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Yan X, Niu Y, Yang X, Zhao R, Cui W, Guo X, Zhang J, Ma M. FDP/FIB ratio serves as a novel biomarker for diagnosing bone marrow invasion in gastric cancer and predicting patient prognosis\. Sci Rep 2025; 15:9462. [PMID: 40108276 PMCID: PMC11923145 DOI: 10.1038/s41598-025-93056-8] [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: 08/11/2024] [Accepted: 03/04/2025] [Indexed: 03/22/2025] Open
Abstract
Objective This study aimed to identify laboratory indicators with significant implications for bone marrow invasion in gastric cancer patients and to evaluate their prognostic value. Methods A retrospective analysis of the clinical data of 320 gastric cancer patients who underwent either bone marrow cytological examination or bone marrow biopsy at our hospital between January 2013 and December 2023 was conducted. Among these patients, 31 patients with confirmed bone marrow invasion composed the study group, whereas 34 stage IV gastric cancer patients without bone marrow invasion composed the control group. Differences in demographic and laboratory data between the two groups were compared. Receiver operating characteristic curves were used to identify valuable indicators for predicting bone marrow invasion in patients with gastric cancer. Survival analysis was performed using the Kaplan‒Meier method and included the plotting of survival curves. Additionally, Cox proportional hazards regression analysis was performed to evaluate independent prognostic factors. Results Significantly different values (all P < 0.05) were observed for age, peripheral blood immature cells, Hb, PLT, SII, FIB, PT, FDP, D-Dimer, FDP/FIB, CEA, and CA72-4 between stage IV gastric cancer patients with and without bone marrow infiltration. The ROC analysis indicated that at a threshold value of 5.197 for FDP/FIB, the AUC was 0.958 (P < 0.01). Within the cohort of 65 stage IV gastric cancer patients, those with bone marrow invasion and high FDP/FIB ratios exhibited notably shorter median survival times than those without bone marrow invasion and with low FDP/FIB ratios (χ2 = 25.928, 20.128, P < 0.001). Multivariate analysis demonstrated that bone marrow invasion (HR = 4.148, P = 0.020) and the FDP/FIB ratio (HR = 1.026, P = 0.024) were independent risk factors influencing the prognosis and survival outcome of stage IV gastric cancer patients. Among the subset of 31 gastric cancer patients with bone marrow invasion, the median survival time for the high FDP/FIB group was 22 days, which was significantly shorter than the 60 days observed in the low FDP/FIB group (χ2 = 8.479, P = 0.004). Conclusion The FDP/FIB ratio can serve as an important indicator for the diagnosis and prognostic evaluation of bone marrow invasion in patients with gastric cancer.
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Affiliation(s)
- Xi Yan
- Department of Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yinghao Niu
- Department of Clinical Biobank, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xingxiao Yang
- Department of Hospital Infection Management, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Riyang Zhao
- Department of Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Wenxuan Cui
- Department of Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiujuan Guo
- Department of Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
- , 12# Jiankang Road, Shijiazhuang, China.
| | - Jinyan Zhang
- Department of Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
- , 12# Jiankang Road, Shijiazhuang, China.
| | - Ming Ma
- Department of Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
- , 12# Jiankang Road, Shijiazhuang, China.
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Yang R, Jia L, Cui J. Mechanism and clinical progression of solid tumors bone marrow metastasis. Front Pharmacol 2024; 15:1390361. [PMID: 38770000 PMCID: PMC11102981 DOI: 10.3389/fphar.2024.1390361] [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: 02/23/2024] [Accepted: 04/22/2024] [Indexed: 05/22/2024] Open
Abstract
The rich blood supply of the bone marrow provides favorable conditions for tumor cell proliferation and growth. In the disease's early stages, circulating tumor cells can escape to the bone marrow and form imperceptible micro metastases. These tumor cells may be reactivated to regain the ability to grow aggressively and eventually develop into visible metastases. Symptomatic bone marrow metastases with abnormal hematopoiesis solid tumor metastases are rare and have poor prognoses. Treatment options are carefully chosen because of the suppression of bone marrow function. In this review, we summarized the mechanisms involved in developing bone marrow metastases from tumor cells and the clinical features, treatment options, and prognosis of patients with symptomatic bone marrow metastases from different solid tumors reported in the literature.
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Mardelle U, Bretaud N, Daher C, Feuillet V. From pain to tumor immunity: influence of peripheral sensory neurons in cancer. Front Immunol 2024; 15:1335387. [PMID: 38433844 PMCID: PMC10905387 DOI: 10.3389/fimmu.2024.1335387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/29/2024] [Indexed: 03/05/2024] Open
Abstract
The nervous and immune systems are the primary sensory interfaces of the body, allowing it to recognize, process, and respond to various stimuli from both the external and internal environment. These systems work in concert through various mechanisms of neuro-immune crosstalk to detect threats, provide defense against pathogens, and maintain or restore homeostasis, but can also contribute to the development of diseases. Among peripheral sensory neurons (PSNs), nociceptive PSNs are of particular interest. They possess a remarkable capability to detect noxious stimuli in the periphery and transmit this information to the brain, resulting in the perception of pain and the activation of adaptive responses. Pain is an early symptom of cancer, often leading to its diagnosis, but it is also a major source of distress for patients as the disease progresses. In this review, we aim to provide an overview of the mechanisms within tumors that are likely to induce cancer pain, exploring a range of factors from etiological elements to cellular and molecular mediators. In addition to transmitting sensory information to the central nervous system, PSNs are also capable, when activated, to produce and release neuropeptides (e.g., CGRP and SP) from their peripheral terminals. These neuropeptides have been shown to modulate immunity in cases of inflammation, infection, and cancer. PSNs, often found within solid tumors, are likely to play a significant role in the tumor microenvironment, potentially influencing both tumor growth and anti-tumor immune responses. In this review, we discuss the current state of knowledge about the degree of sensory innervation in tumors. We also seek to understand whether and how PSNs may influence the tumor growth and associated anti-tumor immunity in different mouse models of cancer. Finally, we discuss the extent to which the tumor is able to influence the development and functions of the PSNs that innervate it.
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Affiliation(s)
- Ugo Mardelle
- Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Ninon Bretaud
- Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Clara Daher
- Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Vincent Feuillet
- Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
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Watanabe H, Maishi N, Hoshi-Numahata M, Nishiura M, Nakanishi-Kimura A, Hida K, Iimura T. Skeletal-Vascular Interactions in Bone Development, Homeostasis, and Pathological Destruction. Int J Mol Sci 2023; 24:10912. [PMID: 37446097 DOI: 10.3390/ijms241310912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 06/28/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Bone is a highly vascularized organ that not only plays multiple roles in supporting the body and organs but also endows the microstructure, enabling distinct cell lineages to reciprocally interact. Recent studies have uncovered relevant roles of the bone vasculature in bone patterning, morphogenesis, homeostasis, and pathological bone destruction, including osteoporosis and tumor metastasis. This review provides an overview of current topics in the interactive molecular events between endothelial cells and bone cells during bone ontogeny and discusses the future direction of this research area to find novel ways to treat bone diseases.
