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Kimura S, Iwano S, Akioka T, Kuchimaru T, Kawaguchi M, Fukushima T, Sato Y, Kataoka H, Kamoto T, Mukai S, Sawada A. Combined Therapy Targeting MET and Pro-HGF Activation Shows Significant Therapeutic Effect Against Liver Metastasis of CRPC. Int J Mol Sci 2025; 26:2308. [PMID: 40076928 PMCID: PMC11900290 DOI: 10.3390/ijms26052308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 02/27/2025] [Accepted: 03/04/2025] [Indexed: 03/14/2025] Open
Abstract
The liver is the most lethal metastatic site in castration-resistant prostate cancer (CRPC). Overexpression of MET protein has been reported in CRPC, and MET is an important driver gene in androgen-independent CRPC cells. Mouse CRPC cell line CRTC2 was established by subcutaneous injection of hormone-sensitive PC cells (TRAMP-C2) in castrated nude mice. CRCT2/luc2 cells were injected into the spleen of castrated nude mice, and liver metastasis was confirmed at 2 weeks post-injection. We administered MET inhibitor (MET-I) and HGF activator inhibitor (HGFA-I) to this liver metastasis model and assessed the therapeutic effect. After intrasplenic injection, CRTC2 showed a higher incidence of liver metastasis whereas no metastasis was observed in TRAMP-C2. Microarray analysis revealed increased expression of HGF, MET, and HPN, HGFAC (encoding HGF activating proteases) in liver metastasis. Proliferation of CRCT2 was significantly inhibited by co-administration of MET-I and HGFA-I by in vitro analysis with HGF-enriched condition. In an analysis of the mouse model, the combination-therapy group showed the strongest reduction for liver metastasis. Immunohistochemical staining also revealed the strongest decrease in phosphorylation of MET in the combination-therapy group. Co-culture with HGF-expressed mouse fibroblasts showed attenuation of the inhibitory effect of MET-I; however, additional HGFA-I overcame the resistance. We established an androgen-independent CRPC cell line, CRTC2, and liver metastasis model in mice. Significant effect was confirmed by combined treatment of MET-I and HGFA-I by in vitro and in vivo analysis. The results suggested the importance of combined treatment with both MET- and HGF-targeting agents in the treatment of HGF-enriched conditions including liver metastasis.
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Affiliation(s)
- Shoichi Kimura
- Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Satoshi Iwano
- Institute for Tenure Track Promotion, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Takahiro Akioka
- Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Takahiro Kuchimaru
- Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Makiko Kawaguchi
- Section of Oncopathology and Morphological Pathology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan; (M.K.)
| | - Tsuyoshi Fukushima
- Section of Oncopathology and Morphological Pathology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan; (M.K.)
| | - Yuichiro Sato
- Section of Oncopathology and Morphological Pathology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan; (M.K.)
| | - Hiroaki Kataoka
- Organization for Promotion of Research and Industry Academic Regional Collaboration, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Toshiyuki Kamoto
- Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Shoichiro Mukai
- Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Atsuro Sawada
- Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
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Othman AM, Abdel-Rahman N, Denewer M, Eissa LA. Sinapic acid and 3,3′-diindolylmethane potentiate cyclophosphamide antitumor activity through induction of apoptosis and inhibition of metastasis. Int Immunopharmacol 2023; 118:110074. [PMID: 36989898 DOI: 10.1016/j.intimp.2023.110074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/08/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023]
