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Rathi A, Chaudhury A, Anjum F, Ahmad S, Haider S, Khan ZF, Taiyab A, Chakrabarty A, Islam A, Hassan MI, Haque MM. Targeting prostate cancer via therapeutic targeting of PIM-1 kinase by Naringenin and Quercetin. Int J Biol Macromol 2024; 276:133882. [PMID: 39019373 DOI: 10.1016/j.ijbiomac.2024.133882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 07/08/2024] [Accepted: 07/13/2024] [Indexed: 07/19/2024]
Abstract
PIM-1 kinase belongs to the Ser/Thr kinases family, an attractive therapeutic target for prostate cancer. Here, we screened about 100 natural substances to find potential PIM-1 inhibitors. Two natural compounds, Naringenin and Quercetin, were finally selected based on their PIM-1 inhibitory potential and binding affinities. The docking score of Naringenin and Quercetin with PIM-1 is -8.4 and - 8.1 kcal/mol, respectively. Fluorescence binding studies revealed a strong affinity (Ka values, 3.1 × 104 M-1 and 4.6 × 107 M-1 for Naringenin and Quercetin, respectively) with excellent IC50 values for Naringenin and Quercetin (28.6 μM and 34.9 μM, respectively). Both compounds inhibited the growth of prostate cancer cells (LNCaP) in a dose-dependent manner, with the IC50 value of Naringenin at 17.5 μM and Quercetin at 8.88 μM. To obtain deeper insights into the PIM-1 inhibitory effect of Naringenin and Quercetin, we performed extensive molecular dynamics simulation studies, which provided insights into the binding mechanisms of PIM-1 inhibitors. Finally, Naringenin and Quercetin were suggested to serve as potent PIM-1 inhibitors, offering targeted treatments of prostate cancer. In addition, our findings may help to design novel Naringenin and Quercetin derivatives that could be effective in therapeutic targeting of prostate cancer.
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Affiliation(s)
- Aanchal Rathi
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Arunabh Chaudhury
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Farah Anjum
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, PO Box 11099, 21944 Taif, Saudi Arabia
| | - Shahbaz Ahmad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Shaista Haider
- Department of Life Sciences, School of Natural Sciences, Shiv Nadar Institution of Eminence Deemed to be University, NH91, Tehsil Dadri, Gautam Buddha Nagar, Uttar Pradesh 201314, India
| | - Zeba Firdos Khan
- Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Aaliya Taiyab
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Anindita Chakrabarty
- Department of Life Sciences, School of Natural Sciences, Shiv Nadar Institution of Eminence Deemed to be University, NH91, Tehsil Dadri, Gautam Buddha Nagar, Uttar Pradesh 201314, India
| | - Asimul Islam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.
| | - Mohammad Mahfuzul Haque
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.
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Valencia I, Nuzzo PV, Francini E, Ravera F, Fanelli GN, Bleve S, Scatena C, Marchionni L, Omar M. Gene Signature for Predicting Metastasis in Prostate Cancer Using Primary Tumor Expression Profiles. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.08.30.24312735. [PMID: 39252915 PMCID: PMC11383506 DOI: 10.1101/2024.08.30.24312735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Abstract
Prostate cancer (PCa) is currently the most commonly diagnosed cancer and second leading cause of cancer-related death in men in the United States. The development of metastases is associated with a poor prognosis in PCa patients. Since current clinicopathological classification schemes are unable to accurately prognosticate the risk of metastasis for those diagnosed with localized PCa, there is a pressing need for precise and easily attainable biomarkers of metastatic risk in these patients. Primary tumor samples from 1239 individuals with PCa were divided into development (n=1000) and validation (n=239) cohorts. In the development cohort, we utilized a meta-analysis workflow on retrospective primary tumor gene expression profiles to identify a subset of genes predictive of metastasis. For each gene, we computed Hedges' g effect size and combined their p-values using Fisher's combined probability test. We then adjusted for multiple hypothesis testing using the Benjamini-Hochberg method. Our developed gene signature, termed Meta-Score, achieved a robust performance at predicting metastasis from primary tumor gene expression profiles, with an AUC of 0.72 in the validation cohort. In addition to its robust predictive power, Meta-Score also demonstrated a significant prognostic utility in two independent cohorts. Specifically, patients with a higher risk-score had a significantly worse metastasis-free survival and progression-free survival compared to those with lower score. Multivariate cox proportional hazards model showed that Meta-Score is significantly associated with worse survival even after adjusting for Gleason score. Our findings suggest that our primary tumor transcriptional signature, Meta-Score, could be a valuable tool to assess the risk of metastasis in PCa patients with localized disease, pending validation in large prospective studies. Author Summary Metastasis is the leading cause of death in patients diagnosed with prostate cancer (PCa), underscoring the need for reliable prediction tools to forecast the risk of metastasis at an early stage. Here, we utilize the gene expression profiles of 1,000 unique primary tumors from patients with localized PCa to develop a gene signature capable of predicting metastasis. Our signature, termed Meta-Score, comprises forty-five genes that can accurately distinguish primary tumor with high propensity for metastasis across different patient cohorts. Notably, Meta-Score maintained its robust predictive performance in an internal validation cohort of comprising primary tumor samples from 239 patients. In addition to its robust predictive performance, Meta-Score demonstrates a significant association with survival, independent of Gleason score in two independent patient cohorts, underscoring its prognostic utility. Taken together, Meta-Score is a robust risk-stratification tool that can be leveraged to identify patients at high-risk of metastasis and unfavorable survival using their primary tumor gene expression profiles.
