65 Nagaur Road, Karwar, Jodhpur District, Rajasthan, 342037, India
| | - Mirza S Baig
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India
| | - Hem Chandra Jha
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India.
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13
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Fernandes S, Oliver-De La Cruz J, Morazzo S, Niro F, Cassani M, Ďuríková H, Caravella A, Fiore P, Azzato G, De Marco G, Lauria A, Izzi V, Bosáková V, Fric J, Filipensky P, Forte G. TGF-β induces matrisome pathological alterations and EMT in patient-derived prostate cancer tumoroids. Matrix Biol 2024; 125:12-30. [PMID: 37944712 DOI: 10.1016/j.matbio.2023.11.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 09/28/2023] [Accepted: 11/06/2023] [Indexed: 11/12/2023]
Abstract
Extracellular matrix (ECM) tumorigenic alterations resulting in high matrix deposition and stiffening are hallmarks of adenocarcinomas and are collectively defined as desmoplasia. Here, we thoroughly analysed primary prostate cancer tissues obtained from numerous patients undergoing radical prostatectomy to highlight reproducible structural changes in the ECM leading to the loss of the glandular architecture. Starting from patient cells, we established prostate cancer tumoroids (PCTs) and demonstrated they require TGF-β signalling pathway activity to preserve phenotypical and structural similarities with the tissue of origin. By modulating TGF-β signalling pathway in PCTs, we unveiled its role in ECM accumulation and remodelling in prostate cancer. We also found that TGF-β-induced ECM remodelling is responsible for the initiation of prostate cell epithelial-to-mesenchymal transition (EMT) and the acquisition of a migratory, invasive phenotype. Our findings highlight the cooperative role of TGF-β signalling and ECM desmoplasia in prompting prostate cell EMT and promoting tumour progression and dissemination.
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Affiliation(s)
- Soraia Fernandes
- International Clinical Research Center, St. Anne's University Hospital, Brno 60200, Czech Republic.
| | - Jorge Oliver-De La Cruz
- International Clinical Research Center, St. Anne's University Hospital, Brno 60200, Czech Republic
| | - Sofia Morazzo
- International Clinical Research Center, St. Anne's University Hospital, Brno 60200, Czech Republic; Faculty of Medicine, Department of Biomedical Sciences, Masaryk University, Brno 62500, Czech Republic
| | - Francesco Niro
- International Clinical Research Center, St. Anne's University Hospital, Brno 60200, Czech Republic; Faculty of Medicine, Department of Biomedical Sciences, Masaryk University, Brno 62500, Czech Republic
| | - Marco Cassani
- International Clinical Research Center, St. Anne's University Hospital, Brno 60200, Czech Republic
| | - Helena Ďuríková
- International Clinical Research Center, St. Anne's University Hospital, Brno 60200, Czech Republic
| | - Alessio Caravella
- Department of Computer Engineering, Modelling, Electronics and Systems Engineering (DIMES), University of Calabria (UNICAL), Via P. Bucci, Cubo 42C, Rende (CS) 87036, Italy
| | - Piergiuseppe Fiore
- Department of Computer Engineering, Modelling, Electronics and Systems Engineering (DIMES), University of Calabria (UNICAL), Via P. Bucci, Cubo 42C, Rende (CS) 87036, Italy
| | - Giulia Azzato
- Department of Computer Engineering, Modelling, Electronics and Systems Engineering (DIMES), University of Calabria (UNICAL), Via P. Bucci, Cubo 42C, Rende (CS) 87036, Italy
| | - Giuseppe De Marco
- Information Technology Center (ICT), University of Calabria (UNICAL), Via P. Bucci, Cubo 22B, Rende (CS) 87036, Italy
| | - Agostino Lauria
- Department of Engineering for Innovation, University of Salento (UNISALENTO), Corpo Z, Campus Ecotekne, SP.6 per Monteroni, Lecce (LE), Italy
| | - Valerio Izzi
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu FI-90014, Finland; Faculty of Medicine, BioIM Research Unit, University of Oulu, Oulu FI-90014, Finland; Foundation for the Finnish Cancer Institute, Tukholmankatu 8, Helsinki, Finland
| | - Veronika Bosáková
- International Clinical Research Center, St. Anne's University Hospital, Brno 60200, Czech Republic; Faculty of Medicine, Department of Biomedical Sciences, Masaryk University, Brno 62500, Czech Republic
| | - Jan Fric
- International Clinical Research Center, St. Anne's University Hospital, Brno 60200, Czech Republic; Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Petr Filipensky
- Department of Urology, St. Anne's University Hospital, Brno 60200, Czech Republic
| | - Giancarlo Forte
- International Clinical Research Center, St. Anne's University Hospital, Brno 60200, Czech Republic; School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London SE5 9NU, UK.
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14
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Beunk L, Wen N, van Helvert S, Bekker B, Ran L, Kang R, Paulat T, Syga S, Deutsch A, Friedl P, Wolf K. Cell jamming in a collagen-based interface assay is tuned by collagen density and proteolysis. J Cell Sci 2023; 136:jcs260207. [PMID: 37987169 PMCID: PMC10753497 DOI: 10.1242/jcs.260207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 11/15/2023] [Indexed: 11/22/2023] Open
Abstract
Tumor cell invasion into heterogenous interstitial tissues consisting of network-, channel- or rift-like architectures involves both matrix metalloproteinase (MMP)-mediated tissue remodeling and cell shape adaptation to tissue geometry. Three-dimensional (3D) models composed of either porous or linearly aligned architectures have added to the understanding of how physical spacing principles affect migration efficacy; however, the relative contribution of each architecture to decision making in the presence of varying MMP availability is not known. Here, we developed an interface assay containing a cleft between two high-density collagen lattices, and we used this assay to probe tumor cell invasion efficacy, invasion mode and MMP dependence in concert. In silico modeling predicted facilitated cell migration into confining clefts independently of MMP activity, whereas migration into dense porous matrix was predicted to require matrix degradation. This prediction was verified experimentally, where inhibition of collagen degradation was found to strongly compromise migration into 3D collagen in a density-dependent manner, but interface-guided migration remained effective, occurring by cell jamming. The 3D interface assay reported here may serve as a suitable model to better understand the impact of in vivo-relevant interstitial tissue topologies on tumor invasion patterning and responses to molecular interventions.
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Affiliation(s)
- Lianne Beunk
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, GA 6525, The Netherlands
| | - Nan Wen
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, GA 6525, The Netherlands
| | - Sjoerd van Helvert
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, GA 6525, The Netherlands
| | - Bram Bekker
- Department of Mathematics, Faculty of Natural Science, Mathematics and Informatics, Radboud University, 6500 GL Nijmegen, The Netherlands
| | - Lars Ran
- Department of Mathematics, Faculty of Natural Science, Mathematics and Informatics, Radboud University, 6500 GL Nijmegen, The Netherlands
| | - Ross Kang
- Department of Mathematics, Faculty of Natural Science, Mathematics and Informatics, Radboud University, 6500 GL Nijmegen, The Netherlands
| | - Tom Paulat
- Department of Innovative Computing, Centre for Information Services and High Performance Computing, Technical University Dresden, 01062 Dresden, Germany
| | - Simon Syga
- Department of Innovative Computing, Centre for Information Services and High Performance Computing, Technical University Dresden, 01062 Dresden, Germany
| | - Andreas Deutsch
- Department of Innovative Computing, Centre for Information Services and High Performance Computing, Technical University Dresden, 01062 Dresden, Germany
| | - Peter Friedl
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, GA 6525, The Netherlands
- David H. Koch Center for Applied Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Katarina Wolf
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, GA 6525, The Netherlands
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15
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Yeung CYC, Garva R, Pickard A, Lu Y, Mallikarjun V, Swift J, Taylor SH, Rai J, Eyre DR, Chaturvedi M, Itoh Y, Meng QJ, Mauch C, Zigrino P, Kadler KE. Mmp14 is required for matrisome homeostasis and circadian rhythm in fibroblasts. Matrix Biol 2023; 124:8-22. [PMID: 37913834 DOI: 10.1016/j.matbio.2023.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 10/03/2023] [Accepted: 10/25/2023] [Indexed: 11/03/2023]
Abstract
The circadian clock in tendon regulates the daily rhythmic synthesis of collagen-I and the appearance and disappearance of small-diameter collagen fibrils in the extracellular matrix. How the fibrils are assembled and removed is not fully understood. Here, we first showed that the collagenase, membrane type I-matrix metalloproteinase (MT1-MMP, encoded by Mmp14), is regulated by the circadian clock in postnatal mouse tendon. Next, we generated tamoxifen-induced Col1a2-Cre-ERT2::Mmp14 KO mice (Mmp14 conditional knockout (CKO)). The CKO mice developed hind limb dorsiflexion and thickened tendons, which accumulated narrow-diameter collagen fibrils causing ultrastructural disorganization. Mass spectrometry of control tendons identified 1195 proteins of which 212 showed time-dependent abundance. In Mmp14 CKO mice 19 proteins had reversed temporal abundance and 176 proteins lost time dependency. Among these, the collagen crosslinking enzymes lysyl oxidase-like 1 (LOXL1) and lysyl hydroxylase 1 (LH1; encoded by Plod2) were elevated and had lost time-dependent regulation. High-pressure chromatography confirmed elevated levels of hydroxylysine aldehyde (pyridinoline) crosslinking of collagen in CKO tendons. As a result, collagen-I was refractory to extraction. We also showed that CRISPR-Cas9 deletion of Mmp14 from cultured fibroblasts resulted in loss of circadian clock rhythmicity of period 2 (PER2), and recombinant MT1-MMP was highly effective at cleaving soluble collagen-I but less effective at cleaving collagen pre-assembled into fibrils. In conclusion, our study shows that circadian clock-regulated Mmp14 controls the rhythmic synthesis of small diameter collagen fibrils, regulates collagen crosslinking, and its absence disrupts the circadian clock and matrisome in tendon fibroblasts.
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Affiliation(s)
- Ching-Yan Chloé Yeung
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK; Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark; Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Denmark.
| | - Richa Garva
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
| | - Adam Pickard
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
| | - Yinhui Lu
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
| | - Venkatesh Mallikarjun
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
| | - Joe Swift
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
| | - Susan H Taylor
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
| | - Jyoti Rai
- Department of Orthopedics and Sports Medicine, University of Washington, Seattle, WA, USA
| | - David R Eyre
- Department of Orthopedics and Sports Medicine, University of Washington, Seattle, WA, USA
| | | | - Yoshifumi Itoh
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Qing-Jun Meng
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
| | - Cornelia Mauch
- Department of Dermatology and Venereology, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany
| | - Paola Zigrino
- Department of Dermatology and Venereology, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany
| | - Karl E Kadler
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK.