Abstract
AIM New therapeutic strategies are required to enhance the anticancer efficacy of chemotherapeutic drugs and to reduce their cytotoxicity. The purpose of this study was to assess the anti-tumor, antimetastatic and anti-apoptotic activities of sinapic acid (SA) and 3,3'-diindolylmethane (DIM) in solid Ehrlich carcinoma (SEC) induced in mice and combining SA or DIM compounds with cyclophosphamide (CYP). METHODS For induction of solid tumor, the right hind limbs of mice were inoculated subcutaneously with Ehrlich carcinoma cells. After 5 days of tumor inoculation, mice were treated with SA (56 mg/kg), DIM (40 mg/kg), CYP (10 mg/kg), and their combinations (SA/CYP) and (SA/DIM) for 21 days. The mRNA levels of Elabela, Serpina3, caspase-3, MMP-2 and MMP-9 were assessed by qPCR. Tumor and liver tissues were stained with hematoxylin and eosin for histological examination. Serum was investigated for ALT and AST activities. MAIN FINDINGS Treatment of SEC mice with SA and DIM significantly reduced solid tumor weight by 45.6% and 33.2%, respectively. They also reduced tumor size and increased life span of SEC mice. SA and DIM diminished area of metastatic nodules of tumor cells in the liver by 54.1% and 47.4%, respectively. They also reduced serum aminotransferases activities. Both SA and DIM were found to upregulate caspase 3 and downregulate MMP-2 and MMP-9. Furthermore, SA and DIM reduced gene expression of Elabela by (44.8% and 35.1%) and Serpina3 by (30.7% and 23.5%), respectively. SA and DIM were also shown to potentiate the anti-tumor activity CYP. SA and DIM showed promising antitumor effects and enhanced CYP antitumor activity mostly through upregulation of apoptotic caspase 3 and suppressing metastatic enzymes MMP-2 and MMP-9. Additionally, SA and DIM exhibited a hepatoprotective effect. Our results suggest that these natural compounds may be used to improve the efficacy and reduce the adverse effects of chemotherapeutic drugs in the treatment of solid malignancies.
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Zafari N, Khosravi F, Rezaee Z, Esfandyari S, Bahiraei M, Bahramy A, Ferns GA, Avan A. The role of the tumor microenvironment in colorectal cancer and the potential therapeutic approaches. J Clin Lab Anal 2022; 36:e24585. [PMID: 35808903 PMCID: PMC9396196 DOI: 10.1002/jcla.24585] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/07/2022] [Accepted: 06/23/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) with a high prevalence is recognized as the fourth most common cause of cancer-related death globally. Over the past decade, there has been growing interest in the network of tumor cells, stromal cells, immune cells, blood vessel cells, and fibroblasts that comprise the tumor microenvironment (TME) to identify new therapeutic interventions. METHODS Databases, such as Google Scholar, PubMed, and Scopus, were searched to provide an overview of the recent research progress related to targeting the TME as a novel therapeutic approach. RESULTS Tumor microenvironment as a result of the cross talk between these cells may result in either advantages or disadvantages in tumor development and metastasis, affecting the signals and responses from the surrounding cells. Whilst chemotherapy has led to an improvement in CRC patients' survival, the metastatic aspect of the disease remains difficult to avoid. CONCLUSIONS The present review emphasizes the structure and function of the TME, alterations in the TME, its role in the incidence and progression of CRC, the effects on tumor development and metastasis, and also the potential of its alterations as therapeutic targets. It should be noted that providing novel studies in this field of research might help us to achieve practical therapeutic strategies based on their interaction.