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Wang X, Yang C, Huang C, Wang W. Dysfunction of the carnitine cycle in tumor progression. Heliyon 2024; 10:e35961. [PMID: 39211923 PMCID: PMC11357771 DOI: 10.1016/j.heliyon.2024.e35961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 08/06/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024] Open
Abstract
The carnitine cycle is responsible for the transport of cytoplasmic fatty acids to the mitochondria for subsequent β-oxidation to maintain intracellular energy homeostasis. Recent studies have identified abnormalities in the carnitine cycle in various types of tumors; these abnormalities include the altered expression levels of carnitine cycle-related metabolic enzymes and transport proteins. Dysfunction of the carnitine cycle has been shown to influence tumorigenesis and progression by altering intracellular oxidative and inflammatory status or regulating tumor metabolic flexibility. Many therapeutic strategies targeting the carnitine cycle are actively being explored to modify the dysfunction of the carnitine cycle in patients with malignant tumors; such approaches include carnitine cycle-related enzyme inhibitors and exogenous carnitine supplementation. Therefore, here, we review the studies of carnitine in tumors, aiming to scientifically illustrate the dysfunction of the carnitine cycle in tumor progression and provide new ideas for further research.
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Affiliation(s)
- Xiangjun Wang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Chuanxin Yang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Chao Huang
- Department of Cell Biology, Medical School, Kunming University of Science and Technology, Kunming, 650500, China
| | - Wei Wang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
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Lan H, Wu B, Jin K, Chen Y. Beyond boundaries: unraveling innovative approaches to combat bone-metastatic cancers. Front Endocrinol (Lausanne) 2024; 14:1260491. [PMID: 38260135 PMCID: PMC10800370 DOI: 10.3389/fendo.2023.1260491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 12/12/2023] [Indexed: 01/24/2024] Open
Abstract
Evidence demonstrated that bones, liver, and lungs are the most common metastasis sites in some human malignancies, especially in prostate and breast cancers. Bone is the third most frequent target for spreading tumor cells among these organs and tissues. Patients with bone-metastatic cancers face a grim prognosis characterized by short median survival time. Current treatments have proven insufficient, as they can only inhibit metastasis or tumor progression within the bone tissues rather than providing a curative solution. Gaining a more profound comprehension of the interplay between tumor cells and the bone microenvironment (BME) is of utmost importance in tackling this issue. This knowledge will pave the way for developing innovative diagnostic and therapeutic approaches. This review summarizes the mechanisms underlying bone metastasis and discusses the clinical aspects of this pathologic condition. Additionally, it highlights emerging therapeutic interventions aimed at enhancing the quality of life for patients affected by bone-metastatic cancers. By synthesizing current research, this review seeks to shed light on the complexities of bone metastasis and offer insights for future advancements in patient care.
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Affiliation(s)
- Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Bo Wu
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hosptial, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Yefeng Chen
- Department of Respiratory Medicine, Shaoxing People’s Hospital, Shaoxing, Zhejiang, China
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Govindarajan B, Sbrissa D, Pressprich M, Kim S, Rishi AK, Vaishampayan U, Cher ML, Chinni SR. Adaptor proteins mediate CXCR4 and PI4KA crosstalk in prostate cancer cells and the significance of PI4KA in bone tumor growth. Sci Rep 2023; 13:20634. [PMID: 37996444 PMCID: PMC10667255 DOI: 10.1038/s41598-023-47633-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 11/16/2023] [Indexed: 11/25/2023] Open
Abstract
The chemokine receptor, CXCR4 signaling regulates cell growth, invasion, and metastasis to the bone-marrow niche in prostate cancer (PCa). Previously, we established that CXCR4 interacts with phosphatidylinositol 4-kinase IIIα (PI4KIIIα encoded by PI4KA) through its adaptor proteins and PI4KA overexpressed in the PCa metastasis. To further characterize how the CXCR4-PI4KIIIα axis promotes PCa metastasis, here we identify CXCR4 binds to PI4KIIIα adaptor proteins TTC7 and this interaction induce plasma membrane PI4P production in prostate cancer cells. Inhibiting PI4KIIIα or TTC7 reduces plasma membrane PI4P production, cellular invasion, and bone tumor growth. Using metastatic biopsy sequencing, we found PI4KA expression in tumors correlated with overall survival and contributes to immunosuppressive bone tumor microenvironment through preferentially enriching non-activated and immunosuppressive macrophage populations. Altogether we have characterized the chemokine signaling axis through CXCR4-PI4KIIIα interaction contributing to the growth of prostate cancer bone metastasis.
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Affiliation(s)
- Barani Govindarajan
- Department of Pathology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA
| | - Diego Sbrissa
- Department of Urology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Mark Pressprich
- Department of Urology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Seongho Kim
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
- Biostatistics and Bioinformatics Core, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Arun K Rishi
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Ulka Vaishampayan
- Department of Oncology, University of Michigan, 7217 Rogel Cancer Center, Ann Arbor, MI, USA
| | - Michael L Cher
- Department of Pathology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA
- Department of Urology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Sreenivasa R Chinni
- Department of Pathology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA.
- Department of Urology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA.
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA.