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16
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Zhuang Y, Li C, Jiang H, Li L, Zhang Y, Yu W, Fu W. Multi-omics investigation of the resistance mechanisms of pomalidomide in multiple myeloma. Front Oncol 2023; 13:1264422. [PMID: 37799465 PMCID: PMC10549987 DOI: 10.3389/fonc.2023.1264422] [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: 07/20/2023] [Accepted: 08/31/2023] [Indexed: 10/07/2023] Open
Abstract
Background Despite significant therapeutic advances over the last decade, multiple myeloma remains an incurable disease. Pomalidomide is the third Immunomodulatory drug that is commonly used to treat patients with relapsed/refractory multiple myeloma. However, approximately half of the patients exhibit resistance to pomalidomide treatment. While previous studies have identified Cereblon as a primary target of Immunomodulatory drugs' anti-myeloma activity, it is crucial to explore additional mechanisms that are currently less understood. Methods To comprehensively investigate the mechanisms of drug resistance, we conducted integrated proteomic and metabonomic analyses of 12 plasma samples from multiple myeloma patients who had varying responses to pomalidomide. Differentially expressed proteins and metabolites were screened, and were further analyzed using pathway analysis and functional correlation analysis. Also, we estimated the cellular proportions based on ssGSEA algorithm. To investigate the potential role of glycine in modulating the response of MM cells to pomalidomide, cell viability and apoptosis were analyzed. Results Our findings revealed a consistent decrease in the levels of complement components in the pomalidomide-resistant group. Additionally, there were significant differences in the proportion of T follicular helper cell and B cells in the resistant group. Furthermore, glycine levels were significantly decreased in pomalidomide-resistant patients, and exogenous glycine administration increased the sensitivity of MM cell lines to pomalidomide. Conclusion These results demonstrate distinct molecular changes in the plasma of resistant patients that could be used as potential biomarkers for identifying resistance mechanisms for pomalidomide in multiple myeloma and developing immune-related therapeutic strategies.
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Affiliation(s)
- Yan Zhuang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- Department of Hematology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Chenyu Li
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Hua Jiang
- Department of Hematology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lu Li
- Department of Hematology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yuanteng Zhang
- Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Wei Yu
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - WeiJun Fu
- Department of Hematology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
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17
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Zhao P, Sun T, Lyu C, Liang K, Du Y. Cell mediated ECM-degradation as an emerging tool for anti-fibrotic strategy. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:29. [PMID: 37653282 PMCID: PMC10471565 DOI: 10.1186/s13619-023-00172-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 07/10/2023] [Indexed: 09/02/2023]
Abstract
Investigation into the role of cells with respect to extracellular matrix (ECM) remodeling is still in its infancy. Particularly, ECM degradation is an indispensable process during the recovery from fibrosis. Cells with ECM degradation ability due to the secretion of various matrix metalloproteinases (MMPs) have emerged as novel contributors to the treatment of fibrotic diseases. In this review, we focus on the ECM degradation ability of cells associated with the repertoire of MMPs that facilitate the attenuation of fibrosis through the inhibition of ECM deposition. Besides, innovative approaches to engineering and characterizing cells with degradation ability, as well as elucidating the mechanism of the ECM degradation, are also illustrated. Studies conducted to date on the use of cell-based degradation for therapeutic purposes to combat fibrosis are summarized. Finally, we discuss the therapeutic potential of cells with high degradation ability, hoping to bridge the gap between benchside research and bedside applications in treating fibrotic diseases.
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Affiliation(s)
- Peng Zhao
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Tian Sun
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Cheng Lyu
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Kaini Liang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China.
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18
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Koistinen H, Kovanen RM, Hollenberg MD, Dufour A, Radisky ES, Stenman UH, Batra J, Clements J, Hooper JD, Diamandis E, Schilling O, Rannikko A, Mirtti T. The roles of proteases in prostate cancer. IUBMB Life 2023; 75:493-513. [PMID: 36598826 PMCID: PMC10159896 DOI: 10.1002/iub.2700] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 11/22/2022] [Indexed: 01/05/2023]
Abstract
Since the proposition of the pro-invasive activity of proteolytic enzymes over 70 years ago, several roles for proteases in cancer progression have been established. About half of the 473 active human proteases are expressed in the prostate and many of the most well-characterized members of this enzyme family are regulated by androgens, hormones essential for development of prostate cancer. Most notably, several kallikrein-related peptidases, including KLK3 (prostate-specific antigen, PSA), the most well-known prostate cancer marker, and type II transmembrane serine proteases, such as TMPRSS2 and matriptase, have been extensively studied and found to promote prostate cancer progression. Recent findings also suggest a critical role for proteases in the development of advanced and aggressive castration-resistant prostate cancer (CRPC). Perhaps the most intriguing evidence for this role comes from studies showing that the protease-activated transmembrane proteins, Notch and CDCP1, are associated with the development of CRPC. Here, we review the roles of proteases in prostate cancer, with a special focus on their regulation by androgens.
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Affiliation(s)
- Hannu Koistinen
- Department of Clinical Chemistry and Haematology, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Finland
| | - Ruusu-Maaria Kovanen
- Department of Clinical Chemistry and Haematology, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Finland
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Finland
- Department of Pathology, HUS Diagnostic Centre, Helsinki University Hospital, Helsinki, Finland
| | - Morley D Hollenberg
- Department of Physiology & Pharmacology and Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Antoine Dufour
- Department of Physiology & Pharmacology and Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Evette S. Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, U.S.A
| | - Ulf-Håkan Stenman
- Department of Clinical Chemistry and Haematology, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Finland
| | - Jyotsna Batra
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia
- Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Judith Clements
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia
- Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - John D. Hooper
- Mater Research Institute, The University of Queensland, Brisbane, Australia
| | - Eleftherios Diamandis
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Oliver Schilling
- Institute for Surgical Pathology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Antti Rannikko
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Finland
- Department of Urology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Tuomas Mirtti
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Finland
- Department of Pathology, HUS Diagnostic Centre, Helsinki University Hospital, Helsinki, Finland
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19
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Chhichholiya Y, Ruthuparna M, Velagaleti H, Munshi A. Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood-brain barrier and treatment strategies. Clin Transl Oncol 2023; 25:1218-1241. [PMID: 36897508 DOI: 10.1007/s12094-022-03050-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/12/2022] [Indexed: 03/11/2023]
Abstract
Breast cancer (BC) is one of the most prevalent types of cancer in women. Despite advancement in early detection and efficient treatment, recurrence and metastasis continue to pose a significant risk to the life of BC patients. Brain metastasis (BM) reported in 17-20 percent of BC patients is considered as a major cause of mortality and morbidity in these patients. BM includes various steps from primary breast tumor to secondary tumor formation. Various steps involved are primary tumor formation, angiogenesis, invasion, extravasation, and brain colonization. Genes involved in different pathways have been reported to be associated with BC cells metastasizing to the brain. ADAM8 gene, EN1 transcription factor, WNT, and VEGF signaling pathway have been associated with primary breast tumor; MMP1, COX2, XCR4, PI3k/Akt, ERK and MAPK pathways in angiogenesis; Noth, CD44, Zo-1, CEMIP, S0X2 and OLIG2 are involved in invasion, extravasation and colonization, respectively. In addition, the blood-brain barrier is also a key factor in BM. Dysregulation of cell junctions, tumor microenvironment and loss of function of microglia leads to BBB disruption ultimately resulting in BM. Various therapeutic strategies are currently used to control the BM in BC. Oncolytic virus therapy, immune checkpoint inhibitors, mTOR-PI3k inhibitors and immunotherapy have been developed to target various genes involved in BM in BC. In addition, RNA interference (RNAi) and CRISPR/Cas9 are novel interventions in the field of BCBM where research to validate these and clinical trials are being carried out. Gaining a better knowledge of metastasis biology is critical for establishing better treatment methods and attaining long-term therapeutic efficacies against BC. The current review has been compiled with an aim to evaluate the role of various genes and signaling pathways involved in multiple steps of BM in BC. The therapeutic strategies being used currently and the novel ones being explored to control BM in BC have also been discussed at length.
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Affiliation(s)
- Yogita Chhichholiya
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India
| | - Malayil Ruthuparna
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India
| | - Harini Velagaleti
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India.
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20
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Mao S, Xia A, Tao X, Ye D, Qu J, Sun M, Wei H, Li G. A pan-cancer analysis of the prognostic and immunological roles of matrix metalloprotease-1 (MMP1) in human tumors. Front Oncol 2023; 12:1089550. [PMID: 36727076 PMCID: PMC9885257 DOI: 10.3389/fonc.2022.1089550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 12/28/2022] [Indexed: 01/18/2023] Open
Abstract
Objective Cancer remains the leading killer of human health worldwide. It has been shown that matrix metalloproteinase-1(MMP1) is related to poor prognosis in cancers such as BRCA, CESC and COAD. However, systematic pan-cancer analysis about the prognostic and immunological roles of MMP1 has not been explored. Here, the purpose of this study was to investigate the prognostic and immunological roles of MMP1 in pan-cancer and confirm cancer-promoting effect in pancreatic cancer. Methods In our study, bioinformatics were first used to analyze data from multiple databases. Then, several bioinformatics tools were utilized to investigate the role of MMP1 in 33 tumor types. Finally, molecular biology experiments were carried out to prove the cancer-promoting effect of MMP1 in pancreatic cancer. Results MMP1 expression was higher in tumor tissues than in control tissues in most tumor types. High expression of MMP1 was associated with poor overall survival (OS) and disease-free survival (DFS) in some tumor types. Further analysis of MMP1 gene mutation data showed that MMP1 mutations significantly influenced the prognosis of STAD. In addition, MMP1 expression was closely related to cancer-associated fibroblast (CAFs) infiltration in a variety of cancers and played an important role on immune infiltration score, tumor mutational burden (TMB) and microsatellite instability (MSI). Gene Ontology enrichment analysis indicated that these 20 genes were mainly related to extracellular structure organization/extracellular matrix organization/extracellular matrix disassembly/collagen metabolic process in the enriched biological processes. Finally, molecular biology experiments confirmed the cancer-promoting effect of MMP1 in pancreatic cancer. Conclusions Our pan-cancer analysis comprehensively proved that MMP1 expression is related with clinical prognosis and tumor immune infiltration, and MMP1 can become a prognostic and immunological biomarker.