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Affiliation(s)
- Haruhisa Watanabe
- Department of Pharmacology, Faculty and Graduate School of Dental Medicine, Hokkaido University, N13 W7, Sapporo 060-8586, Hokkaido, Japan
| | - Nako Maishi
- Department of Vascular Biology, Faculty and Graduate School of Dental Medicine, Hokkaido University, N13 W7, Sapporo 060-8586, Hokkaido, Japan
| | - Marie Hoshi-Numahata
- Department of Pharmacology, Faculty and Graduate School of Dental Medicine, Hokkaido University, N13 W7, Sapporo 060-8586, Hokkaido, Japan
| | - Mai Nishiura
- Department of Pharmacology, Faculty and Graduate School of Dental Medicine, Hokkaido University, N13 W7, Sapporo 060-8586, Hokkaido, Japan
| | - Atsuko Nakanishi-Kimura
- Department of Pharmacology, Faculty and Graduate School of Dental Medicine, Hokkaido University, N13 W7, Sapporo 060-8586, Hokkaido, Japan
| | - Kyoko Hida
- Department of Vascular Biology, Faculty and Graduate School of Dental Medicine, Hokkaido University, N13 W7, Sapporo 060-8586, Hokkaido, Japan
| | - Tadahiro Iimura
- Department of Pharmacology, Faculty and Graduate School of Dental Medicine, Hokkaido University, N13 W7, Sapporo 060-8586, Hokkaido, Japan
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Brook N, Dharmarajan A, Chan A, Dass CR. Potential therapeutic role for pigment epithelium-derived factor in post-menopausal breast cancer bone metastasis. J Pharm Pharmacol 2023:7146711. [PMID: 37116213 DOI: 10.1093/jpp/rgad039] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 04/12/2023] [Indexed: 04/30/2023]
Abstract
OBJECTIVES This review discusses key oestrogens associated with the circulating pre- and post-menopausal milieu and how they may impact intratumoral oestrogen levels and breast cancer (BC) metastasis. It also identifies critical steps in BC metastasis to bone from the viewpoint of pigment epithelium-derived factor (PEDF) function, and discusses the role of several associated pro-metastatic biomarkers in BC bone metastasis. KEY FINDINGS PEDF is regulated by oestrogen in a number of oestrogen-sensitive tissues. Changes in circulating oestrogen levels associated with menopause may enhance the growth of BC bone metastases, leading to the establishment of a pre-metastatic niche. The establishment of such a pre-metastatic niche is driven by several key mediators, with pro-osteoclastic and pro-metastatic function which are upregulated by BC cells. These mediators appear to be regulated by oestrogen, as well as differentially affected by menopausal status. PEDF interacts with several pro-metastatic, pro-osteoclastic biomarkers, including C-X-C motif chemokine receptor 4 (CXCR4) and nuclear factor kappa B (NFκB) in BC bone metastasis. CONCLUSION Mediators such as CXCR4 and MT1-MMP underpin the ability of PEDF to function as an antimetastatic in other cancers such as osteosarcoma, highlighting the possibility that this serpin could be used as a therapeutic against BC metastasis in future.
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Affiliation(s)
- Naomi Brook
- Curtin Medical School, Curtin University, Bentley 6102, Australia
- Curtin Health Innovation Research Institute, Bentley 6102, Australia
| | - Arun Dharmarajan
- Curtin Medical School, Curtin University, Bentley 6102, Australia
- Curtin Health Innovation Research Institute, Bentley 6102, Australia
- Department of Biomedical Sciences, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India
| | - Arlene Chan
- Curtin Medical School, Curtin University, Bentley 6102, Australia
- Breast Cancer Research Centre-Western Australia, Hollywood Private Hospital, Nedlands 6009, Australia
| | - Crispin R Dass
- Curtin Medical School, Curtin University, Bentley 6102, Australia
- Curtin Health Innovation Research Institute, Bentley 6102, Australia
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NFκB-Mediated Mechanisms Drive PEDF Expression and Function in Pre- and Post-Menopausal Oestrogen Levels in Breast Cancer. Int J Mol Sci 2022; 23:ijms232415641. [PMID: 36555293 PMCID: PMC9779285 DOI: 10.3390/ijms232415641] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/02/2022] [Accepted: 12/04/2022] [Indexed: 12/14/2022] Open
Abstract
Pigment epithelium-derived factor (PEDF) protein regulates normal bone, with anti-tumour roles in bone and breast cancer (BC). Pre- and post-menopausal oestrogen levels may regulate PEDF expression and function in BC, though the mechanisms behind this remain unknown. In this study, in vitro models simulating pre- and post-menopausal bone microenvironments were used to evaluate if PEDF regulates pro-metastatic biomarker expression and downstream functional effects on BC cells. PEDF treatment reduced phosphorylated-nuclear factor-κB p65 subunit (p-NFκB-p65), tumour necrosis factor-α (TNFα), C-X-C chemokine receptor type-4 (CXCR4), and urokinase plasminogen activator receptor (uPAR) in oestrogen receptor (ER)+/human epidermal growth factor receptor-2 (HER2)- BC cells under post-menopausal oestrogen conditions. In triple negative BC (TNBC) cells, PEDF treatment reduced pNFκB-p65 and uPAR expression under pre-menopausal oestrogen conditions. A potential reciprocal regulatory axis between p-NFκB-65 and PEDF in BC was identified, which was BC subtype-specific and differentially regulated by menopausal oestrogen conditions. The effects of PEDF treatment and NFκB inhibition on BC cell function under menopausal conditions were also compared. PEDF treatment exhibited superior anti-viability effects, while combined PEDF and NFκB-p65 inhibitor treatment was superior in reducing BC cell colony formation in a subtype-specific manner. Lastly, immunohistochemical evaluation of p-NFκB-p65 and PEDF expression in human BC and bone metastases specimens revealed an inverse correlation between nuclear PEDF and NFκB expression in bone metastases. We propose that menopausal status is associated with a PEDF/NFκB reciprocal regulatory axis, which drives PEDF expression and anti-metastatic function in a subtype-specific manner. Altogether, our findings identify pre-menopausal TNBC and post-menopausal ER+/HER2- BC patients as target populations for future PEDF research.