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Bao S, Darvishi M, H Amin A, Al-Haideri MT, Patra I, Kashikova K, Ahmad I, Alsaikhan F, Al-Qaim ZH, Al-Gazally ME, Kiasari BA, Tavakoli-Far B, Sidikov AA, Mustafa YF, Akhavan-Sigari R. CXC chemokine receptor 4 (CXCR4) blockade in cancer treatment. J Cancer Res Clin Oncol 2023; 149:7945-7968. [PMID: 36905421 DOI: 10.1007/s00432-022-04444-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 10/19/2022] [Indexed: 03/12/2023]
Abstract
CXC chemokine receptor type 4 (CXCR4) is a member of the G protein-coupled receptors (GPCRs) superfamily and is specific for CXC chemokine ligand 12 (CXCL12, also known as SDF-1), which makes CXCL12/CXCR4 axis. CXCR4 interacts with its ligand, triggering downstream signaling pathways that influence cell proliferation chemotaxis, migration, and gene expression. The interaction also regulates physiological processes, including hematopoiesis, organogenesis, and tissue repair. Multiple evidence revealed that CXCL12/CXCR4 axis is implicated in several pathways involved in carcinogenesis and plays a key role in tumor growth, survival, angiogenesis, metastasis, and therapeutic resistance. Several CXCR4-targeting compounds have been discovered and used for preclinical and clinical cancer therapy, most of which have shown promising anti-tumor activity. In this review, we summarized the physiological signaling of the CXCL12/CXCR4 axis and described the role of this axis in tumor progression, and focused on the potential therapeutic options and strategies to block CXCR4.
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Affiliation(s)
- Shunshun Bao
- The First Clinical Medical College, Xuzhou Medical University, 221000, Xuzhou, China
| | - Mohammad Darvishi
- Infectious Diseases and Tropical Medicine Research Center (IDTMRC), Department of Aerospace and Subaquatic Medicine, AJA University of Medicinal Sciences, Tehran, Iran
| | - Ali H Amin
- Deanship of Scientific Research, Umm Al-Qura University, 21955, Makkah, Saudi Arabia
- Zoology Department, Faculty of Science, Mansoura University, 35516, Mansoura, Egypt
| | - Maysoon T Al-Haideri
- Department of Physiotherapy, Cihan University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Indrajit Patra
- An Independent Researcher, National Institute of Technology Durgapur, Durgapur, West Bengal, India
| | | | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
| | | | | | - Bahman Abedi Kiasari
- Virology Department, Faculty of Veterinary Medicine, The University of Tehran, Tehran, Iran.
| | - Bahareh Tavakoli-Far
- Dietary Supplements and Probiotic Research Center, Alborz University of Medical Sciences, Karaj, Iran.
- Department of Physiology and Pharmacology, Faculty of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
| | - Akmal A Sidikov
- Rector, Ferghana Medical Institute of Public Health, Ferghana, Uzbekistan
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Tübingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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Jasuja H, Jaswandkar SV, Katti DR, Katti KS. Interstitial fluid flow contributes to prostate cancer invasion and migration to bone; study conducted using a novel horizontal flow bioreactor. Biofabrication 2023; 15:025017. [PMID: 36863017 PMCID: PMC10020972 DOI: 10.1088/1758-5090/acc09a] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 03/01/2023] [Indexed: 03/04/2023]
Abstract
Prostate cancer bone metastasis is the leading cause of cancer-related mortality in men in the United States, causing severe damage to skeletal tissue. The treatment of advanced-stage prostate cancer is always challenging due to limited drug treatment options, resulting in low survival rates. There is a scarcity of knowledge regarding the mechanisms associated with the effects of biomechanical cues by the interstitial fluid flow on prostate cancer cell growth and migration. We have designed a novel bioreactor system to demonstrate the impact of interstitial fluid flow on the migration of prostate cancer cells to the bone during extravasation. First, we demonstrated that a high flow rate induces apoptosis in PC3 cells via TGF-β1 mediated signaling; thus, physiological flow rate conditions are optimum for cell growth. Next, to understand the role of interstitial fluid flow in prostate cancer migration, we evaluated the migration rate of cells under static and dynamic conditions in the presence or absence of bone. We report that CXCR4 levels were not significantly changed under static and dynamic conditions, indicating that CXCR4 activation in PC3 cells is not influenced by flow conditions but by the bone, where CXCR4 levels were upregulated. The bone-upregulated CXCR4 levels led to increased MMP-9 levels resulting in a high migration rate in the presence of bone. In addition, upregulated levels ofαvβ3integrins under fluid flow conditions contributed to an overall increase in the migration rate of PC3 cells. Overall, this study demonstrates the potential role of interstitial fluid flow in prostate cancer invasion. Understanding the critical role of interstitial fluid flow in promoting prostate cancer cell progression will enhance current therapies for advanced-stage prostate cancer and provide improved treatment options for patients.
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Affiliation(s)
- Haneesh Jasuja
- Department of Civil, Construction and Environmental Engineering North Dakota State University, Fargo, ND 58108, United States of America
| | - Sharad V Jaswandkar
- Department of Civil, Construction and Environmental Engineering North Dakota State University, Fargo, ND 58108, United States of America
| | - Dinesh R Katti
- Department of Civil, Construction and Environmental Engineering North Dakota State University, Fargo, ND 58108, United States of America
| | - Kalpana S Katti
- Department of Civil, Construction and Environmental Engineering North Dakota State University, Fargo, ND 58108, United States of America
- Author to whom any correspondence should be addressed
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Baldessari C, Pipitone S, Molinaro E, Cerma K, Fanelli M, Nasso C, Oltrecolli M, Pirola M, D’Agostino E, Pugliese G, Cerri S, Vitale MG, Madeo B, Dominici M, Sabbatini R. Bone Metastases and Health in Prostate Cancer: From Pathophysiology to Clinical Implications. Cancers (Basel) 2023; 15:1518. [PMID: 36900309 PMCID: PMC10000416 DOI: 10.3390/cancers15051518] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/15/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
Clinically relevant bone metastases are a major cause of morbidity and mortality for prostate cancer patients. Distinct phenotypes are described: osteoblastic, the more common osteolytic and mixed. A molecular classification has been also proposed. Bone metastases start with the tropism of cancer cells to the bone through different multi-step tumor-host interactions, as described by the "metastatic cascade" model. Understanding these mechanisms, although far from being fully elucidated, could offer several potential targets for prevention and therapy. Moreover, the prognosis of patients is markedly influenced by skeletal-related events. They can be correlated not only with bone metastases, but also with "bad" bone health. There is a close correlation between osteoporosis-a skeletal disorder with decreased bone mass and qualitative alterations-and prostate cancer, in particular when treated with androgen deprivation therapy, a milestone in its treatment. Systemic treatments for prostate cancer, especially with the newest options, have improved the survival and quality of life of patients with respect to skeletal-related events; however, all patients should be evaluated for "bone health" and osteoporotic risk, both in the presence and in the absence of bone metastases. Treatment with bone-targeted therapies should be evaluated even in the absence of bone metastases, as described in special guidelines and according to a multidisciplinary evaluation.