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Affiliation(s)
- Shuai Mao
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China
| | - Anliang Xia
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China
| | - Xuewen Tao
- Department of Hepatobiliary Surgery, Medicine School of Southeast University Nanjing Drum Tower Hospital, Nanjing, China
| | - Dingde Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jiamu Qu
- Department of Hepatobiliary Surgery, Medicine School of Southeast University Nanjing Drum Tower Hospital, Nanjing, China
| | - Meiling Sun
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China
| | - Haowei Wei
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China
| | - Guoqiang Li
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China,*Correspondence: Guoqiang Li,
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21
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Ikeda K, Kaneko R, Tsukamoto E, Funahashi N, Koshikawa N. Proteolytic cleavage of membrane proteins by membrane type-1 MMP regulates cancer malignant progression. Cancer Sci 2022; 114:348-356. [PMID: 36336966 PMCID: PMC9899627 DOI: 10.1111/cas.15638] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/24/2022] [Accepted: 10/27/2022] [Indexed: 11/09/2022] Open
Abstract
Strategies to develop cancer therapies using inhibitors that target matrix metalloproteinases (MMPs), particularly membrane type-1 MMP (MT1-MMP), have failed. This is predominantly attributed to the specificity of MMP inhibitors and numerous functions of MMPs; therefore, targeting substrates with such broad specificity can lead to off-target effects. Thus, new drug development for cancer therapeutics should focus on the ability of MT1-MMP to break down substrates, such as functional cell membrane proteins, to regulate the functions of these proteins that promote tumor malignancy. In this review, we discuss the mechanism by which proteolysis of cell surface proteins by MT1-MMP promotes progression of malignant tumor cells. In addition, we discuss the two protein fragments generated by limited cleavage of erythropoietin-producing hepatoma receptor tyrosine kinase A2 (EphA2-NF, -CF), which represent a promising basis for developing new cancer therapies and diagnostic techniques.
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Affiliation(s)
- Kazuki Ikeda
- Department of Life Science and TechnologyTokyo Institute of TechnologyYokohamaJapan
| | - Ryo Kaneko
- Department of Life Science and TechnologyTokyo Institute of TechnologyYokohamaJapan
| | - Eiki Tsukamoto
- Department of Life Science and TechnologyTokyo Institute of TechnologyYokohamaJapan
| | - Nobuaki Funahashi
- Department of Life Science and TechnologyTokyo Institute of TechnologyYokohamaJapan
| | - Naohiko Koshikawa
- Department of Life Science and TechnologyTokyo Institute of TechnologyYokohamaJapan,Clinical Proteomics LaboratoryKanagawa Cancer Center Research InstituteYokohamaJapan
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22
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Hsu KS, Dunleavey JM, Szot C, Yang L, Hilton MB, Morris K, Seaman S, Feng Y, Lutz EM, Koogle R, Tomassoni-Ardori F, Saha S, Zhang XM, Zudaire E, Bajgain P, Rose J, Zhu Z, Dimitrov DS, Cuttitta F, Emenaker NJ, Tessarollo L, St. Croix B. Cancer cell survival depends on collagen uptake into tumor-associated stroma. Nat Commun 2022; 13:7078. [PMID: 36400786 PMCID: PMC9674701 DOI: 10.1038/s41467-022-34643-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 11/01/2022] [Indexed: 11/19/2022] Open
Abstract
Collagen I, the most abundant protein in humans, is ubiquitous in solid tumors where it provides a rich source of exploitable metabolic fuel for cancer cells. While tumor cells were unable to exploit collagen directly, here we show they can usurp metabolic byproducts of collagen-consuming tumor-associated stroma. Using genetically engineered mouse models, we discovered that solid tumor growth depends upon collagen binding and uptake mediated by the TEM8/ANTXR1 cell surface protein in tumor-associated stroma. Tumor-associated stromal cells processed collagen into glutamine, which was then released and internalized by cancer cells. Under chronic nutrient starvation, a condition driven by the high metabolic demand of tumors, cancer cells exploited glutamine to survive, an effect that could be reversed by blocking collagen uptake with TEM8 neutralizing antibodies. These studies reveal that cancer cells exploit collagen-consuming stromal cells for survival, exposing an important vulnerability across solid tumors with implications for developing improved anticancer therapy.
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Affiliation(s)
- Kuo-Sheng Hsu
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - James M. Dunleavey
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Christopher Szot
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Liping Yang
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Mary Beth Hilton
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA ,grid.418021.e0000 0004 0535 8394Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research (FNLCR), Frederick, MD 21702 USA
| | - Karen Morris
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA ,grid.418021.e0000 0004 0535 8394Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research (FNLCR), Frederick, MD 21702 USA
| | - Steven Seaman
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Yang Feng
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Emily M. Lutz
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Robert Koogle
- grid.418021.e0000 0004 0535 8394MCGP, NCI, Frederick, MD 21702 USA
| | | | - Saurabh Saha
- BioMed Valley Discoveries, Inc, Kansas City, MO 64111 USA ,Present Address: Centessa Pharmaceuticals, Cambridge, MA 02139 USA
| | - Xiaoyan M. Zhang
- BioMed Valley Discoveries, Inc, Kansas City, MO 64111 USA ,Present Address: Ikena Oncology, Cambridge, MA 02210 USA
| | - Enrique Zudaire
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA ,Present Address: Janssen Pharmaceutical Companies, J&J, R&D, Welsh Road McKean Road, Spring House, PA 19477 USA
| | - Pradip Bajgain
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Joshua Rose
- grid.48336.3a0000 0004 1936 8075Biomolecular Structure Section, Center for Structural Biology, NCI, NIH, Frederick, MD 21702 USA
| | - Zhongyu Zhu
- grid.48336.3a0000 0004 1936 8075Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, MD 21702 USA ,grid.420872.bPresent Address: Lentigen Technology, Inc. 1201 Clopper Road, Gaithersburg, MD 20878 USA
| | - Dimiter S. Dimitrov
- grid.48336.3a0000 0004 1936 8075Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, MD 21702 USA ,grid.21925.3d0000 0004 1936 9000Present Address: Center for Antibody Therapeutics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA
| | - Frank Cuttitta
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Nancy J. Emenaker
- grid.48336.3a0000 0004 1936 8075Division of Cancer Prevention, NCI, NIH, Bethesda, MD 20892 USA
| | - Lino Tessarollo
- grid.48336.3a0000 0004 1936 8075Neural Development Section, MCGP, NCI, NIH, Frederick, MD 21702 USA
| | - Brad St. Croix
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
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23
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Lee YC, Lam HM, Rosser C, Theodorescu D, Parks WC, Chan KS. The dynamic roles of the bladder tumour microenvironment. Nat Rev Urol 2022; 19:515-533. [PMID: 35764795 PMCID: PMC10112172 DOI: 10.1038/s41585-022-00608-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2022] [Indexed: 02/07/2023]
Abstract
Bladder cancer is a prevalent but currently understudied cancer type and patient outcomes are poor when it progresses to the muscle-invasive stage. Current research in bladder cancer focuses on the genetic and epigenetic alterations occurring within the urothelial cell compartment; however, the stromal compartment receives less attention. Dynamic changes and intercellular communications occur in the tumour microenvironment (TME) of the bladder - a new concept and niche that we designate as the bladder TME (bTME) - during tumour evolution, metastatic progression and in the context of therapeutic response. Collagens and their cognate receptors, the discoidin domain receptors, have a role in various steps of the metastatic cascade and in immune checkpoint resistance. Furthermore, the presence of another TME niche, the metastatic TME (met-TME), is a novel concept that could support divergent progression of metastatic colonization in different organs, resulting in distant metastases with distinct characteristics and genetics from the primary tumour. The stroma has divergent roles in mediating therapeutic response to BCG immunotherapy and immune checkpoint inhibitors, as well as conventional chemotherapy or trimodality therapy (that is, maximal transurethral resection of bladder tumour, chemotherapy and radiotherapy). The local bTME and distant met-TME are currently conceptually and therapeutically unexploited niches that should be actively investigated. New biological insights from these TMEs will enable rational design of strategies that co-target the tumour and stroma, which are expected to improve the outcomes of patients with advanced bladder cancer.
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Affiliation(s)
- Yu-Cheng Lee
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hung-Ming Lam
- Department of Urology, University of Washington, Seattle, WA, USA
| | - Charles Rosser
- Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Dan Theodorescu
- Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - William C Parks
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Keith Syson Chan
- Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Department of Academic Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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24
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Novel Roles of MT1-MMP and MMP-2: Beyond the Extracellular Milieu. Int J Mol Sci 2022; 23:ijms23179513. [PMID: 36076910 PMCID: PMC9455801 DOI: 10.3390/ijms23179513] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/17/2022] [Accepted: 08/21/2022] [Indexed: 12/14/2022] Open
Abstract
Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular matrix (ECM) and their extracellular role in cell migration. Recently, more research has been conducted on investigating novel subcellular localizations of MMPs and their intracellular roles at their respective locations. In this review article, we focus on the subcellular localization and novel intracellular roles of two closely related MMPs: membrane-type-1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). Although MT1-MMP is commonly known to localize on the cell surface, the protease also localizes to the cytoplasm, caveolae, Golgi, cytoskeleton, centrosome, and nucleus. At these subcellular locations, MT1-MMP functions in cell migration, macrophage metabolism, invadopodia development, spindle formation and gene expression, respectively. Similar to MT1-MMP, MMP-2 localizes to the caveolae, mitochondria, cytoskeleton, nucleus and nucleolus and functions in calcium regulation, contractile dysfunction, gene expression and ribosomal RNA transcription. Our particular interest lies in the roles MMP-2 and MT1-MMP serve within the nucleus, as they may provide critical insights into cancer epigenetics and tumor migration and invasion. We suggest that targeting nuclear MT1-MMP or MMP-2 to reduce or halt cell proliferation and migration may lead to the development of new therapies for cancer and other diseases.