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A fragment integrational approach to GPCR inhibition: Identification of a high affinity small molecule CXCR4 antagonist. Eur J Med Chem 2022; 231:114150. [DOI: 10.1016/j.ejmech.2022.114150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/11/2022] [Accepted: 01/19/2022] [Indexed: 11/23/2022]
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Xu H, Peng C, Chen XT, Yao YY, Chen LP, Yin Q, Shen W. Chemokine receptor CXCR4 activates the RhoA/ROCK2 pathway in spinal neurons that induces bone cancer pain. Mol Pain 2021; 16:1744806920919568. [PMID: 32349612 PMCID: PMC7227150 DOI: 10.1177/1744806920919568] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background Chemokine receptor CXCR4 has been found to be associated with spinal neuron and glial cell activation during bone cancer pain. However, the underlying mechanism remains unknown. Furthermore, the RhoA/ROCK2 pathway serves as a downstream pathway activated by CXCR4 during bone cancer pain. We first validated the increase in the expressions of CXCR4, p-RhoA, and p-ROCK2 in the spinal dorsal horn of a well-characterized tumor cell implantation-induced cancer pain rat model and how these expressions contributed to the pain behavior in tumor cell implantation rats. We hypothesized that spinal blockade of the CXCR4-RhoA/ROCK2 pathway is a potential analgesic therapy for cancer pain management. Methods Adult female Sprague–Dawley rats (body weight of 180–220 g) and six- to seven-week old female Sprague–Dawley rats (body weight of 80–90 g) were taken. Ascitic cancer cells were extracted from the rats (body weight of 80–90 g) with intraperitoneally implanted Walker 256 mammary gland carcinoma cells. Walker 256 rat mammary gland carcinoma cells were then injected (tumor cell implantation) into the intramedullary space of the tibia to establish a rat model of bone cancer pain. Results We found increased expressions of CXCR4, p-RhoA, and p-ROCK2 in the neurons in the spinal cord. p-RhoA and p-ROCK2 were co-expressed in the neurons and promoted by overexpressed CXCR4. Intrathecal delivery of CXCR4 inhibitor Plerixafor (AMD3100) or ROCK2 inhibitor Fasudil abrogated tumor cell implantation-induced pain hypersensitivity and tumor cell implantation-induced increase in p-RhoA and p-ROCK2 expressions. Intrathecal injection of stromal-derived factor-1, the principal ligand for CXCR4, accelerated p-RhoA expression in naive rats, which was prevented by postadministration of CXCR4 inhibitor Plerixafor (AMD3100) or ROCK2 inhibitor Fasudil. Conclusions Collectively, the spinal RhoA/ROCK2 pathway could be a critical downstream target for CXCR4-mediated neuronal sensitization and pain hypersensitivity in bone cancer pain, and it may serve as a potent therapeutic target for pain treatment.
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Affiliation(s)
- Heng Xu
- Department of Pain Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Chong Peng
- Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xue-Tai Chen
- Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Ying-Ying Yao
- Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of Anesthesiology, Xuzhou First People's Hospital, Xuzhou, Jiangsu, China
| | - Li-Ping Chen
- Department of Pain Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Qin Yin
- Department of Pain Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Wen Shen
- Department of Pain Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China
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Zhang H, Li X, Li J, Zhong L, Chen X, Chen S. SDF-1 mediates mesenchymal stem cell recruitment and migration via the SDF-1/CXCR4 axis in bone defect. J Bone Miner Metab 2021; 39:126-138. [PMID: 33079278 DOI: 10.1007/s00774-020-01122-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 06/27/2020] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Recent studies have indicated the potential of stem cell therapy in combination with cytokines to restore the bone repair via migration and homing of stem cells to the defected area. The present study aimed to investigate the mobilization and recruitment of mesenchymal stem cells (MSCs) in response to SDF-1. MATERIALS AND METHODS Herein, the knockout rat model of the bone defect (BD) was treated with the induced membrane technique. Then, wild type Wistar rats and SDF-1-knockout rats were selected for the establishment of BD-induced membrane (BD-IM) models and bone-graft (BG) models. The number of MSCs was evaluated by flow cytometry, along with the expression pattern of the SDF-1/CXCR4 axis as well as osteogenic factors was identified by RT-qPCR and Western blot analyses. Finally, the MSC migration ability was assessed by the Transwell assay. RESULTS Our data illustrated that in the induced membrane tissues, the number of MSCs among the BD-IM modeled rats was increased, whereas, a lower number was documented among BG modeled rats. Besides, we found that lentivirus-mediated over-expression of SDF-1 in BG modeled rats could activate the SDF-1/CXCR4 axis, mobilize MSCs into the defect area, and up-regulate the osteogenic proteins. CONCLUSIONS Collectively, our study speculated that up-regulation of SDF-1 promotes the mobilization and migration of MSCs through the activation of the SDF-1/CXCR4 signal pathway.
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Affiliation(s)
- Heli Zhang
- Department of Outpatient, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Xijing Li
- Department of Emergency, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Junfeng Li
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Lili Zhong
- Jilin Provincial Key Laboratory On Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Xue Chen
- Department of Orthopedics, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, 130041, Jilin, People's Republic of China.
| | - Si Chen
- Department of Geriatric Medicine, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, 130041, Jilin, People's Republic of China.
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Pisani A, Donno R, Gennari A, Cibecchini G, Catalano F, Marotta R, Pompa PP, Tirelli N, Bardi G. CXCL12-PLGA/Pluronic Nanoparticle Internalization Abrogates CXCR4-Mediated Cell Migration. NANOMATERIALS 2020; 10:nano10112304. [PMID: 33233846 PMCID: PMC7699919 DOI: 10.3390/nano10112304] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 02/06/2023]
Abstract
Chemokine-induced chemotaxis mediates physiological and pathological immune cell trafficking, as well as several processes involving cell migration. Among them, the role of CXCL12/CXCR4 signaling in cancer and metastasis is well known, and CXCR4 has been often targeted with small molecule-antagonists or short CXCL12-derived peptides to limit the pathological processes of cell migration and invasion. To reduce CXCR4-mediated chemotaxis, we adopted a different approach. We manufactured poly(lactic acid-co-glycolic acid) (PLGA)/Pluronic F127 nanoparticles through microfluidics-assisted nanoprecipitation and functionalized them with streptavidin to docking a biotinylated CXCL12 to be exposed on the nanoparticle surface. Our results show that CXCL12-decorated nanoparticles are non-toxic and do not induce inflammatory cytokine release in THP-1 monocytes cultured in fetal bovine and human serum-supplemented media. The cell internalization of our chemokine receptor-targeting particles increases in accordance with CXCR4 expression in FBS/medium. We demonstrated that CXCL12-decorated nanoparticles do not induce cell migration on their own, but their pre-incubation with THP-1 significantly decreases CXCR4+-cell migration, thereby antagonizing the chemotactic action of CXCL12. The use of biodegradable and immune-compatible chemokine-mimetic nanoparticles to reduce cell migration opens the way to novel antagonists with potential application in cancer treatments and inflammation.