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Affiliation(s)
- Cinzia Baldessari
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria of Modena, 41125 Modena, Italy
| | - Stefania Pipitone
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria of Modena, 41125 Modena, Italy
| | - Eleonora Molinaro
- Oncology, AUSL of Modena Area Sud, Sassuolo-Vignola-Pavullo, 41121 Modena, Italy
| | - Krisida Cerma
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV—IRCCS, 35128 Padova, Italy
| | - Martina Fanelli
- Department of Oncology, Azienda Ospedaliero Universitaria S. M. della Misericordia, 33100 Udine, Italy
| | - Cecilia Nasso
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria of Modena, 41125 Modena, Italy
- Medical Oncology, Ospedale Santa Corona, 17027 Pietra Ligure, Italy
| | - Marco Oltrecolli
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria of Modena, 41125 Modena, Italy
| | - Marta Pirola
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria of Modena, 41125 Modena, Italy
| | - Elisa D’Agostino
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria of Modena, 41125 Modena, Italy
| | - Giuseppe Pugliese
- Department of Oncology and Hematology, Univerity of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Sara Cerri
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria of Modena, 41125 Modena, Italy
| | - Maria Giuseppa Vitale
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria of Modena, 41125 Modena, Italy
| | - Bruno Madeo
- Unit of Endocrinology, Department of Medical Specialities, Azienda Ospedaliero Universitaria of Modena, 41125 Modena, Italy
| | - Massimo Dominici
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria of Modena, 41125 Modena, Italy
| | - Roberto Sabbatini
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria of Modena, 41125 Modena, Italy
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Govindarajan B, Sbrissa D, Pressprich M, Kim S, Vaishampayan U, Cher ML, Chinni S. Adaptor proteins mediate CXCR4 and PI4KA crosstalk in prostate cancer cells and the significance of PI4KA in bone tumor growth. RESEARCH SQUARE 2023:rs.3.rs-2590830. [PMID: 36865146 PMCID: PMC9980273 DOI: 10.21203/rs.3.rs-2590830/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
The chemokine receptor, CXCR4 signaling regulates cell growth, invasion, and metastasis to the bone-marrow niche in prostate cancer (PCa). Previously, we established that CXCR4 interacts with phosphatidylinositol 4-kinase IIIα (PI4KIIIα encoded by PI4KA) through its adaptor proteins and PI4KA overexpressed in the PCa metastasis. To further characterize how the CXCR4-PI4KIIIα axis promotes PCa metastasis, here we identify CXCR4 binds to PI4KIIIα adaptor proteins TTC7 and this interaction induce plasma membrane PI4P production in prostate cancer cells. Inhibiting PI4KIIIα or TTC7 reduces plasma membrane PI4P production, cellular invasion, and bone tumor growth. Using metastatic biopsy sequencing, we found PI4KA expression in tumors correlated with overall survival and contributes to immunosuppressive bone tumor microenvironment through preferentially enriching non-activated and immunosuppressive macrophage populations. Altogether we have characterized the chemokine signaling axis through CXCR4-PI4KIIIα interaction contributing to the growth of prostate cancer bone metastasis.
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10
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Advances in Molecular Regulation of Prostate Cancer Cells by Top Natural Products of Malaysia. Curr Issues Mol Biol 2023; 45:1536-1567. [PMID: 36826044 PMCID: PMC9954984 DOI: 10.3390/cimb45020099] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023] Open
Abstract
Prostate cancer (PCa) remains both a global health burden and a scientific challenge. We present a review of the molecular targets driving current drug discovery to fight this disease. Moreover, the preventable nature of most PCa cases represents an opportunity for phytochemicals as chemopreventive when adequately integrated into nutritional interventions. With a renovated interest in natural remedies as a commodity and their essential role in cancer drug discovery, Malaysia is looking towards capitalizing on its mega biodiversity, which includes the oldest rainforest in the world and an estimated 1200 medicinal plants. We here explore whether the list of top Malay plants prioritized by the Malaysian government may fulfill the potential of becoming newer, sustainable sources of prostate cancer chemotherapy. These include Andrographis paniculate, Centella asiatica, Clinacanthus nutans, Eurycoma longifolia, Ficus deltoidea, Hibiscus sabdariffa, Marantodes pumilum (syn. Labisia pumila), Morinda citrifolia, Orthosiphon aristatus, and Phyllanthus niruri. Our review highlights the importance of resistance factors such as Smac/DIABLO in cancer progression, the role of the CXCL12/CXCR4 axis in cancer metastasis, and the regulation of PCa cells by some promising terpenes (andrographolide, Asiatic acid, rosmarinic acid), flavonoids (isovitexin, gossypin, sinensetin), and alkylresorcinols (labisiaquinones) among others.