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25
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Makutani Y, Kawakami H, Tsujikawa T, Yoshimura K, Chiba Y, Ito A, Kawamura J, Haratani K, Nakagawa K. Contribution of MMP14-expressing cancer-associated fibroblasts in the tumor immune microenvironment to progression of colorectal cancer. Front Oncol 2022; 12:956270. [PMID: 36052235 PMCID: PMC9424903 DOI: 10.3389/fonc.2022.956270] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
Matrix metalloproteinase 14 (MMP14) expression is implicated in progression of colorectal cancer, but its role in the tumor microenvironment (TME) has been unclear. The relevance of MMP14 to colorectal cancer progression was explored by analysis of transcriptomic data for colorectal adenocarcinoma patients (n = 592) in The Cancer Genome Atlas. The role of MMP14 in the TME was investigated in a retrospective analysis of tumor samples from 86 individuals with stage III colorectal cancer by single cell–based spatial profiling of MMP14 expression as performed by 12-color multiplex immunohistochemistry (mIHC). Analysis of gene expression data revealed that high MMP14 expression was associated with tumor progression and implicated both cancer-associated fibroblasts (CAFs) and tumor-associated macrophages in such progression. Spatial profiling by mIHC revealed that a higher percentage of MMP14+ cells among intratumoral CAFs (MMP14+ CAF/CAF ratio) was associated with poorer relapse-free survival. Multivariable analysis including key clinical factors identified the MMP14+ CAF/CAF ratio as an independent poor prognostic factor. Moreover, the patient subset with both a high MMP14+ CAF/CAF ratio and a low tumor-infiltrating lymphocyte density showed the worst prognosis. Our results suggest that MMP14+ CAFs play an important role in progression of stage III colorectal cancer and may therefore be a promising therapeutic target.
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Affiliation(s)
- Yusuke Makutani
- Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Hisato Kawakami
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
- *Correspondence: Hisato Kawakami, ; Koji Haratani,
| | - Takahiro Tsujikawa
- Department of Otolaryngology–Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kanako Yoshimura
- Department of Otolaryngology–Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yasutaka Chiba
- Clinical Research Center, Kindai University Hospital, Osaka-Sayama, Japan
| | - Akihiko Ito
- Department of Pathology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Junichiro Kawamura
- Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Koji Haratani
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
- *Correspondence: Hisato Kawakami, ; Koji Haratani,
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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26
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Hwang CD, Pagani CA, Nunez JH, Cherief M, Qin Q, Gomez-Salazar M, Kadaikal B, Kang H, Chowdary AR, Patel N, James AW, Levi B. Contemporary perspectives on heterotopic ossification. JCI Insight 2022; 7:158996. [PMID: 35866484 PMCID: PMC9431693 DOI: 10.1172/jci.insight.158996] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Heterotopic ossification (HO) is the formation of ectopic bone that is primarily genetically driven (fibrodysplasia ossificans progressiva [FOP]) or acquired in the setting of trauma (tHO). HO has undergone intense investigation, especially over the last 50 years, as awareness has increased around improving clinical technologies and incidence, such as with ongoing wartime conflicts. Current treatments for tHO and FOP remain prophylactic and include NSAIDs and glucocorticoids, respectively, whereas other proposed therapeutic modalities exhibit prohibitive risk profiles. Contemporary studies have elucidated mechanisms behind tHO and FOP and have described new distinct niches independent of inflammation that regulate ectopic bone formation. These investigations have propagated a paradigm shift in the approach to treatment and management of a historically difficult surgical problem, with ongoing clinical trials and promising new targets.
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Affiliation(s)
- Charles D Hwang
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA
| | - Chase A Pagani
- Department of Surgery, Center for Organogenesis Research and Trauma, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Johanna H Nunez
- Department of Surgery, Center for Organogenesis Research and Trauma, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Masnsen Cherief
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Qizhi Qin
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA
| | | | - Balram Kadaikal
- Department of Surgery, Center for Organogenesis Research and Trauma, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Heeseog Kang
- Department of Surgery, Center for Organogenesis Research and Trauma, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Ashish R Chowdary
- Department of Surgery, Center for Organogenesis Research and Trauma, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Nicole Patel
- Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Aaron W James
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Benjamin Levi
- Department of Surgery, Center for Organogenesis Research and Trauma, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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27
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de Almeida LGN, Thode H, Eslambolchi Y, Chopra S, Young D, Gill S, Devel L, Dufour A. Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology. Pharmacol Rev 2022; 74:712-768. [PMID: 35738680 DOI: 10.1124/pharmrev.121.000349] [Citation(s) in RCA: 195] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.
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Affiliation(s)
- Luiz G N de Almeida
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Hayley Thode
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Yekta Eslambolchi
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Sameeksha Chopra
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Daniel Young
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Sean Gill
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Laurent Devel
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Antoine Dufour
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
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Wolff DW, Deng Z, Bianchi-Smiraglia A, Foley CE, Han Z, Wang X, Shen S, Rosenberg MM, Moparthy S, Yun DH, Chen J, Baker BK, Roll MV, Magiera AJ, Li J, Hurley E, Feltri ML, Cox AO, Lee J, Furdui CM, Liu L, Bshara W, LaConte LE, Kandel ES, Pasquale EB, Qu J, Hedstrom L, Nikiforov MA. Phosphorylation of guanosine monophosphate reductase triggers a GTP-dependent switch from pro- to anti-oncogenic function of EPHA4. Cell Chem Biol 2022; 29:970-984.e6. [PMID: 35148834 PMCID: PMC9620470 DOI: 10.1016/j.chembiol.2022.01.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 11/19/2021] [Accepted: 01/11/2022] [Indexed: 12/11/2022]
Abstract
Signal transduction pathways post-translationally regulating nucleotide metabolism remain largely unknown. Guanosine monophosphate reductase (GMPR) is a nucleotide metabolism enzyme that decreases GTP pools by converting GMP to IMP. We observed that phosphorylation of GMPR at Tyr267 is critical for its activity and found that this phosphorylation by ephrin receptor tyrosine kinase EPHA4 decreases GTP pools in cell protrusions and levels of GTP-bound RAC1. EPHs possess oncogenic and tumor-suppressor activities, although the mechanisms underlying switches between these two modes are poorly understood. We demonstrated that GMPR plays a key role in EPHA4-mediated RAC1 suppression. This supersedes GMPR-independent activation of RAC1 by EPHA4, resulting in a negative overall effect on melanoma cell invasion and tumorigenicity. Accordingly, EPHA4 levels increase during melanoma progression and inversely correlate with GMPR levels in individual melanoma tumors. Therefore, phosphorylation of GMPR at Tyr267 is a metabolic signal transduction switch controlling GTP biosynthesis and transformed phenotypes.
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Affiliation(s)
- David W. Wolff
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA,Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
| | - Zhiyong Deng
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
| | - Anna Bianchi-Smiraglia
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Colleen E. Foley
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Zhannan Han
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA,Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
| | - Xingyou Wang
- Department of Chemistry, Brandeis University, Waltham, MA 02453, USA
| | - Shichen Shen
- Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14214, USA
| | | | - Sudha Moparthy
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
| | - Dong Hyun Yun
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
| | - Jialin Chen
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA,Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
| | - Brian K. Baker
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
| | - Matthew V. Roll
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA,Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
| | - Andrew J. Magiera
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
| | - Jun Li
- Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14214, USA
| | - Edward Hurley
- Department of Biochemistry and Neurology, Hunter James Kelly Research Institute, University at Buffalo, Buffalo NY, USA
| | - Maria Laura Feltri
- Department of Biochemistry and Neurology, Hunter James Kelly Research Institute, University at Buffalo, Buffalo NY, USA
| | - Anderson O. Cox
- Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem NC, USA
| | - Jingyun Lee
- Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem NC, USA
| | - Cristina M. Furdui
- Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem NC, USA
| | - Liang Liu
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
| | - Wiam Bshara
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo NY 14203, USA
| | - Leslie E.W. LaConte
- Fralin Biomedical Research Institute at Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
| | - Eugene S. Kandel
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Elena B. Pasquale
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Jun Qu
- Department of Chemistry, Brandeis University, Waltham, MA 02453, USA
| | - Lizbeth Hedstrom
- Department of Chemistry, Brandeis University, Waltham, MA 02453, USA,Department of Biology, Brandeis University, Waltham, MA 02453, USA
| | - Mikhail A. Nikiforov
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA,Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA,Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA,Corresponding author and lead contact: Mikhail A. Nikiforov,
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29
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He X, Lee B, Jiang Y. Extracellular matrix in cancer progression and therapy. MEDICAL REVIEW (2021) 2022; 2:125-139. [PMID: 37724245 PMCID: PMC10471113 DOI: 10.1515/mr-2021-0028] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 03/31/2022] [Indexed: 09/20/2023]
Abstract
The tumor ecosystem with heterogeneous cellular compositions and the tumor microenvironment has increasingly become the focus of cancer research in recent years. The extracellular matrix (ECM), the major component of the tumor microenvironment, and its interactions with the tumor cells and stromal cells have also enjoyed tremendously increased attention. Like the other components of the tumor microenvironment, the ECM in solid tumors differs significantly from that in normal organs and tissues. We review recent studies of the complex roles the tumor ECM plays in cancer progression, from tumor initiation, growth to angiogenesis and invasion. We highlight that the biomolecular, biophysical, and mechanochemical interactions between the ECM and cells not only regulate the steps of cancer progression, but also affect the efficacy of systemic cancer treatment. We further discuss the strategies to target and modify the tumor ECM to improve cancer therapy.