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Affiliation(s)
- Narges Zafari
- Department of Medical Genetics, School of MedicineTehran University of Medical SciencesTehranIran
| | - Fatemeh Khosravi
- Molecular Medicine Research Center, Hormozgan Health InstituteHormozgan University of Medical SciencesBandar AbbasIran
| | - Zahra Rezaee
- Department of Medical Genetics, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran
| | - Sahar Esfandyari
- Department of Anatomy, School of MedicineTehran University of Medical SciencesTehranIran
| | - Mohamad Bahiraei
- Department of Radiology, Besat HospitalHamedan University of Medical SciencesHamedanIran
| | - Afshin Bahramy
- Department of Medical Genetics, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran
| | - Gordon A. Ferns
- Brighton & Sussex Medical SchoolDivision of Medical EducationSussexUK
| | - Amir Avan
- Metabolic Syndrome Research CenterMashhad University of Medical SciencesMashhadIran
- Basic Medical Sciences InstituteMashhad University of Medical SciencesMashhadIran
- Medical Genetics Research CenterMashhad University of Medical SciencesMashhadIran
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Zheng W, Wu F, Fu K, Sun G, Sun G, Li X, Jiang W, Cao H, Wang H, Tang W. Emerging Mechanisms and Treatment Progress on Liver Metastasis of Colorectal Cancer. Onco Targets Ther 2021; 14:3013-3036. [PMID: 33986602 PMCID: PMC8110277 DOI: 10.2147/ott.s301371] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 03/24/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is currently the third largest malignant tumor in the world, with high new cases and high mortality. Metastasis is one of the most common causes of death of colorectal cancer, of which liver metastasis is the most fatal. Since the beginning of the Human Genome Project in 2001, people have gradually recognized the 3 billion base pairs that make up the human genome, of which only about 1.5% of the nucleic acid sequences are used for protein coding, including proto-oncogenes and tumor suppressor genes. A large number of differences in the expression of proto-oncogenes and tumor suppressor genes have also been found in the study of colorectal cancer, which proves that they are also actively involved in the progression of colorectal cancer and promote the occurrence of liver metastasis. Except for 1.5% of the coding sequence, the rest of the nucleic acid sequence does not encode any protein, which is called non-coding RNA. With the deepening of research, genome sequences without protein coding potential that were originally considered “junk sequences” may have important biological functions. Many years of studies have found that a large number of abnormal expression of ncRNA in colorectal cancer liver metastasis, indicating that ncRNA plays an important role in it. To explore the role and mechanism of these coding sequences and non-coding RNA in liver metastasis of colorectal cancer is very important for the early diagnosis and treatment of liver metastasis of colorectal cancer. This article reviews the coding genes and ncRNA that have been found in the study of liver metastasis of colorectal cancer in recent years, as well as the mechanisms that have been identified or are still under study, as well as the clinical treatment of liver metastasis of colorectal cancer.
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Affiliation(s)
- Wubin Zheng
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Fan Wu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Kai Fu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Guoqiang Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiao Li
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Wei Jiang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hongyong Cao
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hanjin Wang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Weiwei Tang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, People's Republic of China
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Parizadeh SM, Jafarzadeh-Esfehani R, Fazilat-Panah D, Hassanian SM, Shahidsales S, Khazaei M, Parizadeh SMR, Ghayour-Mobarhan M, Ferns GA, Avan A. The potential therapeutic and prognostic impacts of the c-MET/HGF signaling pathway in colorectal cancer. IUBMB Life 2019; 71:802-811. [PMID: 31116909 DOI: 10.1002/iub.2063] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 04/10/2019] [Indexed: 12/22/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer and a common cause of cancer-related mortality globally. In spite of the improvements in the early diagnosis of CRC, approximately one-third of patients develop metastasis and then have a very poor survival rate. The mesenchymal-epithelial transition factor (c-MET) is a tyrosine kinase cell surface receptor activated by hepatocyte growth factor (HGF). Activation of c-MET/HGF signaling pathway regulates a variety of biological processes including cell motility, cell proliferation, angiogenesis, the epithelial-to-mesenchymal transition, and the development and progression of cancer cells. Recent studies have suggested that the c-MET/HGF signaling pathway is involved in the carcinogenesis of CRC. In this review, we summarize the main findings of recent studies investigating the role of c-MET/HGF signaling pathway in CRC and the potential of the c-MET/HGF signaling pathways in the diagnosis and treatment of CRC. © 2019 IUBMB Life, 2019.