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Johnson CS, Cook LM. Osteoid cell-derived chemokines drive bone-metastatic prostate cancer. Front Oncol 2023; 13:1100585. [PMID: 37025604 PMCID: PMC10070788 DOI: 10.3389/fonc.2023.1100585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 03/07/2023] [Indexed: 04/08/2023] Open
Abstract
One of the greatest challenges in improving prostate cancer (PCa) survival is in designing new therapies to effectively target bone metastases. PCa regulation of the bone environment has been well characterized; however, bone-targeted therapies have little impact on patient survival, demonstrating a need for understanding the complexities of the tumor-bone environment. Many factors contribute to creating a favorable microenvironment for prostate tumors in bone, including cell signaling proteins produced by osteoid cells. Specifically, there has been extensive evidence from both past and recent studies that emphasize the importance of chemokine signaling in promoting PCa progression in the bone environment. Chemokine-focused strategies present promising therapeutic options for treating bone metastasis. These signaling pathways are complex, with many being produced by (and exerting effects on) a plethora of different cell types, including stromal and tumor cells of the prostate tumor-bone microenvironment. This review highlights an underappreciated molecular family that should be interrogated for treatment of bone metastatic prostate cancer (BM-PCa).
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Affiliation(s)
- Catherine S. Johnson
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
- Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE, United States
| | - Leah M. Cook
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
- *Correspondence: Leah M. Cook,
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Heidary Z, Haghjooy Javanmard S, Izadi I, Zare N, Ghaisari J. Multiscale modeling of collective cell migration elucidates the mechanism underlying tumor-stromal interactions in different spatiotemporal scales. Sci Rep 2022; 12:16242. [PMID: 36171274 PMCID: PMC9519582 DOI: 10.1038/s41598-022-20634-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 09/15/2022] [Indexed: 11/09/2022] Open
Abstract
Metastasis is the pathogenic spread of cancer cells from a primary tumor to a secondary site which happens at the late stages of cancer. It is caused by a variety of biological, chemical, and physical processes, such as molecular interactions, intercellular communications, and tissue-level activities. Complex interactions of cancer cells with their microenvironment components such as cancer associated fibroblasts (CAFs) and extracellular matrix (ECM) cause them to adopt an invasive phenotype that promotes tumor growth and migration. This paper presents a multiscale model for integrating a wide range of time and space interactions at the molecular, cellular, and tissue levels in a three-dimensional domain. The modeling procedure starts with presenting nonlinear dynamics of cancer cells and CAFs using ordinary differential equations based on TGFβ, CXCL12, and LIF signaling pathways. Unknown kinetic parameters in these models are estimated using hybrid unscented Kalman filter and the models are validated using experimental data. Then, the principal role of CAFs on metastasis is revealed by spatial-temporal modeling of circulating signals throughout the TME. At this stage, the model has evolved into a coupled ODE-PDE system that is capable of determining cancer cells' status in one of the quiescent, proliferating or migratory conditions due to certain metastasis factors and ECM characteristics. At the tissue level, we consider a force-based framework to model the cancer cell proliferation and migration as the final step towards cancer cell metastasis. The ability of the multiscale model to depict cancer cells' behavior in different levels of modeling is confirmed by comparing its outputs with the results of RT PCR and wound scratch assay techniques. Performance evaluation of the model indicates that the proposed multiscale model can pave the way for improving the efficiency of therapeutic methods in metastasis prevention.
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Affiliation(s)
- Zarifeh Heidary
- Department of Electrical and Computer Engineering, Isfahan University of Technology, Isfahan, 84156-83111, Iran
| | - Shaghayegh Haghjooy Javanmard
- Department of Physiology, Applied Physiology Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
| | - Iman Izadi
- Department of Electrical and Computer Engineering, Isfahan University of Technology, Isfahan, 84156-83111, Iran
| | - Nasrin Zare
- School of Medicine, Najafabad Branch, Islamic Azad University, Isfahan, Iran
| | - Jafar Ghaisari
- Department of Electrical and Computer Engineering, Isfahan University of Technology, Isfahan, 84156-83111, Iran.
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13
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Candido S, Tomasello B, Lavoro A, Falzone L, Gattuso G, Russo A, Paratore S, McCubrey JA, Libra M. Bioinformatic analysis of the LCN2-SLC22A17-MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment. Front Cell Dev Biol 2022; 10:945586. [PMID: 36211450 PMCID: PMC9532607 DOI: 10.3389/fcell.2022.945586] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/24/2022] [Indexed: 11/13/2022] Open
Abstract
Several features of cancer cells such as proliferation, invasion, metastatic spreading, and drug resistance are affected by their interaction with several tumor microenvironment (TME) components, including neutrophil gelatinase-associated lipocalin (NGAL), solute carrier family 22 member 17 (SLC22A17), and matrix metallopeptidase 9 (MMP9). These molecules play a key role in tumor growth, invasion, and iron-dependent metabolism of cancer cells. However, the precise epigenetic mechanisms underlying the gene regulation of Lipocalin 2 (LCN2), SLC22A17, and MMP9 in cancer still remain unclear. To this purpose, computational analysis was performed on TCGA and GTEx datasets to evaluate the expression and DNA methylation status of LCN2, SLC22A17, and MMP9 genes in different tumor types. Correlation analysis between gene/isoforms expression and DNA methylation levels of LCN2, SLC22A17, and MMP9 was performed to investigate the role of DNA methylation in the modulation of these genes. Protein network analysis was carried out using reverse phase protein arrays (RPPA) data to identify protein-protein interactions of the LCN2-SLC22A17-MMP9 network. Furthermore, survival analysis was performed according to gene expression and DNA methylation levels. Our results demonstrated that LCN2 and MMP9 were mainly upregulated in most tumor types, whereas SLC22A17 was largely downregulated, representing a specific hallmark signature for all gastrointestinal tumors. Notably, the expression of LCN2, SLC22A17, and MMP9 genes was negatively affected by promoter methylation. Conversely, intragenic hypermethylation was associated with the overexpression of SLC22A17 and MMP9 genes. Protein network analysis highlighted the role of the LCN2-SLC22A17-MMP9 network in TME by the interaction with fibronectin 1 and claudin 7, especially in rectal tumors. Moreover, the impact of expression and methylation status of LCN2, SLC22A17, and MMP9 on overall survival and progression free interval was tumor type-dependent. Overall, our analyses provide a detailed overview of the expression and methylation status of LCN2, SLC22A17, and MMP9 in all TCGA tumors, indicating that the LCN2-SLC22A17-MMP9 network was strictly regulated by DNA methylation within TME. Our findings pave the way for the identification of novel DNA methylation hotspots with diagnostic and prognostic values and suitable for epi-drug targeting.