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Affiliation(s)
- Xiuxiu He
- Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Byoungkoo Lee
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Yi Jiang
- Department of Mathematics and Statistics, Georgia State University, Atlanta, GA, USA
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30
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Balinda HU, Sedgwick A, D'Souza-Schorey C. Mechanisms underlying melanoma invasion as a consequence of MLK3 loss. Exp Cell Res 2022; 415:113106. [DOI: 10.1016/j.yexcr.2022.113106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 11/27/2022]
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31
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Zhang X, Zheng Q, Wang Z, Xu C, Han H, Li A, Ma G, Li J, Lu C, Chen H, Zhang Z. Qualitative and Quantitative Analysis of Tumor Cell Invasion Using Au Clusters. NANOMATERIALS (BASEL, SWITZERLAND) 2021; 12:145. [PMID: 35010094 PMCID: PMC8746878 DOI: 10.3390/nano12010145] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/20/2021] [Accepted: 12/24/2021] [Indexed: 12/11/2022]
Abstract
Tumor invasion/metastasis is still the major cause of death in cancer patients. Membrane type-1 matrix metalloproteinase (MT1-MMP) is directly related to tumor invasion/metastasis. To accurately and quickly distinguish the risk of invasion/metastasis of primary tumor cells, it is urgent to develop a simple and precise quantitative method to distinguish the expression level of MT1-MMP. In this work, we have constructed red fluorescent Au clusters with peroxidase-like properties that could specifically bind to MT1-MMP on human cervical cancer cells. After MT1-MMP was labelled with Au clusters, we could visually see red fluorescence of MT1-MMP on cervical cancer cells via fluorescence microscopy and catalytic color imaging using an ordinary optical microscope. The constructed Au clusters contained 26 Au atoms; thus, the amount of MT1-MMP on cervical cancer cells could be accurately quantified using inductively coupled plasma mass spectrometry (ICP-MS). More importantly, the invasion/metastasis capabilities of the cervical cancer Siha, Caski and Hela cells with different MT1-MMP amounts could be accurately distinguished by fluorescence/catalysis qualitative imaging and ICP-MS quantitative analysis. This method of qualitative/quantitative analysis of tumor-associated proteins on cancer cells has great potential for accurately diagnosing aggressive tumor cells and assessment of their invasion/metastasis risk.
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Affiliation(s)
- Xiangchun Zhang
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Qinqin Zheng
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Ziqi Wang
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Chao Xu
- College of Chemistry and Material Science, Shandong Agricultural University, Taian 271018, China;
| | - Haolei Han
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Aiping Li
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Guicen Ma
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Jiaojiao Li
- Department of Chemistry and Biology, Faculty of Environment and Life Science, Beijing University of Technology, Beijing 100124, China;
| | - Chengyin Lu
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Hongping Chen
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Zhichao Zhang
- Department of Musculoskeletal Tumor, Fudan University Shanghai Cancer Center, Shanghai 200032, China
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Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression. Int J Mol Sci 2021; 23:ijms23010146. [PMID: 35008569 PMCID: PMC8745566 DOI: 10.3390/ijms23010146] [Citation(s) in RCA: 212] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, and tissue turnover by degrading extracellular matrix (ECM) components and by releasing matrikines, cell surface-bound cytokines, growth factors, or their receptors. Among the MMPs, MMP-14 is the driving force behind extracellular matrix and tissue destruction during cancer invasion and metastasis. MMP-14 also influences both intercellular as well as cell-matrix communication by regulating the activity of many plasma membrane-anchored and extracellular proteins. Cancer cells and other cells of the tumor stroma, embedded in a common extracellular matrix, interact with their matrix by means of various adhesive structures, of which particularly invadopodia are capable to remodel the matrix through spatially and temporally finely tuned proteolysis. As a deeper understanding of the underlying functional mechanisms is beneficial for the development of new prognostic and predictive markers and for targeted therapies, this review examined the current knowledge of the interplay of the various MMPs in the cancer context on the protein, subcellular, and cellular level with a focus on MMP14.
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Jiang L, Yang M, He S, Li Z, Li H, Niu T, Xie D, Mei Y, He X, Wei L, Huang P, Huang M, Zhang R, Wang L, Li J. MMP12 knockout prevents weight and muscle loss in tumor-bearing mice. BMC Cancer 2021; 21:1297. [PMID: 34863141 PMCID: PMC8642861 DOI: 10.1186/s12885-021-09004-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 11/13/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Colorectal cancer is a malignant gastrointestinal cancer, in which some advanced patients would develop cancer cachexia (CAC). CAC is defined as a multi-factorial syndrome characterized by weight loss and muscle loss (with or without fat mass), leading to progressive dysfunction, thereby increasing morbidity and mortality. ApcMin/+ mice develop spontaneous intestinal adenoma, which provides an established model of colorectal cancer for CAC study. Upon studying the ApcMin/+ mouse model, we observed a marked decrease in weight gain beginning around week 15. Such a reduction in weight gain was rescued when ApcMin/+ mice were crossed with MMP12-/- mice, indicating that MMP12 has a role in age-related ApcMin/+-associated weight loss. As a control, the weight of MMP12-/- mice on a weekly basis, their weight were not significantly different from those of WT mice. METHODS ApcMin/+; MMP12-/- mice were obtained by crossing ApcMin/+ mice with MMP12 knockout (MMP12 -/-) mice. Histological scores were assessed using hematoxylin-eosin (H&E) staining. MMP12 expression was confirmed by immunohistochemistry and immunofluorescence staining. ELISA, protein microarrays and quantitative Polymerase Chain Reaction (qPCR) were used to investigate whether tumor could up-regulate IL-6. Cell-based assays and western blot were used to verify the regulatory relationship between IL-6 and MMP12. Fluorescence intensity was measured to determine whether MMP12 is associated with insulin and insulin-like growth factor 1 (IGF-1) in vitro. MMP12 inhibitors were used to explore whether MMP12 could affect the body weight of ApcMin/+ mice. RESULTS MMP12 knockout led to weight gain and expansion of muscle fiber cross-sectional area (all mice had C57BL/6 background) in ApcMin/+ mice, while inhibiting MMP12 could suppress weight loss in ApcMin/+ mice. MMP12 was up-regulated in muscle tissues and peritoneal macrophages of ApcMin/+ mice. IL-6 in tumor cells and colorectal cancer patients is up-regulation. IL-6 stimulated MMP12 secretion of macrophage. CONCLUSIONS MMP12 is essential for controlling body weight of Apc Min/+ mice. Our study shows that it exists the crosstalk between cancer cells and macrophages in muscle tissues that tumor cells secrete IL-6 inducing macrophages to up-regulate MMP12. This study may provide a new perspective of MMP12 in the treatment for weight loss induced by CAC.
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Affiliation(s)
- Lingbi Jiang
- Institute of Basic Medical Sciences, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, No. 280 Waihuan Rd. E, Higher Education Mega Center, Guangzhou, 510006, China
| | - Mingming Yang
- Institute of Basic Medical Sciences, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, No. 280 Waihuan Rd. E, Higher Education Mega Center, Guangzhou, 510006, China.,The State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Shihui He
- Institute of Basic Medical Sciences, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, No. 280 Waihuan Rd. E, Higher Education Mega Center, Guangzhou, 510006, China
| | - Zhengyang Li
- Institute of Basic Medical Sciences, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, No. 280 Waihuan Rd. E, Higher Education Mega Center, Guangzhou, 510006, China
| | - Haobin Li
- Institute of Basic Medical Sciences, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, No. 280 Waihuan Rd. E, Higher Education Mega Center, Guangzhou, 510006, China
| | - Ting Niu
- Institute of Basic Medical Sciences, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, No. 280 Waihuan Rd. E, Higher Education Mega Center, Guangzhou, 510006, China
| | - Dehuan Xie
- The State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yan Mei
- The State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Xiaodong He
- Institute of Basic Medical Sciences, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, No. 280 Waihuan Rd. E, Higher Education Mega Center, Guangzhou, 510006, China
| | - Lili Wei
- The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510060, China
| | - Pinzhu Huang
- The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510060, China
| | - Mingzhe Huang
- The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510060, China
| | - Rongxin Zhang
- Institute of Basic Medical Sciences, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, No. 280 Waihuan Rd. E, Higher Education Mega Center, Guangzhou, 510006, China.,Guangdong Province Key Laboratory for Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Lijing Wang
- Institute of Basic Medical Sciences, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, No. 280 Waihuan Rd. E, Higher Education Mega Center, Guangzhou, 510006, China.
| | - Jiangchao Li
- Institute of Basic Medical Sciences, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, No. 280 Waihuan Rd. E, Higher Education Mega Center, Guangzhou, 510006, China.
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Ren Z, Niu Y, Fan B, Zhang A. Upregulation of homeobox D10 expression suppresses invasion and migration of clear cell renal cell carcinoma through targeting of E-cadherin. Mol Biol Rep 2021; 49:1837-1846. [PMID: 34825321 PMCID: PMC8863706 DOI: 10.1007/s11033-021-06993-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 11/19/2021] [Indexed: 11/25/2022]
Abstract
Background Clear cell renal cell carcinoma (CCRCC) is one of the most common types of renal cell carcinoma. Accumulating evidence indicates that homeobox D10 (HOXD10) acts as a tumor suppressor or oncogene in various carcinomas. However, the regulation and potential mechanisms of HOXD10 in CCRCC remain largely unknown. Purpose To explore the effect and potential mechanism of HOXD10 on the invasion and migration of CCRCC cells. Methods The expression of HOXD10, E-cadherin and other epithelial mesenchymal transition (EMT)-related proteins was assessed by reverse transcription-quantitative real-time PCR (qRT-PCR) and Western blots. A series of functional assays were performed in RCC cell lines to explore the function of HOXD10 in CCRCC progression. Bioinformatics analysis, ChIP assays, and dual luciferase reporter assays were utilized to identify the interaction between HOXD10 and E-cadherin. Results Low expression of HOXD10 and E-cadherin was observed in CCRCC tissues and ACHN and 786-O cells. Downregulation of HOXD10 expression was correlated with the TNM stage of CCRCC patients. Functional experiments demonstrated that malignant biological ability was significantly inhibited by HOXD10 overexpression in RCC cells. Moreover, E-cadherin was a potential target gene of HOXD10, as evidenced by a series of assays. In addition, overexpression of HOXD10 inhibited the progression of CCRCC by regulating the expression of E-cadherin, vimentin, and β-catenin in vitro. Conclusion HOXD10 acts as a tumor suppressor and suppresses invasion and migration of CCRCC cells by regulating E-cadherin and EMT processes. Thus, targeting HOXD10 may be a therapeutic strategy for CCRCC treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s11033-021-06993-8.
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Affiliation(s)
- Zongtao Ren
- Department of Urology, The Fourth Hospital of Hebei Medical University, No. 12 Jian-Kang Road, Shijiazhuang, 050011, Hebei Province, China
| | - Yunfeng Niu
- Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Bo Fan
- Department of Urology, The Fourth Hospital of Hebei Medical University, No. 12 Jian-Kang Road, Shijiazhuang, 050011, Hebei Province, China
| | - Aili Zhang
- Department of Urology, The Fourth Hospital of Hebei Medical University, No. 12 Jian-Kang Road, Shijiazhuang, 050011, Hebei Province, China.