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Affiliation(s)
- Anissa Pisani
- Nanobiointeractions & Nanodiagnostics, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy; (A.P.); (G.C.); (P.P.P.)
- Department of Chemistry and Industrial Chemistry, University of Genova, Via Dodecaneso 31, 16146 Genova, Italy
| | - Roberto Donno
- Laboratory of Polymers and Biomaterials, Istituto Italiano di Tecnologia, 16163 Genova, Italy; (R.D.); (A.G.)
| | - Arianna Gennari
- Laboratory of Polymers and Biomaterials, Istituto Italiano di Tecnologia, 16163 Genova, Italy; (R.D.); (A.G.)
| | - Giulia Cibecchini
- Nanobiointeractions & Nanodiagnostics, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy; (A.P.); (G.C.); (P.P.P.)
- Department of Chemistry and Industrial Chemistry, University of Genova, Via Dodecaneso 31, 16146 Genova, Italy
| | - Federico Catalano
- Electron Microscopy Laboratory, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy; (F.C.); (R.M.)
| | - Roberto Marotta
- Electron Microscopy Laboratory, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy; (F.C.); (R.M.)
| | - Pier Paolo Pompa
- Nanobiointeractions & Nanodiagnostics, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy; (A.P.); (G.C.); (P.P.P.)
| | - Nicola Tirelli
- Laboratory of Polymers and Biomaterials, Istituto Italiano di Tecnologia, 16163 Genova, Italy; (R.D.); (A.G.)
- Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK
- Correspondence: (N.T.); (G.B.); Tel.: +39-010-289-6923 (N.T.); +39-010-289-6519 (G.B.)
| | - Giuseppe Bardi
- Nanobiointeractions & Nanodiagnostics, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy; (A.P.); (G.C.); (P.P.P.)
- Correspondence: (N.T.); (G.B.); Tel.: +39-010-289-6923 (N.T.); +39-010-289-6519 (G.B.)
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Zhuo Y, Gurevich VV, Vishnivetskiy SA, Klug CS, Marchese A. A non-GPCR-binding partner interacts with a novel surface on β-arrestin1 to mediate GPCR signaling. J Biol Chem 2020; 295:14111-14124. [PMID: 32753481 DOI: 10.1074/jbc.ra120.015074] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/29/2020] [Indexed: 12/30/2022] Open
Abstract
The multifaceted adaptor protein β-arr1 (β-arrestin1) promotes activation of focal adhesion kinase (FAK) by the chemokine receptor CXCR4, facilitating chemotaxis. This function of β-arr1 requires the assistance of the adaptor protein STAM1 (signal-transducing adaptor molecule 1) because disruption of the interaction between STAM1 and β-arr1 reduces CXCR4-mediated activation of FAK and chemotaxis. To begin to understand the mechanism by which β-arr1 together with STAM1 activates FAK, we used site-directed spin-labeling EPR spectroscopy-based studies coupled with bioluminescence resonance energy transfer-based cellular studies to show that STAM1 is recruited to activated β-arr1 by binding to a novel surface on β-arr1 at the base of the finger loop, at a site that is distinct from the receptor-binding site. Expression of a STAM1-deficient binding β-arr1 mutant that is still able to bind to CXCR4 significantly reduced CXCL12-induced activation of FAK but had no impact on ERK-1/2 activation. We provide evidence of a novel surface at the base of the finger loop that dictates non-GPCR interactions specifying β-arrestin-dependent signaling by a GPCR. This surface might represent a previously unidentified switch region that engages with effector molecules to drive β-arrestin signaling.
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Affiliation(s)
- Ya Zhuo
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Vsevolod V Gurevich
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA
| | | | - Candice S Klug
- Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Adriano Marchese
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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12
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Pansy K, Feichtinger J, Ehall B, Uhl B, Sedej M, Roula D, Pursche B, Wolf A, Zoidl M, Steinbauer E, Gruber V, Greinix HT, Prochazka KT, Thallinger GG, Heinemann A, Beham-Schmid C, Neumeister P, Wrodnigg TM, Fechter K, Deutsch AJ. The CXCR4-CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro. Int J Mol Sci 2019; 20:E4740. [PMID: 31554271 PMCID: PMC6801866 DOI: 10.3390/ijms20194740] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/19/2019] [Accepted: 09/21/2019] [Indexed: 12/13/2022] Open
Abstract
In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.
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MESH Headings
- Aminoquinolines
- Antineoplastic Agents/pharmacology
- Apoptosis/drug effects
- Benzimidazoles
- Biomarkers
- Butylamines
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Chemokine CXCL12/genetics
- Chemokine CXCL12/metabolism
- Exons
- Female
- Gene Expression
- Heterocyclic Compounds, 1-Ring/pharmacology
- Humans
- Lymphoma, Large B-Cell, Diffuse/metabolism
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/pathology
- Male
- Mutation
- Neoplasm Staging
- Prognosis
- Receptors, CXCR4/antagonists & inhibitors
- Receptors, CXCR4/genetics
- Receptors, CXCR4/metabolism
- Signal Transduction/drug effects
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Affiliation(s)
- Katrin Pansy
- Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria.
| | - Julia Feichtinger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstraße 6/II, 8010 Graz, Austria.
| | - Barbara Ehall
- Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria.
| | - Barbara Uhl
- Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria.
| | - Miriam Sedej
- Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4/I, 8010 Graz, Austria.
| | - David Roula
- Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4/I, 8010 Graz, Austria.
| | - Beata Pursche
- Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria.
| | - Axel Wolf
- Division of General Otorhinolaryngology, Medical University of Graz, Auenbruggerplatz 26, 8036 Graz, Austria.
| | - Manuel Zoidl
- Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9/4, 8010 Graz, Austria.
| | - Elisabeth Steinbauer
- Diagnostic & Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria.
| | - Verena Gruber
- Diagnostic & Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria.
| | - Hildegard T Greinix
- Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria.
| | - Katharina T Prochazka
- Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria.
| | - Gerhard G Thallinger
- Institute of Computational Biotechnology, Graz University of Technology, Petersgasse 14/V, 8010 Graz, Austria.