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Affiliation(s)
- Saverio Candido
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, Catania, Italy
| | - Barbara Tomasello
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
| | - Alessandro Lavoro
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Luca Falzone
- Epidemiology Unit, IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, Italy
| | - Giuseppe Gattuso
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Angela Russo
- Pathological Anatomy Unit, ARNAS Garibaldi Hospital, Catania, Italy
| | - Sabrina Paratore
- Pathological Anatomy Unit, ARNAS Garibaldi Hospital, Catania, Italy
| | - James A. McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, Catania, Italy
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14
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Chen C, Huang R, Zhou J, Guo L, Xiang S. Formation of pre-metastatic bone niche in prostate cancer and regulation of traditional chinese medicine. Front Pharmacol 2022; 13:897942. [PMID: 36059977 PMCID: PMC9428453 DOI: 10.3389/fphar.2022.897942] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 07/06/2022] [Indexed: 11/24/2022] Open
Abstract
Prostate cancer with bone metastasis has a high cancer-specific mortality. Thus, it is essential to delineate the mechanism of bone metastasis. Pre-metastatic niche (PMN) is a concept in tumor metastasis, which is characterized by tumor-secreted factors, reprogramming of stromal cells, and immunosuppression by myeloid-derived suppressor cells (MDSC), which is induced by bone marrow-derived cells (BMDC) in the target organ. However, PMN does not explain the predilection of prostate cancer towards bone metastasis. In this review, we discuss the initiation of bone metastasis of prostate cancer from the perspective of PMN and tumor microenvironment in a step-wise manner. Furthermore, we present a new concept called pre-metastatic bone niche, featuring inherent BMDC, to interpret bone metastasis. Moreover, we illustrate the regulation of traditional Chinese medicine on PMN.
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15
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Parol-Kulczyk M, Gzil A, Ligmanowska J, Grzanka D. Prognostic significance of SDF-1 chemokine and its receptors CXCR4 and CXCR7 involved in EMT of prostate cancer. Cytokine 2021; 150:155778. [PMID: 34920230 DOI: 10.1016/j.cyto.2021.155778] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 10/18/2021] [Accepted: 11/18/2021] [Indexed: 12/11/2022]
Abstract
Tendency to conversion from state of chronic inflammation to malignancy is a tumor characteristic trait, which encourages progression to its metastatic stage.. The inflammatory cells maintaining in the tumor inaugurate a communication with cancer cells and become tumor-fostering cells. Epithelial-mesenchymal transition (EMT) is a program supporting malignant cells during switch phenotype into metastatic form, providing looseness of cell-cell adherence and strengthens migratory or invasive features. EMT-undergone tumor cells become more aggressive and resistant to apoptosis. Additionally, malignant cells can be stimulated to manufacture proinflammatory factors throughout EMT program. Chronic inflammation is responsible for EMT induction in malignancies. Developed tumors induce inflammatory response through excretion of cytokines, chemokines and growth factors, which recruit populations of infiltrating immune cells straight to the tumor microenvironment. The inflammatory reaction potentially exerts tumor control, but instead it can be intercepted by the tumor to stimulate its own development in direction to metastatic form. Our study confirmed that SDF-1 chemokine and its receptors, CXCR4 and CXCR7 may participate in initiation of metastases formation and EMT process.
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Affiliation(s)
- Martyna Parol-Kulczyk
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland.
| | - Arkadiusz Gzil
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland.
| | - Joanna Ligmanowska
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland.
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland.
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16
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Midavaine É, Côté J, Sarret P. The multifaceted roles of the chemokines CCL2 and CXCL12 in osteophilic metastatic cancers. Cancer Metastasis Rev 2021; 40:427-445. [PMID: 33973098 DOI: 10.1007/s10555-021-09974-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/30/2021] [Indexed: 02/06/2023]
Abstract
Breast and prostate cancers have a great propensity to metastasize to long bones. The development of bone metastases is life-threatening, incurable, and drastically reduces patients' quality of life. The chemokines CCL2 and CXCL12 and their respective receptors, CCR2 and CXCR4, are central instigators involved in all stages leading to cancer cell dissemination and secondary tumor formation in distant target organs. They orchestrate tumor cell survival, growth and migration, tumor invasion and angiogenesis, and the formation of micrometastases in the bone marrow. The bone niche is of particular importance in metastasis formation, as it expresses high levels of CCL2 and CXCL12, which attract tumor cells and contribute to malignancy. The limited number of available effective treatment strategies highlights the need to better understand the pathophysiology of bone metastases and reduce the skeletal tumor burden in patients diagnosed with metastatic bone disease. This review focuses on the involvement of the CCL2/CCR2 and CXCL12/CXCR4 chemokine axes in the formation and development of bone metastases, as well as on therapeutic perspectives aimed at targeting these chemokine-receptor pairs.