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Baglieri J, Zhang C, Liang S, Liu X, Nishio T, Rosenthal SB, Dhar D, Su H, Cong M, Jia J, Hosseini M, Karin M, Kisseleva T, Brenner DA. Nondegradable Collagen Increases Liver Fibrosis but Not Hepatocellular Carcinoma in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1564-1579. [PMID: 34119473 PMCID: PMC8406794 DOI: 10.1016/j.ajpath.2021.05.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/20/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022]
Abstract
Although hepatocellular cancer (HCC) usually occurs in the setting of liver fibrosis, the causal relationship between liver fibrosis and HCC is unclear. in vivo and in vitro models of HCC involving Colr/r mice (that produce a collagenase-resistant type I collagen) or wild-type (WT) mice were used to assess the relationship between type I collagen, liver fibrosis, and experimental HCC. HCC was either chemically induced in WT and Colr/r mice or Hepa 1-6 cells were engrafted into WT and Colr/r livers. The effect of hepatic stellate cells (HSCs) from WT and Colr/r mice on the growth of Hepa 1-6 cells was studied by using multicellular tumor spheroids and xenografts. Collagen type I deposition and fibrosis were increased in Colr/r mice, but they developed fewer and smaller tumors. Hepa 1-6 cells had reduced tumor growth in the livers of Colr/r mice. Although Colr/r HSCs exhibited a more activated phenotype, Hepa 1-6 growth and malignancy were suppressed in multicellular tumor spheroids and in xenografts containing Colr/r HSCs. Treatment with vitronectin, which mimics the presence of degraded collagen fragments, converted the Colr/r phenotype into a WT phenotype. Although Colr/r mice have increased liver fibrosis, they exhibited decreased HCC in several models. Thus, increased liver type I collagen does not produce increased experimental HCC.
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Affiliation(s)
- Jacopo Baglieri
- Department of Medicine, University of California San Diego, San Diego, California; Department of Surgery, University of California San Diego, San Diego, California
| | - Cuili Zhang
- Department of Medicine, University of California San Diego, San Diego, California
| | - Shuang Liang
- Department of Medicine, University of California San Diego, San Diego, California
| | - Xiao Liu
- Department of Medicine, University of California San Diego, San Diego, California
| | - Takahiro Nishio
- Department of Medicine, University of California San Diego, San Diego, California
| | - Sara B Rosenthal
- Center for Computational Biology and Bioinformatics, University of California San Diego, San Diego, California
| | - Debanjan Dhar
- Department of Medicine, University of California San Diego, San Diego, California
| | - Hua Su
- Department of Pharmacology, University of California San Diego, San Diego, California
| | - Min Cong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Mojgan Hosseini
- Department of Pathology, University of California San Diego, San Diego, California
| | - Michael Karin
- Department of Pharmacology, University of California San Diego, San Diego, California
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, San Diego, California
| | - David A Brenner
- Department of Medicine, University of California San Diego, San Diego, California.
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36
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Li J, Zhang X, Gao F, Yuan Q, Zhang C, Yuan H, Liu Y, Chen L, Han Y, Gao X, Gao L. Catalytic Clusterbody for Enhanced Quantitative Protein Immunoblot. Anal Chem 2021; 93:10807-10815. [PMID: 34328735 DOI: 10.1021/acs.analchem.1c00779] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
To assess low-abundance protein biomarkers associated with tumor progression, we have developed artificial catalytic antibodies based on well-defined metal clusters modified with rationally designed peptides, termed clusterbodies. Such clusterbodies possess favorable integrated features of matched ultrasmall sizes, intrinsic fluorescence, and enzyme-like catalytic and selective recognition properties that are inaccessible to traditional antibodies. Consequently, a quantitative assay with high accuracy and high sensitivity is established by measuring the fluorescence and catalytic chemiluminescence of metal clusters preferentially recognizing the protein biomarker, which is confirmed by the molecular-weight marker references of immunoblotting. The results of quantitative immunoblotting are highly close to that derived from the enzyme-linked immunosorbent assay, implying the reliability of this protocol. Remarkably, the detection limit of the aimed protein achieved is as low as 1.0 pg, one magnitude lower than that of the conventional immunoassay. The significant variation of expression levels of the biomarker in tumor cells evidently indicates their distinguished invasion ability. This platform has potential application in analyzing low-abundance protein biomarkers in complex biological matrixes, which is essential to corroborate tumor malignancy in early stage. It inspires the construction of clusterbody-based precise bioprobes with customized structures and integrative functions for advanced quantitative biosensing.
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Affiliation(s)
- Jiaojiao Li
- Department of Chemistry and Biology, Faculty of Environment and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Xiangchun Zhang
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China
| | - Fuping Gao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China
| | - Qing Yuan
- Department of Chemistry and Biology, Faculty of Environment and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Chunyu Zhang
- Department of Chemistry and Biology, Faculty of Environment and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Hui Yuan
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China
| | - Yanhong Liu
- Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Lu Chen
- Department of Chemistry and Biology, Faculty of Environment and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Ying Han
- Department of Chemistry and Biology, Faculty of Environment and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Xueyun Gao
- Department of Chemistry and Biology, Faculty of Environment and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Liang Gao
- Department of Chemistry and Biology, Faculty of Environment and Life Science, Beijing University of Technology, Beijing 100124, China
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37
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Moracho N, Learte AIR, Muñoz-Sáez E, Marchena MA, Cid MA, Arroyo AG, Sánchez-Camacho C. Emerging roles of MT-MMPs in embryonic development. Dev Dyn 2021; 251:240-275. [PMID: 34241926 DOI: 10.1002/dvdy.398] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 06/17/2021] [Accepted: 06/30/2021] [Indexed: 12/19/2022] Open
Abstract
Membrane-type matrix metalloproteinases (MT-MMPs) are cell membrane-tethered proteinases that belong to the family of the MMPs. Apart from their roles in degradation of the extracellular milieu, MT-MMPs are able to activate through proteolytic processing at the cell surface distinct molecules such as receptors, growth factors, cytokines, adhesion molecules, and other pericellular proteins. Although most of the information regarding these enzymes comes from cancer studies, our current knowledge about their contribution in distinct developmental processes occurring in the embryo is limited. In this review, we want to summarize the involvement of MT-MMPs in distinct processes during embryonic morphogenesis, including cell migration and proliferation, epithelial-mesenchymal transition, cell polarity and branching, axon growth and navigation, synapse formation, and angiogenesis. We also considered information about MT-MMP functions from studies assessed in pathological conditions and compared these data with those relevant for embryonic development.
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Affiliation(s)
- Natalia Moracho
- Department of Medicine, School of Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain
| | - Ana I R Learte
- Department of Dentistry, School of Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain
| | - Emma Muñoz-Sáez
- Department of Health Science, School of Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain
| | - Miguel A Marchena
- Department of Medicine, School of Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain
| | - María A Cid
- Department of Dentistry, School of Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain
| | - Alicia G Arroyo
- Vascular Pathophysiology Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC-CSIC), Madrid, Spain.,Molecular Biomedicine Department, Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid, Spain
| | - Cristina Sánchez-Camacho
- Department of Medicine, School of Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain.,Vascular Pathophysiology Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC-CSIC), Madrid, Spain
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38
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Mechanical Intermittent Compression Affects the Progression Rate of Malignant Melanoma Cells in a Cycle Period-Dependent Manner. Diagnostics (Basel) 2021; 11:diagnostics11061112. [PMID: 34207144 PMCID: PMC8234529 DOI: 10.3390/diagnostics11061112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/09/2021] [Accepted: 06/16/2021] [Indexed: 12/31/2022] Open
Abstract
Static mechanical compression is a biomechanical factor that affects the progression of melanoma cells. However, little is known about how dynamic mechanical compression affects the progression of melanoma cells. In the present study, we show that mechanical intermittent compression affects the progression rate of malignant melanoma cells in a cycle period-dependent manner. Our results suggest that intermittent compression with a cycle of 2 h on/2 h off could suppress the progression rate of melanoma cells by suppressing the elongation of F-actin filaments and mRNA expression levels related to collagen degradation. In contrast, intermittent compression with a cycle of 4 h on/4 h off could promote the progression rate of melanoma cells by promoting cell proliferation and mRNA expression levels related to collagen degradation. Mechanical intermittent compression could therefore affect the progression rate of malignant melanoma cells in a cycle period-dependent manner. Our results contribute to a deeper understanding of the physiological responses of melanoma cells to dynamic mechanical compression.
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39
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Vasilaki D, Bakopoulou A, Tsouknidas A, Johnstone E, Michalakis K. Biophysical interactions between components of the tumor microenvironment promote metastasis. Biophys Rev 2021; 13:339-357. [PMID: 34168685 PMCID: PMC8214652 DOI: 10.1007/s12551-021-00811-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 05/03/2021] [Indexed: 02/07/2023] Open
Abstract
During metastasis, tumor cells need to adapt to their dynamic microenvironment and modify their mechanical properties in response to both chemical and mechanical stimulation. Physical interactions occur between cancer cells and the surrounding matrix including cell movements and cell shape alterations through the process of mechanotransduction. The latter describes the translation of external mechanical cues into intracellular biochemical signaling. Reorganization of both the cytoskeleton and the extracellular matrix (ECM) plays a critical role in these spreading steps. Migrating tumor cells show increased motility in order to cross the tumor microenvironment, migrate through ECM and reach the bloodstream to the metastatic site. There are specific factors affecting these processes, as well as the survival of circulating tumor cells (CTC) in the blood flow until they finally invade the secondary tissue to form metastasis. This review aims to study the mechanisms of metastasis from a biomechanical perspective and investigate cell migration, with a focus on the alterations in the cytoskeleton through this journey and the effect of biologic fluids on metastasis. Understanding of the biophysical mechanisms that promote tumor metastasis may contribute successful therapeutic approaches in the fight against cancer.