- OMICS Center Graz, BioTechMed Graz, Stiftingtalstraße 24, 8010 Graz, Austria.
| | - Akos Heinemann
- Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4/I, 8010 Graz, Austria.
| | - Christine Beham-Schmid
- Diagnostic & Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria.
| | - Peter Neumeister
- Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria.
| | - Tanja M Wrodnigg
- Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9/4, 8010 Graz, Austria.
| | - Karoline Fechter
- Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria.
| | - Alexander Ja Deutsch
- Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria.
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13
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Mannavola F, Tucci M, Felici C, Passarelli A, D'Oronzo S, Silvestris F. Tumor-derived exosomes promote the in vitro osteotropism of melanoma cells by activating the SDF-1/CXCR4/CXCR7 axis. J Transl Med 2019; 17:230. [PMID: 31324252 PMCID: PMC6642540 DOI: 10.1186/s12967-019-1982-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 07/12/2019] [Indexed: 01/22/2023] Open
Abstract
Background Bone metastases occur rarely in patients suffering from malignant melanoma, although their onset severely worsens both prognosis and quality of life. Extracellular vesicles (EVs) including exosomes (Exos) are active players in melanoma progression involved in the formation of the pre-metastatic niche. Methods Trans-well assays explored the basal migratory and invasive potential of four melanoma cell lines and investigated their different propensity to be attracted toward the bone. Exosomes were purified from cell supernatants by ultracentrifugation and explored in their ability to influence the bone tropism of melanoma cells. The molecular machinery activated during this process was investigated by RT-PCR, droplet digital-PCR, flow-cytometry and Western blot, while loss of function studies with dedicated siRNAs defined the single contribute of CXCR4 and CXCR7 molecules. Results Melanoma cells revealed a variable propensity to be attracted toward bone fragments. Gene profiling of both osteotropic and not-osteotropic cells did not show a different expression of those genes notoriously correlated to chemotaxis and bone metastasis. However, bone conditioned medium significantly increased CXCR4, CXCR7 and PTHrP expression solely to osteotropic cells, while their Exos were able to revert the original poor bone tropism of not-osteotropic cells through CXCR7 up-regulation. Silencing experiments also demonstrated that membrane expression of CXCR7 is required by melanoma cells to promote their chemotaxis toward SDF-1 gradients. Conclusions Our data correlated the osteotropism of melanoma cells to the activation of the SDF-1/CXCR4/CXCR7 axis following the exposition of tumor cells to bone-derived soluble factors. Also, we demonstrated in vitro that tumor-derived Exos can reprogram the innate osteotropism of melanoma cells by up-regulating membrane CXCR7. These results may have a potential translation to future identification of druggable targets for the treatment of skeletal metastases from malignant melanoma. Electronic supplementary material The online version of this article (10.1186/s12967-019-1982-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Francesco Mannavola
- Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', P.za Giulio Cesare, 11-70124, Bari, Italy
| | - Marco Tucci
- Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', P.za Giulio Cesare, 11-70124, Bari, Italy.
| | - Claudia Felici
- Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', P.za Giulio Cesare, 11-70124, Bari, Italy
| | - Anna Passarelli
- Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', P.za Giulio Cesare, 11-70124, Bari, Italy
| | - Stella D'Oronzo
- Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', P.za Giulio Cesare, 11-70124, Bari, Italy
| | - Francesco Silvestris
- Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', P.za Giulio Cesare, 11-70124, Bari, Italy
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14
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Brickute D, Braga M, Kaliszczak MA, Barnes C, Lau D, Carroll L, Stevens E, Trousil S, Alam IS, Nguyen QD, Aboagye EO. Development and Evaluation of an 18F-Radiolabeled Monocyclam Derivative for Imaging CXCR4 Expression. Mol Pharm 2019; 16:2106-2117. [PMID: 30883140 PMCID: PMC6522096 DOI: 10.1021/acs.molpharmaceut.9b00069] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 03/14/2019] [Accepted: 03/18/2019] [Indexed: 01/02/2023]
Abstract
In humans, C-X-C chemokine receptor type 4 (CXCR4) is a protein that is encoded by the CXCR4 gene and binds the ligand CXCL12 (also known as SDF-1). The CXCR4-CXCL12 interaction in cancer elicits biological activities that result in tumor progression and has accordingly been the subject of significant investigation for detection and treatment of the disease. Peptidic antagonists have been labeled with a variety of radioisotopes for the detection of CXCR4, but the methodology utilizing small molecules has predominantly used radiometals. We report here the development of a 18F-radiolabeled cyclam-based small molecule radioprobe, [18F]MCFB, for imaging CXCR4 expression. The IC50 value of [19F]MCFB for CXCR4 was similar to that of AMD3465 (111.3 and 89.8 nM, respectively). In vitro binding assays show that the tracer depicted a differential CXCR4 expression, which was blocked in the presence of AMD3465, demonstrating the specificity of [18F]MCFB. Positron emission tomography (PET) imaging studies showed a distinct uptake of the radioprobe in lymphoma and breast cancer xenografts. High liver and kidney uptakes were seen with [18F]MCFB, leading us to further examine the basis of its pharmacokinetics in relation to the tracer's cationic nature and thus the role of organic cation transporters (OCTs). Substrate competition following the intravenous injection of metformin led to a marked decrease in the urinary excretion of [18F]MCFB, with moderate changes observed in other organs, including the liver. Our results suggest involvement of OCTs in the renal elimination of the tracer. In conclusion, the 18F-radiolabeled monocyclam, [18F]MCFB, has potential to detect tumor CXCR4 in nonhepatic tissues.
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Affiliation(s)
| | | | - Maciej A. Kaliszczak
- Cancer Imaging Centre, Department
of
Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, U.K.
| | - Chris Barnes
- Cancer Imaging Centre, Department
of
Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, U.K.
| | - Doreen Lau
- Cancer Imaging Centre, Department
of
Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, U.K.
| | - Laurence Carroll
- Cancer Imaging Centre, Department
of
Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, U.K.
| | - Elizabeth Stevens
- Cancer Imaging Centre, Department
of
Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, U.K.
| | - Sebastian Trousil
- Cancer Imaging Centre, Department
of
Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, U.K.
| | - Israt S. Alam
- Cancer Imaging Centre, Department
of
Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, U.K.
| | - Quang-Dé Nguyen
- Cancer Imaging Centre, Department
of
Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, U.K.
| | - Eric O. Aboagye
- Cancer Imaging Centre, Department
of
Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, U.K.