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Affiliation(s)
| | - Reza Jafarzadeh-Esfehani
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Majid Khazaei
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Majid Ghayour-Mobarhan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton and Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex, UK
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Drug repurposing screening identifies bortezomib and panobinostat as drugs targeting cancer associated fibroblasts (CAFs) by synergistic induction of apoptosis. Invest New Drugs 2018; 36:545-560. [DOI: 10.1007/s10637-017-0547-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 11/22/2017] [Indexed: 02/04/2023]
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S Franco S, Szczesna K, Iliou MS, Al-Qahtani M, Mobasheri A, Kobolák J, Dinnyés A. In vitro models of cancer stem cells and clinical applications. BMC Cancer 2016; 16:738. [PMID: 27766946 PMCID: PMC5073996 DOI: 10.1186/s12885-016-2774-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Cancer cells, stem cells and cancer stem cells have for a long time played a significant role in the biomedical sciences. Though cancer therapy is more effective than it was a few years ago, the truth is that still none of the current non-surgical treatments can cure cancer effectively. The reason could be due to the subpopulation called “cancer stem cells” (CSCs), being defined as those cells within a tumour that have properties of stem cells: self-renewal and the ability for differentiation into multiple cell types that occur in tumours. The phenomenon of CSCs is based on their resistance to many of the current cancer therapies, which results in tumour relapse. Although further investigation regarding CSCs is still needed, there is already evidence that these cells may play an important role in the prognosis of cancer, progression and therapeutic strategy. Therefore, long-term patient survival may depend on the elimination of CSCs. Consequently, isolation of pure CSC populations or reprogramming of cancer cells into CSCs, from cancer cell lines or primary tumours, would be a useful tool to gain an in-depth knowledge about heterogeneity and plasticity of CSC phenotypes and therefore carcinogenesis. Herein, we will discuss current CSC models, methods used to characterize CSCs, candidate markers, characteristic signalling pathways and clinical applications of CSCs. Some examples of CSC-specific treatments that are currently in early clinical phases will also be presented in this review.
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Affiliation(s)
- Sara S Franco
- Szent István University, Gödöllö, Hungary.,Biotalentum Ltd., Gödöllö, Hungary
| | | | - Maria S Iliou
- Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Mohammed Al-Qahtani
- Center of Excellence in Genomic Medicine Research (CEGMR), King AbdulAziz University, Jeddah, Kingdom of Saudi Arabia
| | - Ali Mobasheri
- Center of Excellence in Genomic Medicine Research (CEGMR), King AbdulAziz University, Jeddah, Kingdom of Saudi Arabia.,Department of Veterinary Preclinical Sciences, School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK
| | | | - András Dinnyés
- Szent István University, Gödöllö, Hungary. .,Biotalentum Ltd., Gödöllö, Hungary. .,Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
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Lee H, Hong BJ, Lee JH, Yeo S, Jung HY, Chung J, Ahn GO, Hahn SK. Hyaluronate-Death Receptor 5 Antibody Conjugates for Targeted Treatment of Liver Metastasis. Biomacromolecules 2016; 17:3085-93. [PMID: 27517529 DOI: 10.1021/acs.biomac.6b01022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The liver is the most frequent site of metastasis with a 5-year survival rate of only 20-40%. In this work, hyaluronate (HA)-death receptor 5 antibody (DR5 Ab) conjugate was synthesized as a dual targeting therapeutic agent to treat liver metastasis. Dual targeting was achieved by DR5 Ab, a humanized agonistic monoclonal antibody binding to DR5 frequently overexpressed in many kinds of cancer cells, and by HA, a natural polysaccharide binding to HA receptors highly expressed in both the liver and cancer cells. Thiol end-modified HA was site-specifically conjugated to N-glycan on Fc region of oxidized DR5 Ab using a heterobifunctional linker of 3-(2-pyridyldithio)propionyl hydrazide (PDPH). The successful synthesis of HA-DR5 Ab conjugate was confirmed by (1)H NMR, purpald assay, dynamic light scattering (DLS), and high-performance liquid chromatography (HPLC). In vitro analysis of HA-DR5 Ab conjugate revealed that the conjugation of HA to DR5 Ab did not affect the binding affinity and anticancer efficacy of DR5 Ab. Remarkably, according to in vivo bioimaging study, HA-DR5 Ab conjugate appeared to be highly accumulated in the liver and dramatically effective in inhibiting the tumor growth in liver metastasis model mice.