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Affiliation(s)
- Dimitra Vasilaki
- Department of Prosthodontics, School of Dentistry, Faculty of Health Sciences, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece
| | - Athina Bakopoulou
- Department of Prosthodontics, School of Dentistry, Faculty of Health Sciences, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece
| | - Alexandros Tsouknidas
- Laboratory for Biomaterials and Computational Mechanics, Department of Mechanical Engineering, University of Western Macedonia, Kozani, Greece
| | | | - Konstantinos Michalakis
- Department of Prosthodontics, School of Dentistry, Faculty of Health Sciences, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece
- Division of Graduate Prosthodontics, Tufts University School of Dental Medicine, Boston, MA USA
- University of Oxford, Oxford, UK
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40
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MRC2 Promotes Proliferation and Inhibits Apoptosis of Diabetic Nephropathy. ACTA ACUST UNITED AC 2021; 2021:6619870. [PMID: 34012764 PMCID: PMC8102129 DOI: 10.1155/2021/6619870] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 03/15/2021] [Accepted: 04/17/2021] [Indexed: 11/26/2022]
Abstract
Diabetic nephropathy (DN) is an important microvascular complication of diabetes and is the main cause of end-stage renal disease. Type 2 mannose receptor C (MRC2) is a member of the mannose receptor protein family, which has been confirmed to have the ability to promote the cell migration signaling pathway and invasion. By complementary DNA chip screening and analysis, we found that the expression of MRC2 was upregulated in the kidneys of mice with diabetic nephropathy. However, the role of MRC2 in diabetic nephropathy is still unclear. This work studied the effect of MRC2 on diabetic nephropathy. After verifying the results of the chip by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, we used small interfering RNAs (siRNAs) to knock down the expression of MRC2 in mouse mesangial cells (MMCs) and analyzed the level of cell proliferation and apoptosis using western blotting, Cell Counting Kit-8, and flow cytometry. The results showed that the MRC2 knockdown inhibited MMC proliferation and induced cell apoptosis. These results suggest that MRC2 may be a molecular marker and a therapeutic target for diabetic nephropathy.
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41
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Shapovalov G, Gordienko D, Prevarskaya N. Store operated calcium channels in cancer progression. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 363:123-168. [PMID: 34392928 DOI: 10.1016/bs.ircmb.2021.02.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In recent decades cancer emerged as one of the leading causes of death in the developed countries, with some types of cancer contributing to the top 10 causes of death on the list of the World Health Organization. Carcinogenesis, a malignant transformation causing formation of tumors in normal tissues, is associated with changes in the cell cycle caused by suppression of signaling pathways leading to cell death and facilitation of those enhancing proliferation. Further progression of cancer, during which benign tumors acquire more aggressive phenotypes, is characterized by metastatic dissemination through the body driven by augmented motility and invasiveness of cancer cells. All these processes are associated with alterations in calcium homeostasis in cancer cells, which promote their proliferation, motility and invasion, and dissuade cell death or cell cycle arrest. Remodeling of store-operated calcium entry (SOCE), one of the major pathways regulating intracellular Ca2+ concentration ([Ca2+]i), manifests a key event in many of these processes. This review systematizes current knowledge on the mechanisms recruiting SOCE-related proteins in carcinogenesis and cancer progression.
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Affiliation(s)
- George Shapovalov
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologiesa, University of Lille, Villeneuve d'Ascq, France.
| | - Dmitri Gordienko
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologiesa, University of Lille, Villeneuve d'Ascq, France
| | - Natalia Prevarskaya
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologiesa, University of Lille, Villeneuve d'Ascq, France
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42
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A Cellular Potts Model for Analyzing Cell Migration across Constraining Pillar Arrays. AXIOMS 2021. [DOI: 10.3390/axioms10010032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Cell migration in highly constrained environments is fundamental in a wide variety of physiological and pathological phenomena. In particular, it has been experimentally shown that the migratory capacity of most cell lines depends on their ability to transmigrate through narrow constrictions, which in turn relies on their deformation capacity. In this respect, the nucleus, which occupies a large fraction of the cell volume and is substantially stiffer than the surrounding cytoplasm, imposes a major obstacle. This aspect has also been investigated with the use of microfluidic devices formed by dozens of arrays of aligned polymeric pillars that limit the available space for cell movement. Such experimental systems, in particular, in the designs developed by the groups of Denais and of Davidson, were here reproduced with a tailored version of the Cellular Potts model, a grid-based stochastic approach where cell dynamics are established by a Metropolis algorithm for energy minimization. The proposed model allowed quantitatively analyzing selected cell migratory determinants (e.g., the cell and nuclear speed and deformation, and forces acting at the nuclear membrane) in the case of different experimental setups. Most of the numerical results show a remarkable agreement with the corresponding empirical data.
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43
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Decotret LR, Wadsworth BJ, Li LV, Lim CJ, Bennewith KL, Pallen CJ. Receptor-type protein tyrosine phosphatase alpha (PTPα) mediates MMP14 localization and facilitates triple-negative breast cancer cell invasion. Mol Biol Cell 2021; 32:567-578. [PMID: 33566639 PMCID: PMC8101463 DOI: 10.1091/mbc.e20-01-0060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The ability of cancer cells to invade surrounding tissues requires degradation of the extracellular matrix (ECM). Invasive structures, such as invadopodia, form on the plasma membranes of cancer cells and secrete ECM-degrading proteases that play crucial roles in cancer cell invasion. We have previously shown that the protein tyrosine phosphatase alpha (PTPα) regulates focal adhesion formation and migration of normal cells. Here we report a novel role for PTPα in promoting triple-negative breast cancer cell invasion in vitro and in vivo. We show that PTPα knockdown reduces ECM degradation and cellular invasion of MDA-MB-231 cells through Matrigel. PTPα is not a component of TKS5-positive structures resembling invadopodia; rather, PTPα localizes with endosomal structures positive for MMP14, caveolin-1, and early endosome antigen 1. Furthermore, PTPα regulates MMP14 localization to plasma membrane protrusions, suggesting a role for PTPα in intracellular trafficking of MMP14. Importantly, we show that orthotopic MDA-MB-231 tumors depleted in PTPα exhibit reduced invasion into the surrounding mammary fat pad. These findings suggest a novel role for PTPα in regulating the invasion of triple-negative breast cancer cells.
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Affiliation(s)
- Lisa R Decotret
- Integrative Oncology, BC Cancer, Vancouver, British Columbia, BC V5Z 4E6, Canada.,Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, British Columbia, BC V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, BC V6H 3V4, Canada
| | - Brennan J Wadsworth
- Integrative Oncology, BC Cancer, Vancouver, British Columbia, BC V5Z 4E6, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, BC V6H 3V4, Canada
| | - Ling Vicky Li
- Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, British Columbia, BC V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, BC V6H 3V4, Canada
| | - Chinten J Lim
- Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, British Columbia, BC V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, BC V6H 3V4, Canada.,Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, BC V6H 3V4, Canada
| | - Kevin L Bennewith
- Integrative Oncology, BC Cancer, Vancouver, British Columbia, BC V5Z 4E6, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, BC V6H 3V4, Canada
| | - Catherine J Pallen
- Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, British Columbia, BC V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, BC V6H 3V4, Canada.,Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, BC V6H 3V4, Canada
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44
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Weng J, Chen B, Xie M, Wan X, Wang P, Zhou X, Zhou Z, Mei J, Wang L, Huang D, Wang Z, Wang Z, Chen C. Rabbit thyroid extracellular matrix as a 3D bioscaffold for thyroid bioengineering: a preliminary in vitro study. Biomed Eng Online 2021; 20:18. [PMID: 33563294 PMCID: PMC7871622 DOI: 10.1186/s12938-021-00856-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 02/01/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Advances in regenerative medicine technologies have been strongly proposed in the management of thyroid diseases. Mechanistically, the adoption of thyroid bioengineering requires a scaffold that shares a similar three-dimensional (3D) space structure, biomechanical properties, protein component, and cytokines to the native extracellular matrix (ECM). METHODS 24 male New Zealand white rabbits were used in this experimental study. The rabbit thyroid glands were decellularized by immersion/agitation decellularization protocol. The 3D thyroid decellularization scaffolds were tested with histological and immunostaining analyses, scanning electron microscopy, DNA quantification, mechanical properties test, cytokine assay and cytotoxicity assays. Meanwhile, the decellularization scaffold were seeded with human thyroid follicular cells, cell proliferation and thyroid peroxidase were determined to explore the biocompatibility in vitro. RESULTS Notably, through the imaging studies, it was distinctly evident that our protocol intervention minimized cellular materials and maintained the 3D spatial structure, biomechanical properties, ECM composition, and biologic cytokine. Consequently, the decellularization scaffold was seeded with human thyroid follicular cells, thus strongly revealing its potential in reinforcing cell adhesion, proliferation, and preserve important protein expression. CONCLUSIONS The adoption of our protocol to generate a decellularized thyroid scaffold can potentially be utilized in transplantation to manage thyroid diseases through thyroid bioengineering.
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Affiliation(s)
- Jie Weng
- Department of Emergency Medicine and General Practice, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Bi Chen
- Department of Surgical Oncology, Wenzhou People's Hospital, The Wenzhou Third Clinical Institute Affiliated With Wenzhou Medical University, Wenzhou, 325000, China
| | - Mengying Xie
- Department of Emergency Medicine and General Practice, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Xinlong Wan
- Institute of Bioscaffold Transplantation and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Peng Wang
- Department of Emergency Medicine and General Practice, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiaoming Zhou
- Department of Emergency Medicine and General Practice, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Zhiliang Zhou
- Department of Emergency Medicine and General Practice, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Jin Mei
- Institute of Bioscaffold Transplantation and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Liang Wang
- Department of Public Health, Robbins College of Health and Human Sciences, Baylor University, Waco, TX, USA
| | - Duping Huang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhibin Wang
- Institute of Bioscaffold Transplantation and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Zhiyi Wang
- Department of Emergency Medicine and General Practice, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
- Institute of Bioscaffold Transplantation and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
- Center for Health Assessment, Wenzhou Medical University, Wenzhou, China.
| | - Chan Chen
- Department of Geriatric Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
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45
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Yang D. Application of Nanotechnology in the COVID-19 Pandemic. Int J Nanomedicine 2021; 16:623-649. [PMID: 33531805 PMCID: PMC7847377 DOI: 10.2147/ijn.s296383] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 01/08/2021] [Indexed: 12/12/2022] Open
Abstract
COVID-19, caused by SARS-CoV-2 infection, has been prevalent worldwide for almost a year. In early 2000, there was an outbreak of SARS-CoV, and in early 2010, a similar dissemination of infection by MERS-CoV occurred. However, no clear explanation for the spread of SARS-CoV-2 and a massive increase in the number of infections has yet been proposed. The best solution to overcome this pandemic is the development of suitable and effective vaccines and therapeutics. Fortunately, for SARS-CoV-2, the genome sequence and protein structure have been published in a short period, making research and development for prevention and treatment relatively easy. In addition, intranasal drug delivery has proven to be an effective method of administration for treating viral lung diseases. In recent years, nanotechnology-based drug delivery systems have been applied to intranasal drug delivery to overcome various limitations that occur during mucosal administration, and advances have been made to the stage where effective drug delivery is possible. This review describes the accumulated knowledge of the previous SARS-CoV and MERS-CoV infections and aims to help understand the newly emerged SARS-CoV-2 infection. Furthermore, it elucidates the achievements in developing COVID-19 vaccines and therapeutics to date through existing approaches. Finally, the applicable nanotechnology approach is described in detail, and vaccines and therapeutic drugs developed based on nanomedicine, which are currently undergoing clinical trials, have presented the potential to become innovative alternatives for overcoming COVID-19.