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15
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Mu W, Wang Z, Zöller M. Ping-Pong-Tumor and Host in Pancreatic Cancer Progression. Front Oncol 2019; 9:1359. [PMID: 31921628 PMCID: PMC6927459 DOI: 10.3389/fonc.2019.01359] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 11/18/2019] [Indexed: 12/12/2022] Open
Abstract
Metastasis is the main cause of high pancreatic cancer (PaCa) mortality and trials dampening PaCa mortality rates are not satisfying. Tumor progression is driven by the crosstalk between tumor cells, predominantly cancer-initiating cells (CIC), and surrounding cells and tissues as well as distant organs, where tumor-derived extracellular vesicles (TEX) are of major importance. A strong stroma reaction, recruitment of immunosuppressive leukocytes, perineural invasion, and early spread toward the peritoneal cavity, liver, and lung are shared with several epithelial cell-derived cancer, but are most prominent in PaCa. Here, we report on the state of knowledge on the PaCIC markers Tspan8, alpha6beta4, CD44v6, CXCR4, LRP5/6, LRG5, claudin7, EpCAM, and CD133, which all, but at different steps, are engaged in the metastatic cascade, frequently via PaCIC-TEX. This includes the contribution of PaCIC markers to TEX biogenesis, targeting, and uptake. We then discuss PaCa-selective features, where feedback loops between stromal elements and tumor cells, including distorted transcription, signal transduction, and metabolic shifts, establish vicious circles. For the latter particularly pancreatic stellate cells (PSC) are responsible, furnishing PaCa to cope with poor angiogenesis-promoted hypoxia by metabolic shifts and direct nutrient transfer via vesicles. Furthermore, nerves including Schwann cells deliver a large range of tumor cell attracting factors and Schwann cells additionally support PaCa cell survival by signaling receptor binding. PSC, tumor-associated macrophages, and components of the dysplastic stroma contribute to perineural invasion with signaling pathway activation including the cholinergic system. Last, PaCa aggressiveness is strongly assisted by the immune system. Although rich in immune cells, only immunosuppressive cells and factors are recovered in proximity to tumor cells and hamper effector immune cells entering the tumor stroma. Besides a paucity of immunostimulatory factors and receptors, immunosuppressive cytokines, myeloid-derived suppressor cells, regulatory T-cells, and M2 macrophages as well as PSC actively inhibit effector cell activation. This accounts for NK cells of the non-adaptive and cytotoxic T-cells of the adaptive immune system. We anticipate further deciphering the molecular background of these recently unraveled intermingled phenomena may turn most lethal PaCa into a curatively treatable disease.
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Affiliation(s)
- Wei Mu
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Wei Mu
| | - Zhe Wang
- Department of Oncology, The First Affiliated Hospital of Guangdong, Pharmaceutical University, Guangzhou, China
| | - Margot Zöller
- Department of Oncology, The First Affiliated Hospital of Guangdong, Pharmaceutical University, Guangzhou, China
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16
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Rezaeeyan H, Shirzad R, McKee TD, Saki N. Role of chemokines in metastatic niche: new insights along with a diagnostic and prognostic approach. APMIS 2018; 126:359-370. [PMID: 29676815 DOI: 10.1111/apm.12818] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Accepted: 01/04/2018] [Indexed: 01/10/2023]
Abstract
Chemokines are cytokines that are involved in the movement of leukocytes and the occurrence of immune responses. It has recently been noted that these cytokines play a role in the movement of cancer cells to different parts of the body and create a suitable environment [i.e. (pre) metastatic niche] for their growth and proliferation. We studied the role of chemokines in the metastasis of cancer cells, as well as their involvement in the proliferation and growth of these cells. Relevant literature was identified by a PubMed search (2005-2017) of English language papers using the terms 'chemokine,' 'metastasis niche,' and 'organotropism.' Based on the nature of cancer cells, the expression of chemokine receptors on these cells leads to metastasis to various organs, which ultimately causes changes in different signaling pathways. Finally, the targeting of chemokines on cancer cells could prevent the metastasis of cancer cells toward different organs.
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Affiliation(s)
- Hadi Rezaeeyan
- Research Center of Thalassemia & Hemoglobinopathy, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Reza Shirzad
- WHO-Collaborating Centre for Reference and Research on Rabies, Pasteur Institute of Iran, Tehran, Iran
| | - Trevor D McKee
- Princess Margaret Cancer Centre, STTARR Innovation Facility, Toronto, ON, Canada
| | - Najmaldin Saki
- Research Center of Thalassemia & Hemoglobinopathy, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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17
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MicroRNA-126 inhibits colon cancer cell proliferation and invasion by targeting the chemokine (C-X-C motif) receptor 4 and Ras homolog gene family, member A, signaling pathway. Oncotarget 2018; 7:60230-60244. [PMID: 27517626 PMCID: PMC5312381 DOI: 10.18632/oncotarget.11176] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 07/26/2016] [Indexed: 12/21/2022] Open
Abstract
MicroRNA-126 (miR-126) suppresses the migration, proliferation and invasion of colon cancer cells. However, the underlying mechanisms of miR-126 in colon cancer have not been fully elucidated. In this study, in vivo experiments revealed that miR-126 inhibits colon cancer growth and metastasis. Furthermore, miR-126 was down-regulated in human colon cancer tissue, and its expression was inversely correlated with TNM stage and metastasis of patients. Low level of miR-126 identified patients with poor prognosis. And we found that miR-126 expression was negatively correlated with the expression levels of chemokine (C-X-C motif) receptor 4 (CXCR4) and components of signaling pathway of Ras homolog gene family, member A (RhoA) in vitro and in vivo. Moreover, we verified that miR-126 negatively regulated CXCR4 and RhoA signaling in vitro. In addition, either in miR-126-overexpressing or in miR- 126-silenced colon cancer cells, the restoration of CXCR4 could significantly reverse the proliferation and invasion, as well as abolish the effects of miR-126 on RhoA signaling pathway. Collectively, these results demonstrated that miR-126 acts as a tumor suppressor by inactivating RhoA signaling via CXCR4 in colon cancer. And miR-126 may serve as a prognostic marker for monitoring and treating colon cancer.
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18
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Abstract
Distant metastasis during the advanced stage of malignant tumor progression can cause considerable morbidity in cancer patients. Bone is known to be one of the most common sites of distant metastasis in patients with breast cancer (BC). BC metastases in bone are associated with excessive skeletal complications. These complications can be fatal and reduce quality of life of patients. It is important to understand the metastatic process of BC to bone to improve quality of life and design new therapeutic methods. At present, the molecular mechanisms leading to the BC metastasis to bone are not fully understood. Studying the molecular basis of BC metastasis to bone might improve our insight into this complex process. In addition, it can provide novel approaches for designing advanced and effective targeted therapies. The present article aimed to review the published papers on the molecular basis of the metastatic process of BC to bone, focusing on involved genes and signaling networks. Furthermore, we propose potential therapeutic targets that may be more effective for the inhibition and treatment of BC metastasis to bone.