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Affiliation(s)
| | | | | | | | - Hoe-Yune Jung
- R&D Center, NovMetaPharma Co., Ltd., Jigokdong, Nam-gu, Pohang, 790-834, Korea
| | - Junho Chung
- Department of Biochemistry and Molecular Biology and Cancer Research Institute, Seoul National University College of Medicine , Seoul, Korea
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Shali H, Ahmadi M, Kafil HS, Dorosti A, Yousefi M. IGF1R and c-met as therapeutic targets for colorectal cancer. Biomed Pharmacother 2016; 82:528-36. [DOI: 10.1016/j.biopha.2016.05.034] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 05/01/2016] [Accepted: 05/02/2016] [Indexed: 12/15/2022] Open
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10
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Ahsan A. Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors and Therapeutic Approaches: An Update. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 893:137-153. [DOI: 10.1007/978-3-319-24223-1_7] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Raffaghello L, Vacca A, Pistoia V, Ribatti D. Cancer associated fibroblasts in hematological malignancies. Oncotarget 2015; 6:2589-603. [PMID: 25474039 PMCID: PMC4413603 DOI: 10.18632/oncotarget.2661] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 10/27/2014] [Indexed: 12/21/2022] Open
Abstract
Tumor microenvironment plays an important role in cancer initiation and progression. In hematological malignancies, the bone marrow represents the paradigmatic anatomical site in which tumor microenvironment expresses its morphofunctional features. Among the cells participating in the composition of this microenvironment, cancer associated fibrobasts (CAFs) have received less attention in hematopoietic tumors compared to solid cancers. In this review article, we discuss the involvement of CAFs in progression of hematological malignancies and the potential targeting of CAFs in a therapeutic perspective.
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Affiliation(s)
| | - Angelo Vacca
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Vito Pistoia
- Laboratorio di Oncologia, Istituto G. Gaslini, Genova, Italy
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy, National Cancer Institute "Giovanni Paolo II", Bari, Italy
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Abstract
The key impediment to the successful application of gene therapy in clinics is not the paucity of therapeutic genes. It is rather the lack of nontoxic and efficient strategies to transfer therapeutic genes into target cells. Over the past few decades, considerable progress has been made in gene transfer technologies, and thus far, three different delivery systems have been developed with merits and demerits characterizing each system. Viral and chemical methods of gene transfer utilize specialized carrier to overcome membrane barrier and facilitate gene transfer into cells. Physical methods, on the other hand, utilize various forms of mechanical forces to enforce gene entry into cells. Starting in 1980s, physical methods have been introduced as alternatives to viral and chemical methods to overcome various extra- and intracellular barriers that limit the amount of DNA reaching the intended cells. Accumulating evidence suggests that it is quite feasible to directly translocate genes into cytoplasm or even nuclei of target cells by means of mechanical force, bypassing endocytosis, a common pathway for viral and nonviral vectors. Indeed, several methods have been developed, and the majority of them share the same underlying mechanism of gene transfer, i.e., physically created transient pores in cell membrane through which genes get into cells. Here, we provide an overview of the current status and future research directions in the field of physical methods of gene transfer.