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Affiliation(s)
- Dongki Yang
- Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, South Korea
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46
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Ros M, Nguyen AT, Chia J, Le Tran S, Le Guezennec X, McDowall R, Vakhrushev S, Clausen H, Humphries MJ, Saltel F, Bard FA. ER-resident oxidoreductases are glycosylated and trafficked to the cell surface to promote matrix degradation by tumour cells. Nat Cell Biol 2020; 22:1371-1381. [PMID: 33077910 DOI: 10.1038/s41556-020-00590-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 09/07/2020] [Indexed: 12/17/2022]
Abstract
Tumour growth and invasiveness require extracellular matrix (ECM) degradation and are stimulated by the GALA pathway, which induces protein O-glycosylation in the endoplasmic reticulum (ER). ECM degradation requires metalloproteases, but whether other enzymes are required is unclear. Here, we show that GALA induces the glycosylation of the ER-resident calnexin (Cnx) in breast and liver cancer. Glycosylated Cnx and its partner ERp57 are trafficked to invadosomes, which are sites of ECM degradation. We find that disulfide bridges are abundant in connective and liver ECM. Cell surface Cnx-ERp57 complexes reduce these extracellular disulfide bonds and are essential for ECM degradation. In vivo, liver cancer cells but not hepatocytes display cell surface Cnx. Liver tumour growth and lung metastasis of breast and liver cancer cells are inhibited by anti-Cnx antibodies. These findings uncover a moonlighting function of Cnx-ERp57 at the cell surface that is essential for ECM breakdown and tumour development.
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Affiliation(s)
- Manon Ros
- Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore
- Univ. Bordeaux, INSERM, BaRITOn, U1053, F-33000 Bordeaux, France, Bordeaux, France
| | - Anh Tuan Nguyen
- Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore
| | - Joanne Chia
- Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore
| | - Son Le Tran
- Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore
| | | | - Ruth McDowall
- Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Sergey Vakhrushev
- Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Henrik Clausen
- Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Martin James Humphries
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Frederic Saltel
- Univ. Bordeaux, INSERM, BaRITOn, U1053, F-33000 Bordeaux, France, Bordeaux, France
| | - Frederic André Bard
- Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore.
- Department of Biochemistry, National University of Singapore, Singapore, Singapore.
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47
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Shimoda M, Ohtsuka T, Okada Y, Kanai Y. Stromal metalloproteinases: Crucial contributors to the tumor microenvironment. Pathol Int 2020; 71:1-14. [PMID: 33074556 DOI: 10.1111/pin.13033] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 09/25/2020] [Indexed: 12/30/2022]
Abstract
Proteolytic balance is crucial for the maintenance of tissue homeostasis. In cancer, dysregulated proteolysis is involved in unregulated tissue remodeling and inflammation, leading to the promotion of tumor growth, local invasion, and metastasis. Metalloproteinases, which were first identified as collagen cleaving enzymes, have been shown to extensively degrade extracellular matrix proteins or selectively release cell surface-bound cytokines, growth factors, or their receptors, thereby impacting extracellular matrix integrity, immune cell recruitment and tissue turnover. Although tumor cells produce various metalloproteinases, the major source is thought to be stromal cells infiltrating the tumor. Different types of stromal cells express specific sets of metalloproteinases and their inhibitors, which specifically alter the milieu within the tumor. In this review, recent findings and knowledge regarding metalloproteinases derived from stromal cells during the creation of the tumor microenvironment are described and their contribution to the tumor progression and metastasis discussed.
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Affiliation(s)
- Masayuki Shimoda
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Takashi Ohtsuka
- Division of Thoracic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Yasunori Okada
- Department of Pathophysiology for Locomotive and Neoplastic Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yae Kanai
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
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Gestational arsenite exposure augments hepatic tumors of C3H mice by promoting senescence in F1 and F2 offspring via different pathways. Toxicol Appl Pharmacol 2020; 408:115259. [PMID: 33010264 DOI: 10.1016/j.taap.2020.115259] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 09/23/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023]
Abstract
Previous studies showed that gestational arsenite exposure increases incidence of hepatic tumors in the F1 and F2 male offspring in C3H mice. However, the mechanisms are largely unknown. In this study, we focused on whether cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to tumor formation in C3H mice, and whether gestational arsenite exposure augments hepatic tumors through enhancement of cellular senescence. Three senescence markers (p16, p21 and p15) and two SASP factors (Cxcl1 and Mmp14) were increased in hepatic tumor tissues of 74- or 100-weeks-old C3H mice without arsenite exposure, and treatment with a senolytic drug (ABT-263) diminished hepatic tumor formation. Gestational arsenite exposure enhanced the expression of p16, p21 and Mmp14 in F1 and p15 and Cxcl1 in F2, respectively. Exploring the mechanisms by which arsenite exposure promotes cellular senescence, we found that the expression of antioxidant enzymes (Sod1 and Cat) were reduced in the tumors of F1 in the arsenite group, and Tgf-β and the receptors of Tgf-β were increased in the tumors of F2 in the arsenite group. Furthermore, the analysis of the Cancer Genome Atlas database showed that gene expression levels of the senescence markers and SASP factors were increased and associated with poor prognosis in human hepatocellular carcinoma (HCC). These results suggest that cellular senescence and SASP have important roles in hepatic tumorigenesis in C3H mice as well as HCC in humans, and gestational arsenite exposure of C3H mice enhances senescence in F1 and F2 via oxidative stress and Tgf-β activation, respectively.
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Sala M, Ros M, Saltel F. A Complex and Evolutive Character: Two Face Aspects of ECM in Tumor Progression. Front Oncol 2020; 10:1620. [PMID: 32984031 PMCID: PMC7485352 DOI: 10.3389/fonc.2020.01620] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 07/27/2020] [Indexed: 12/24/2022] Open
Abstract
Tumor microenvironment, including extracellular matrix (ECM) and stromal cells, is a key player during tumor development, from initiation, growth and progression to metastasis. During all of these steps, remodeling of matrix components occurs, changing its biochemical and physical properties. The global and basic cancer ECM model is that tumors are surrounded by activated stromal cells, that remodel physiological ECM to evolve into a stiffer and more crosslinked ECM than in normal conditions, thereby increasing invasive capacities of cancer cells. In this review, we show that this too simple model does not consider the complexity, specificity and heterogeneity of each organ and tumor. First, we describe the general ECM in context of cancer. Then, we go through five invasive and most frequent cancers from different origins (breast, liver, pancreas, colon, and skin), and show that each cancer has its own specific matrix, with different stromal cells, ECM components, biochemical properties and activated signaling pathways. Furthermore, in these five cancers, we describe the dual role of tumor ECM: as a protective barrier against tumor cell proliferation and invasion, and as a major player in tumor progression. Indeed, crosstalk between tumor and stromal cells induce changes in matrix organization by remodeling ECM through invadosome formation in order to degrade it, promoting tumor progression and cell invasion. To sum up, in this review, we highlight the specificities of matrix composition in five cancers and the necessity not to consider the ECM as one general and simple entity, but one complex, dynamic and specific entity for each cancer type and subtype.
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Yoshida T, Suganuma N, Sato S, Toda S, Nakayama H, Masudo K, Okubo Y, Hayashi H, Yokose T, Koshikawa N, Rino Y, Iwasaki H, Miyagi Y, Masuda M, Hoshino D. Membrane type 1 matrix metalloproteinase regulates anaplastic thyroid carcinoma cell growth and invasion into the collagen matrix. Biochem Biophys Res Commun 2020; 529:1195-1200. [PMID: 32819585 DOI: 10.1016/j.bbrc.2020.06.043] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 06/09/2020] [Indexed: 12/12/2022]
Abstract
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive cancer types; however, the molecular mechanism contributing to the aggressive characteristics remain unclear. Membrane type 1 matrix metalloproteinase (MT1-MMP) plays an important role in cancer invasion and has been associated with a poor prognosis in various malignant neoplasms. In this study, we investigated the relationship between MT1-MMP expression and the proliferation and invasion of ATC cells, along with the association with clinicopathologic factors in patients with ATC. Suppression of MT1-MMP reduced the proliferation and invasion of ATC cells, and suppressed ERK activity, indicating a role in cancer cell proliferation in collagen matrix culture conditions. The expression of MT1-MMP was detected in 29 of 34 (85.3%) surgical specimens from ATC patients. In addition, the expression of MT1-MMP in the tumor lesion was higher than that of normal and stromal tissues. Collectively, these results suggest that elevated MT1-MMP expression plays a role in the pathogenesis of ATC, which may promote its aggressive characteristics such as proliferation and invasion, highlighting a potential new therapeutic target.
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Affiliation(s)
- Tatsuya Yoshida
- Department of Surgery, Yokohama City University, Yokohama, Japan; Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Nobuyasu Suganuma
- Department of Surgery, Yokohama City University, Yokohama, Japan; Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Shinya Sato
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Soji Toda
- Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Hirotaka Nakayama
- Department of Surgery, Hiratsuka Kyosai Hospital, Hiratsuka, Kanagawa, Japan
| | - Katsuhiko Masudo
- Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Japan
| | - Yoichiro Okubo
- Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan
| | - Hiroyuki Hayashi
- Department of Pathology, Yokohama Municipal Citizen's Hospital, Japan
| | - Tomoyuki Yokose
- Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan
| | - Naohiko Koshikawa
- Division of Cancer Cell Research, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Yasushi Rino
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Hiroyuki Iwasaki
- Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Munetaka Masuda
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Daisuke Hoshino
- Organoid Biology Unit, Kanagawa Cancer Center Research Institute, Yokohama, Japan.
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