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Affiliation(s)
- Élora Midavaine
- Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, QC, Canada. .,Centre de recherche du Centre hospitalier universitaire de Sherbrooke, CIUSSS de l'Estrie - CHUS, Sherbrooke, QC, Canada.
| | - Jérôme Côté
- Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, QC, Canada.,Centre de recherche du Centre hospitalier universitaire de Sherbrooke, CIUSSS de l'Estrie - CHUS, Sherbrooke, QC, Canada
| | - Philippe Sarret
- Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, QC, Canada.,Centre de recherche du Centre hospitalier universitaire de Sherbrooke, CIUSSS de l'Estrie - CHUS, Sherbrooke, QC, Canada
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17
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Hinz N, Jücker M. AKT in Bone Metastasis of Solid Tumors: A Comprehensive Review. Cancers (Basel) 2021; 13:cancers13102287. [PMID: 34064589 PMCID: PMC8151478 DOI: 10.3390/cancers13102287] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/05/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Bone metastasis is a frequent complication of solid tumors and leads to a reduced overall survival. Although much progress has been made in the field of tumor therapy in the last years, bone metastasis depicts a stage of the disease with a lack of appropriate therapeutical options. Hence, this review aims to present the role of AKT in bone metastasis of solid tumors to place the spotlight on AKT as a possible therapeutical approach for patients with bone metastases. Furthermore, we intended to discuss postulated underlying molecular mechanisms of the bone metastasis-promoting effect of AKT, especially in highly bone-metastatic breast, prostate, and lung cancer. To conclude, this review identified the AKT kinase as a potential therapeutical target in bone metastasis and revealed remaining questions, which need to be addressed in further research projects. Abstract Solid tumors, such as breast cancer and prostate cancer, often form bone metastases in the course of the disease. Patients with bone metastases frequently develop complications, such as pathological fractures or hypercalcemia and exhibit a reduced life expectancy. Thus, it is of vital importance to improve the treatment of bone metastases. A possible approach is to target signaling pathways, such as the PI3K/AKT pathway, which is frequently dysregulated in solid tumors. Therefore, we sought to review the role of the serine/threonine kinase AKT in bone metastasis. In general, activation of AKT signaling was shown to be associated with the formation of bone metastases from solid tumors. More precisely, AKT gets activated in tumor cells by a plethora of bone-derived growth factors and cytokines. Subsequently, AKT promotes the bone-metastatic capacities of tumor cells through distinct signaling pathways and secretion of bone cell-stimulating factors. Within the crosstalk between tumor and bone cells, also known as the vicious cycle, the stimulation of osteoblasts and osteoclasts also causes activation of AKT in these cells. As a consequence, bone metastasis is reduced after experimental inhibition of AKT. In summary, AKT signaling could be a promising therapeutical approach for patients with bone metastases of solid tumors.
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18
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Inhibition of glypican-1 expression induces an activated fibroblast phenotype in a human bone marrow-derived stromal cell-line. Sci Rep 2021; 11:9262. [PMID: 33927256 PMCID: PMC8084937 DOI: 10.1038/s41598-021-88519-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 04/13/2021] [Indexed: 11/25/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are the most abundant stromal cell type in the tumor microenvironment. CAFs orchestrate tumor-stromal interactions, and contribute to cancer cell growth, metastasis, extracellular matrix (ECM) remodeling, angiogenesis, immunomodulation, and chemoresistance. However, CAFs have not been successfully targeted for the treatment of cancer. The current study elucidates the significance of glypican-1 (GPC-1), a heparan sulfate proteoglycan, in regulating the activation of human bone marrow-derived stromal cells (BSCs) of fibroblast lineage (HS-5). GPC-1 inhibition changed HS-5 cellular and nuclear morphology, and increased cell migration and contractility. GPC-1 inhibition also increased pro-inflammatory signaling and CAF marker expression. GPC-1 induced an activated fibroblast phenotype when HS-5 cells were exposed to prostate cancer cell conditioned media (CCM). Further, treatment of human bone-derived prostate cancer cells (PC-3) with CCM from HS-5 cells exhibiting GPC-1 loss increased prostate cancer cell aggressiveness. Finally, GPC-1 was expressed in mouse tibia bone cells and present during bone loss induced by mouse prostate cancer cells in a murine prostate cancer bone model. These data demonstrate that GPC-1 partially regulates the intrinsic and extrinsic phenotype of human BSCs and transformation into activated fibroblasts, identify novel functions of GPC-1, and suggest that GPC-1 expression in BSCs exerts inhibitory paracrine effects on the prostate cancer cells. This supports the hypothesis that GPC-1 may be a novel pharmacological target for developing anti-CAF therapeutics to control cancer.