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19
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Cimadamore A, Scarpelli M, Piva F, Massari F, Gasparrini S, Doria A, Cheng L, Lopez-Beltran A, Montironi R. Activity of chemokines in prostate and renal tumors and their potential role as future therapeutic targets. Future Oncol 2017; 13:1105-1114. [PMID: 28147707 DOI: 10.2217/fon-2016-0481] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Chemokines are a class of low-molecular-weight proteins that induce chemotaxis and are implicated in the modulation of angiogenesis. The imbalance among angiogenic and antiangiogenic chemokines can promote the development of several conditions, including chronic inflammation, dysplastic transformation and cancer. In this review, we describe the activity and clinical significance of chemokines in prostate and renal tumors and provide an update on ongoing studies in this setting.
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Affiliation(s)
- Alessia Cimadamore
- Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy
| | - Marina Scarpelli
- Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy
| | - Francesco Piva
- Department of Specialist Clinical & Odontostomatological Sciences, Università Politecnica delle Marche, Ancona, Italy
| | | | - Silvia Gasparrini
- Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy
| | - Andrea Doria
- Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy
| | - Liang Cheng
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Antonio Lopez-Beltran
- Department of Surgery & Pathology, Faculty of Medicine, Cordoba University Medical School, Cordoba, Spain.,Champalimaud Clinical Center, Lisbon, Portugal
| | - Rodolfo Montironi
- Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy
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20
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Heiler S, Wang Z, Zöller M. Pancreatic cancer stem cell markers and exosomes - the incentive push. World J Gastroenterol 2016; 22:5971-6007. [PMID: 27468191 PMCID: PMC4948278 DOI: 10.3748/wjg.v22.i26.5971] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 06/03/2016] [Accepted: 06/28/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PaCa) has the highest death rate and incidence is increasing. Poor prognosis is due to late diagnosis and early metastatic spread, which is ascribed to a minor population of so called cancer stem cells (CSC) within the mass of the primary tumor. CSC are defined by biological features, which they share with adult stem cells like longevity, rare cell division, the capacity for self renewal, differentiation, drug resistance and the requirement for a niche. CSC can also be identified by sets of markers, which for pancreatic CSC (Pa-CSC) include CD44v6, c-Met, Tspan8, alpha6beta4, CXCR4, CD133, EpCAM and claudin7. The functional relevance of CSC markers is still disputed. We hypothesize that Pa-CSC markers play a decisive role in tumor progression. This is fostered by the location in glycolipid-enriched membrane domains, which function as signaling platform and support connectivity of the individual Pa-CSC markers. Outside-in signaling supports apoptosis resistance, stem cell gene expression and tumor suppressor gene repression as well as miRNA transcription and silencing. Pa-CSC markers also contribute to motility and invasiveness. By ligand binding host cells are triggered towards creating a milieu supporting Pa-CSC maintenance. Furthermore, CSC markers contribute to the generation, loading and delivery of exosomes, whereby CSC gain the capacity for a cell-cell contact independent crosstalk with the host and neighboring non-CSC. This allows Pa-CSC exosomes (TEX) to reprogram neighboring non-CSC towards epithelial mesenchymal transition and to stimulate host cells towards preparing a niche for metastasizing tumor cells. Finally, TEX communicate with the matrix to support tumor cell motility, invasion and homing. We will discuss the possibility that CSC markers are the initial trigger for these processes and what is the special contribution of CSC-TEX.
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21
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The Comparison of Adipose Stem Cell and Placental Stem Cell in Secretion Characteristics and in Facial Antiaging. Stem Cells Int 2016; 2016:7315830. [PMID: 27057176 PMCID: PMC4761676 DOI: 10.1155/2016/7315830] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Revised: 12/15/2015] [Accepted: 01/10/2016] [Indexed: 12/29/2022] Open
Abstract
Background. Mesenchymal stem cells are the most commonly used seed cells in biomedical research and tissue engineering. Their secretory proteins have also been proven to play an important role in tissue healing. Methods. We isolated adipose stem cells and placental stem cells and performed analysis examining characteristics. The secretory proteins were extracted from conditioned medium and analyzed by MALDI-TOF/TOF. The antiaging effect of conditioned mediums was evaluated by the results of facial skin application. Results. Adipose stem cells and placental stem cells were found to be very similar in their surface markers and multipotency. The specific proteins secreted from adipose stem cells were more adept at cell adhesion, migration, wound healing, and tissue remodeling, while the proteins secreted by placental stem cells were more adept at angiogenesis, cell proliferation, differentiation, cell survival, immunomodulation, and collagen degradation. While these two types of conditioned medium could improve the facial index, the improvement of Melanin index after injection of the adipose stem cell conditioned medium was much more significant. Conclusion. The results suggest that the secreted proteins are ideal cell-free substances for regeneration medicine, especially in the antiaging field.
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22
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Tulotta C, Stefanescu C, Beletkaia E, Bussmann J, Tarbashevich K, Schmidt T, Snaar-Jagalska BE. Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model. Dis Model Mech 2016; 9:141-53. [PMID: 26744352 PMCID: PMC4770151 DOI: 10.1242/dmm.023275] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 12/25/2015] [Indexed: 12/15/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes, including breast cancer metastasis. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in the formation of TNBC early metastases, we used the zebrafish xenograft model. Importantly, we demonstrate that cross-communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC. Summary: CXCR4-expressing human tumor cells respond to zebrafish cognate ligands and initiate metastatic events in a zebrafish xenograft model. The CXCR4 antagonist IT1t has promising tumor inhibitory effects.