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Abstract
Dr. Tuveson and colleagues provide a comprehensive review on the fundamental role of cancer-associated fibroblasts in shaping the tumor microenvironment and promoting tumor initiation and progression. Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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15
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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19
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Öhlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med 2014. [DOI: 10.1084/jem.20140692 order by 1-- dyrj] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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20
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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21
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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22
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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23
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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24
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Öhlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med 2014. [DOI: 10.1084/jem.20140692 order by 1#] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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25
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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26
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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27
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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28
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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29
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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30
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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31
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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32
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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33
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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34
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Öhlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med 2014. [DOI: 10.1084/jem.20140692 order by 1-- eloc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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35
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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36
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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37
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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38
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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39
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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40
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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41
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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42
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Abstract
Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Affiliation(s)
- Daniel Öhlund
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - Ela Elyada
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
| | - David Tuveson
- D. Öhlund, E. Elyada, and D. Tuveson are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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43
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Durante M, Reppingen N, Held KD. Immunologically augmented cancer treatment using modern radiotherapy. Trends Mol Med 2013; 19:565-82. [DOI: 10.1016/j.molmed.2013.05.007] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2013] [Revised: 05/27/2013] [Accepted: 05/28/2013] [Indexed: 10/26/2022]
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44
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Mizuno S, Nakamura T. HGF-MET cascade, a key target for inhibiting cancer metastasis: the impact of NK4 discovery on cancer biology and therapeutics. Int J Mol Sci 2013; 14:888-919. [PMID: 23296269 PMCID: PMC3565297 DOI: 10.3390/ijms14010888] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Revised: 12/06/2012] [Accepted: 12/10/2012] [Indexed: 01/14/2023] Open
Abstract
Hepatocyte growth factor (HGF) was discovered in 1984 as a mitogen of rat hepatocytes in a primary culture system. In the mid-1980s, MET was identified as an oncogenic mutant protein that induces malignant phenotypes in a human cell line. In the early 1990s, wild-type MET was shown to be a functional receptor of HGF. Indeed, HGF exerts multiple functions, such as proliferation, morphogenesis and anti-apoptosis, in various cells via MET tyrosine kinase phosphorylation. During the past 20 years, we have accumulated evidence that HGF is an essential conductor for embryogenesis and tissue regeneration in various types of organs. Furthermore, we found in the mid-1990s that stroma-derived HGF is a major contributor to cancer invasion at least in vitro. Based on this background, we prepared NK4 as an antagonist of HGF: NK4 inhibits HGF-mediated MET tyrosine phosphorylation by competing with HGF for binding to MET. In vivo, NK4 treatments produced the anti-tumor outcomes in mice bearing distinct types of malignant cancers, associated with the loss in MET activation. There are now numerous reports showing that HGF-antagonists and MET-inhibitors are logical for inhibiting tumor growth and metastasis. Additionally, NK4 exerts anti-angiogenic effects, partly through perlecan-dependent cascades. This paper focuses on the chronology and significance of HGF-antagonisms in anti-tumor researches, with an interest in NK4 discovery. Tumor HGF–MET axis is now critical for drug resistance and cancer stem cell maintenance. Thus, oncologists cannot ignore this cascade for the future success of anti-metastatic therapy.
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Affiliation(s)
- Shinya Mizuno
- Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, 2-2-B7 Yamadaoka, Suita 565-0871, Japan; E-Mail:
| | - Toshikazu Nakamura
- Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, 2-1 Yamadaoka, Suita 565-0871, Japan
- Author to whom correspondence should be addressed; E-Mail: ; Tel./Fax: +81-6-6879-4130
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Sun YL, Liu WD, Ma GY, Gao DW, Jiang YZ, Liu Q, Du JJ. Expression of HGF and Met in human tissues of colorectal cancers: biological and clinical implications for synchronous liver metastasis. Int J Med Sci 2013; 10:548-59. [PMID: 23532910 PMCID: PMC3607240 DOI: 10.7150/ijms.5191] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2012] [Accepted: 03/12/2013] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND AND AIMS Synchronous liver metastasis (SLM) remains a significant problem in newly diagnosed colorectal cancer (CRC). The system of hepatocyte growth factor (HGF) and Met plays an important role in cancer invasion and metastasis and is being developed to be targeted drugs. We aimed to investigate the role of HGF/Met in SLM based on a case-matched study and comparison between primary tumors and matched metastases. METHODS A group of 30 patients with SLM and other two groups of patients without SLM in a hospital database were collected. They were matched into according to clinicopathological factors. 81 patients were included in the study. Their tissues of primary colorectal cancers, lymph nodes and liver metastases were collected to detect HGF and Met expression by immunohistochemistry and RT-PCR. RESULTS Expression of HGF and Met at the protein level and the RNA level in primary CRCs with SLM were significantly higher than that in primary colorectal carcinomas without liver metastases (all P value<0.05). Their expression was only related to SLM when concurrent with regional lymph node metastasis (all P value<0.05) but had little influence on SLM without involvement of lymph node metastasis (all P value>0.05). Comparison their expression between primary tumors and matched metastases, major concordance and minor difference existed. CONCLUSIONS HGF and Met may exert functions in the development of SLM when concurrent with lymph node metastases but had little influence on SLM without lymph node metastasis, further indicating their roles and potential values for a subtype of colorectal cancer metastasis. Major concordance and minor difference exist between primary tumors and matched metastases, which further provides evidence for evaluating the response to their inhibitors based on primary tumors or metastases.