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Affiliation(s)
- Claudia Tulotta
- Institute of Biology, Animal Sciences and Health, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
| | - Cristina Stefanescu
- Institute of Biology, Animal Sciences and Health, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
| | - Elena Beletkaia
- Physics of Life Processes, Kamerligh Onnes-Huygens Laboratory, Leiden University, Niels Bohrweg 2, Leiden 2333 CA, The Netherlands
| | - Jeroen Bussmann
- Institute of Biology, Animal Sciences and Health, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
| | | | - Thomas Schmidt
- Physics of Life Processes, Kamerligh Onnes-Huygens Laboratory, Leiden University, Niels Bohrweg 2, Leiden 2333 CA, The Netherlands
| | - B Ewa Snaar-Jagalska
- Institute of Biology, Animal Sciences and Health, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
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Disruption of Anti-tumor T Cell Responses by Cancer-Associated Fibroblasts. RESISTANCE TO TARGETED ANTI-CANCER THERAPEUTICS 2016. [DOI: 10.1007/978-3-319-42223-7_4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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24
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Hamal S, D'huys T, Rowley WF, Vermeire K, Aquaro S, Frost BJ, Schols D, Bell TW. Metal complexes of pyridine-fused macrocyclic polyamines targeting the chemokine receptor CXCR4. Org Biomol Chem 2015; 13:10517-26. [PMID: 26338723 DOI: 10.1039/c5ob01557j] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The chemokine receptor CXCR4 acts as a key cell surface receptor in HIV infections, multiple forms of cancer, and various other pathologies, such as rheumatoid arthritis and asthma. Macrocyclic polyamines and their metal complexes are known to exert anti-HIV activity, many acting as HIV entry inhibitors by specifically binding to CXCR4. Three series of pyridopentaazacylopentadecanes, in which the pyridine ring is fused to zero, one, or two saturated six-membered rings, were synthesized by manganese(ii)-templated Schiff-base cyclization of triethylenetetramine with various dicarbonyl compounds. By evaluating these macrocyclic polyamines and their complexes with Mn(2+), Cu(2+), Fe(3+), and Zn(2+), we have discovered novel CXCR4-binding compounds. The MnCl2 complex of a new pentaazacyclopentadecane with one fused carbocyclic ring (11) was found to have the greatest potency as an antagonist of the chemokine receptor CXCR4 (IC50: 0.014 μM), as evidenced by inhibiting binding of CXCL12 to PBMCs (peripheral blood mononuclear cells). Consequently, this compound inhibits replication of the CXCR4-using (X4) HIV-1 strain NL4-3 in the TZM-bl cell line with an IC50 value of 0.52 μM and low cytotoxicity (CC50: >100 μM). In addition, 18 other compounds were evaluated for their interaction with CXCR4 via their ability to interfere with ligand chemokine binding and HIV entry and infection. Of these, the metal complexes of the two more hydrophobic series with one or two fused carbocyclic rings exhibited the greatest potency. The Zn(2+) complex 21 was among the most potent, showing that redox activity of the metal center is not associated with CXCR4 antagonist activity.
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Affiliation(s)
- Sunil Hamal
- Department of Chemistry, University of Nevada, Reno, NV, USA.
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25
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Wang T, Han S, Wu Z, Han Z, Yan W, Liu T, Wei H, Song D, Zhou W, Yang X, Xiao J. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer. Biochem Biophys Res Commun 2015; 464:635-641. [PMID: 26166822 DOI: 10.1016/j.bbrc.2015.06.175] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 06/23/2015] [Indexed: 01/05/2023]
Abstract
Bone metastasis occurs in approximately 30-40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis.
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Affiliation(s)
- Ting Wang
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Shuai Han
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zhipeng Wu
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zhitao Han
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wangjun Yan
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Tielong Liu
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Haifeng Wei
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Dianwen Song
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wang Zhou
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
| | - Xinghai Yang
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
| | - Jianru Xiao
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
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26
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Gab1 regulates SDF-1-induced progression via inhibition of apoptosis pathway induced by PI3K/AKT/Bcl-2/BAX pathway in human chondrosarcoma. Tumour Biol 2015; 37:1141-9. [PMID: 26276357 DOI: 10.1007/s13277-015-3815-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 07/20/2015] [Indexed: 10/23/2022] Open
Abstract
In recent decades, the stromal cell-derived factor-l (SDF-1) and Gab1 have been investigated to be involved in oncogenesis. However, it is scarcely reported that SDF-1-Gab1 pathway mediates proliferation and apoptosis in human chondrosarcoma (CS). In this study, we assessed the expression of Gab1 in 90 CS solid tumors by immunohistochemistry, immunoblotting, and qRT-PCR, and then, some in vitro assays were also applied to CS cells treated with SDF-1. We observed that the overexpression of Gab1 was positively correlated with lung metastasis and recurrence, and acts as an independent prognostic factor for CS patients. Gab1 expression was up-regulated in response to SDF-1 stimulation in CS cell line JJ012, SW1353, L3252. Overexpression of Gab1 increased Bcl-2/BAX ratio to promote cell growth via PI3K/AKT. On the other hand, silencing of Gab1 accelerated apoptosis and repressed the growth of CS cells, which further caused the inhibition of G1/S phase transition and decreased invasion capacity in CS cell lines. In vivo assay identified that the knockdown of Gab1 interfered with the tumor mass formation. In conclusion, our data identified overexpression of Gab1 in CS tissues, and Gab1 can be recommended as a novel biomarker for diagnosis and prognosis in patients with CS. Additionally, PI3K/AKT/Bcl-2/BAX axis was involved in Gab1-induced CS progression, indicating Gab1 might act as a new target for the treatment of CS patients.
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27
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Ahmadzadeh A, Kast RE, Ketabchi N, Shahrabi S, Shahjahani M, Jaseb K, Saki N. Regulatory effect of chemokines in bone marrow niche. Cell Tissue Res 2015; 361:401-10. [DOI: 10.1007/s00441-015-2129-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 01/16/2015] [Indexed: 12/31/2022]
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28
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Hu XM, Liu YN, Zhang HL, Cao SB, Zhang T, Chen LP, Shen W. Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs-mediated neuroinflammation in bone cancer rats. J Neurochem 2015; 132:452-63. [DOI: 10.1111/jnc.12985] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Revised: 09/28/2014] [Accepted: 10/23/2014] [Indexed: 12/30/2022]
Affiliation(s)
- Xue-Ming Hu
- Department of Pain Medicine; The Affiliated Hospital of Xuzhou Medical College; Xuzhou China
| | - Yan-Nan Liu
- Jiangsu Province Key Laboratory of Anesthesiology; Xuzhou Medical College; Xuzhou China
| | - Hai-Long Zhang
- Jiangsu Province Key Laboratory of Anesthesiology; Xuzhou Medical College; Xuzhou China
| | - Shou-Bin Cao
- Jiangsu Province Key Laboratory of Anesthesiology; Xuzhou Medical College; Xuzhou China
| | - Ting Zhang
- Jiangsu Province Key Laboratory of Anesthesiology; Xuzhou Medical College; Xuzhou China
| | - Li-Ping Chen
- Department of Pain Medicine; The Affiliated Hospital of Xuzhou Medical College; Xuzhou China
| | - Wen Shen
- Department of Pain Medicine; The Affiliated Hospital of Xuzhou Medical College; Xuzhou China
- Jiangsu Province Key Laboratory of Anesthesiology; Xuzhou Medical College; Xuzhou China
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29
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Brandes AA, Franceschi E. The metastatic process: a kaleidoscope of concepts. Future Oncol 2014; 10:697-8. [PMID: 24799049 DOI: 10.2217/fon.14.32] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Alba A Brandes
- Department of Medical Oncology, Bellaria-Maggiore Hospital, Azienda USL, IRCCS Institute for Neurological Sciences, Bologna, Italy
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