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Affiliation(s)
- Yan-lai Sun
- Institute of Oncology, Provincial Hospital Affiliated to Shandong University, Shandong University, 324 Jingwu Road, Jinan 250021, China
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Cirri P, Chiarugi P. Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev 2012; 31:195-208. [PMID: 22101652 DOI: 10.1007/s10555-011-9340-x] [Citation(s) in RCA: 380] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Several recent papers have now provided compelling experimental evidence that the progression of tumours towards a malignant phenotype does not depend exclusively on the cell-autonomous properties of cancer cells themselves but is also deeply influenced by tumour stroma reactivity, thereby undergoing a strict environmental control. Tumour microenvironmental elements include structural components such as the extracellular matrix or hypoxia as well as stromal cells, either resident cells or recruited from circulating precursors, as macrophages and other inflammatory cells, endothelial cells and cancer-associated fibroblasts (CAFs). All these elements synergistically play a specific role in cancer progression. This review summarizes our current knowledge on the role of CAFs in tumour progression, with a particular focus on the biunivocal interplay between CAFs and cancer cells leading to the activation of the epithelial-mesenchymal transition programme and the achievement of stem cell traits, as well as to the metabolic reprogramming of both stromal and cancer cells. Recent advances on the role of CAFs in the preparation of metastatic niche, as well as the controversial origin of CAFs, are discussed in light of the new emerging therapeutic implications of targeting CAFs.
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Affiliation(s)
- Paolo Cirri
- Department of Biochemical Science, University of Florence, Florence, Italy
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Belalcazar A, Azaña D, Perez CA, Raez LE, Santos ES. Targeting the Met pathway in lung cancer. Expert Rev Anticancer Ther 2012; 12:519-28. [PMID: 22500688 DOI: 10.1586/era.12.16] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Dysregulation of Met signaling has been implicated in the initiation, progression and metastasis of human cancers, and therefore represents an attractive target for anticancer drug development. Met is overexpressed in non-small-cell lung cancer and its lack of staining in normal lung tissue makes it an attractive target. To date, erlotinib and gefitinib have established themselves as first-line therapy for non-small-cell lung cancer patients whose tumors harbor an EGF receptor gene mutation, and hence, it is crucial that we identify mechanisms of resistance that could be targeted by novel agents, while keeping an acceptable toxicity profile at the same time; something very important when we develop these new drugs. Inhibitors of the Met pathway represent a therapeutic alternative in this setting. In this review, we discuss the early clinical studies reported using two Met inhibitors, a monoclonal antibody (MetMAb) and a small molecule tyrosine kinase inhibitor (MGCD265).
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Affiliation(s)
- Astrid Belalcazar
- Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
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Hill KS, Gaziova I, Harrigal L, Guerra YA, Qiu S, Sastry SK, Arumugam T, Logsdon CD, Elferink LA. Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer. PLoS One 2012; 7:e40420. [PMID: 22815748 PMCID: PMC3398924 DOI: 10.1371/journal.pone.0040420] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Accepted: 06/06/2012] [Indexed: 12/19/2022] Open
Abstract
At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer. Notably, Met is over expressed in up to 80% of invasive pancreatic cancers but not in normal ductal cells correlating with poor overall patient survival and increased recurrence rates following surgical resection. However the functional role of Met signaling in pancreatic cancer remains poorly understood. Here we used RNA interference to directly examine the pathobiological importance of increased Met signaling for pancreatic cancer. We show that Met knockdown in pancreatic tumor cells results in decreased cell survival, cell invasion, and migration on collagen I in vitro. Using an orthotopic model for pancreatic cancer, we provide in vivo evidence that Met knockdown reduced tumor burden correlating with decreased cell survival and tumor angiogenesis, with minimal effect on cell growth. Notably, we report that Met signaling regulates the secretion of the pro-angiogenic chemokine interleukin-8/CXCL8. Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer.
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Affiliation(s)
- Kristen S. Hill
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Ivana Gaziova
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Lindsay Harrigal
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Yvette A. Guerra
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Suimin Qiu
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
- UTMB Cancer Center, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Sarita K. Sastry
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America
- UTMB Cancer Center, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Thiruvengadam Arumugam
- Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Craig D. Logsdon
- Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Lisa A. Elferink
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America
- UTMB Cancer Center, University of Texas Medical Branch, Galveston, Texas, United States of America
- * E-mail:
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Prognostic value of tumor growth factor levels during chemotherapy in patients with metastatic colorectal cancer. Med Oncol 2012; 29:3119-24. [PMID: 22580817 DOI: 10.1007/s12032-012-0250-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2012] [Accepted: 04/25/2012] [Indexed: 12/16/2022]
Abstract
Tumor growth and angiogenic factors are usually overexpressed in colorectal carcinomas. We aimed to assess the prognostic role of VEGF, bFGF, PDGF-AA, EGF, HGF, and E-selectin in patients with metastatic colorectal cancer treated with capecitabine and oxaliplatin (XELOX) chemotherapy protocol. Thirty-eight colorectal cancer patients who had evidence of distant metastasis were enrolled in the study. Angiogenic factors were measured before and after third cycle of chemotherapy. Patients were randomized into three groups, partial response (PR), stable disease (SD), and progressive disease (PD) groups, according to their clinical and radiologic evaluation after three cycles of XELOX chemotherapy. Eighteen patients (47.3 %) achieved partial response, 10 (26.3 %) stable disease, and 10 (26.3 %) progressive disease. VEGF (63.20 Pg/ml vs. 19,79 Pg/ml; p < 0.001), EGF (7.29 ± 3.08 Pg/ml vs. 4.79 ± 2.05 Pg/ml; p < 0.011), HGF (618.16 ± 340.39 Pg/ml vs. 452.02 ± 217.18 Pg/ml; p < 0.049), and PDGF-AA (691.68 ± 187.10 Pg/ml vs. 404.89 ± 168.47 Pg/ml; p < 0.001) were significantly decreased in PR group. PDGF-AA levels were also decreased in SD group (706.66 ± 206.66 Pg/ml vs. 389.79 ± 143.16 Pg/ml; p < 0,001). HGF levels were significantly increased in PD disease group (449.99 Pg/ml vs. 682.22 Pg/ml; p < 0.046). The baseline E-selectin levels were inversely proportional with overall survival that could be an important prognostic factor at the time of diagnosis. This study demonstrated that tumor growth factors can be helpful to determine colorectal cancer prognosis and overall survival in patients with metastatic disease. VEGF, HGF, EGF, and PDGF-AA levels were decreased in PR group. However, meaningful increment was seen HGF levels in PD group. Angiogenic factors and E-selectin provided unique prognostic information in advanced colorectal carcinoma patients.
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Leibovici J, Itzhaki O, Huszar M, Sinai J. Targeting the tumor microenvironment by immunotherapy: part 2. Immunotherapy 2011; 3:1385-408. [DOI: 10.2217/imt.11.112] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cancer therapy was traditionally centered on the neoplastic cells. This included mainly surgery, radiation, and chemotherapy, in some cases hormone therapy and to a lesser extent immunotherapy – all traditionally targeted to the highly proliferating mutated tumor cells. In view of our present understanding of the powerfull influence of the tumor microenvironment (TME) on cancer behavior and response – and lack of response – to treatment, this previously ignored constituent of cancer now has to be considered as an important, even indispensable target for therapy. The TME may be targeted both to its immune and to its nonimmune components. The various immune evasion elements of the TME should be targeted as well.
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Affiliation(s)
| | - Orit Itzhaki
- Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, 69978 Tel-Aviv, Israel
| | - Monica Huszar
- Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, 69978 Tel-Aviv, Israel
| | - Judith Sinai
- Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, 69978 Tel-Aviv, Israel
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