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19
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Roosen K, Scheld M, Mandzhalova M, Clarner T, Beyer C, Zendedel A. CXCL12 inhibits inflammasome activation in LPS-stimulated BV2 cells. Brain Res 2021; 1763:147446. [PMID: 33766517 DOI: 10.1016/j.brainres.2021.147446] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 10/21/2022]
Abstract
The activation of the CXCL12-CXCR4 signaling axis is implicated in the regulation of cell survival, proliferation, and mobilization of bone marrow stem cells into the injured site. We have shown in a previous study that intrathecal administration of CXCL12 reduces spinal cord tissue damage and neuroinflammation and provides functional improvement by reducing inflammasome activity and local inflammatory processes in an experimental spinal cord injury (SCI) rat model. Here, we aimed at investigating whether these neuroprotective effects rely on the control of CXCL12 signaling on microglial activation as microglia cells are known to be the primary immune cells of the brain. LPS induced the expression of the inflammasome components NLRP3, NLRC4 and ASC, the secretion of the cytokines IL-1b and IL-18 and the activation of caspase-1 protease in BV2 cells. Pre-treatment with CXCL12 significantly reduced LPS-induced IL-1b/IL-18 secretion and inflammasome induction. Our results also showed that CXCL12 can suppress caspase-1 activity, which leads to a decrease of SCI-related induction of active IL-1b.
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Affiliation(s)
- Kenza Roosen
- Institute of Neuroanatomy, RWTH Aachen University, 52074 Aachen, Germany
| | - Miriam Scheld
- Anatomy and Cell Biology, University of Augsburg, 86159 Augsburg, Germany
| | | | - Tim Clarner
- Institute of Neuroanatomy, RWTH Aachen University, 52074 Aachen, Germany
| | - Cordian Beyer
- Institute of Neuroanatomy, RWTH Aachen University, 52074 Aachen, Germany
| | - Adib Zendedel
- Institute of Neuroanatomy, RWTH Aachen University, 52074 Aachen, Germany.
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20
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Transcriptomic Analysis of LNCaP Tumor Xenograft to Elucidate the Components and Mechanisms Contributed by Tumor Environment as Targets for Dietary Prostate Cancer Prevention Studies. Nutrients 2021; 13:nu13031000. [PMID: 33808801 PMCID: PMC8003580 DOI: 10.3390/nu13031000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 03/09/2021] [Accepted: 03/11/2021] [Indexed: 11/24/2022] Open
Abstract
LNCaP athymic xenograft model has been widely used to allow researchers to examine the effects and mechanisms of experimental treatments such as diet and diet-derived cancer preventive and therapeutic compounds on prostate cancer. However, the biological characteristics of human LNCaP cells before/after implanting in athymic mouse and its relevance to clinical human prostate outcomes remain unclear and may dictate interpretation of biological efficacies/mechanisms of diet/diet-derived experimental treatments. In this study, transcriptome profiles and pathways of human prostate LNCaP cells before (in vitro) and after (in vivo) implanting into xenograft mouse were compared using RNA-sequencing technology (RNA-seq) followed by bioinformatic analysis. A shift from androgen-responsive to androgen nonresponsive status was observed when comparing LNCaP xenograft tumor to culture cells. Androgen receptor and aryl-hydrocarbon pathway were found to be inhibited and interleukin-1 (IL-1) mediated pathways contributed to these changes. Coupled with in vitro experiments modeling for androgen exposure, cell-matrix interaction, inflammation, and hypoxia, we identified specific mechanisms that may contribute to the observed changes in genes and pathways. Our results provide critical baseline transcriptomic information for a tumor xenograft model and the tumor environments that might be associated with regulating the progression of the xenograft tumor, which may influence interpretation of diet/diet-derived experimental treatments.
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21
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Qin Y, Wang F, Ni H, Liu Y, Yin Y, Zhou X, Gao G, Li Q, Qi X, Li J. Cancer-associated fibroblasts in gastric cancer affect malignant progression via the CXCL12-CXCR4 axis. J Cancer 2021; 12:3011-3023. [PMID: 33854601 PMCID: PMC8040897 DOI: 10.7150/jca.49707] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 02/28/2021] [Indexed: 12/23/2022] Open
Abstract
Background: Cancer-associated fibroblasts (CAFs) are principal constituents of the tumor microenvironment (TME) and play a critical role in tumor progression. The CXCL12/CXCR4 axis regulates multiple facets of the TME. The aim of this study was to determine the relationship between CXCL12 expression in CAFs and the malignant progression of gastric cancer (GC). Methods: In the GEO (Gene Expression Omnibus) database, we performed transcriptome analysis on paired gastric cancer RNA sequencing samples, and scRNA analysis was performed on advanced malignant GC samples from the scRNA sequencing data set. Fibroblast cells were co-cultured with GC cells, and invasion, migration, epithelial-mesenchymal transformation (EMT) were determined. After blocking the expression of fibroblast CXCL12, cells were co-cultured with a GC cell line. Detection of GC cell line invasion, migration, EMT and CXCR4, Wnt5a and β-Catenin expression levels was performed. Primary CAFs and gastric normal fibroblasts were isolated and CXCL12 mRNA and protein expression were determined. In addition, a cohort of 285 GC cases was established, protein expression was evaluated immunohistochemically, and prognostic results were analyzed. Results: GC transcriptome analysis suggested that cytokine-cytokine receptor interaction and the Wnt signaling pathway in GC tissues were significantly up-regulated. scRNA analysis of advanced malignant GC samples showed that severe intestinal metaplasia (SIM) in GC specimens of different malignant grades had obvious fibroblast clusters compared to non-atrophic gastritis (NAG) and early gastric cancer (EGC). In the SIM group, fibroblast cluster, CXCL12, CXCR4, and Wnt5a were overexpressed. Co-culturing with fibroblast cells significantly increased the invasion, migration, and EMT of GC cells, and blocking CXCL12 in CAFs disturbed the expression of Wnt5a and β-catenin. In our cohort of GC patients, high CXCL12 expression in CAFs significantly correlated with histological grade (P = 0.012) and TNM stage (P = 0.014), as well as with poor overall survival (p = 0.0107). Conclusion: High expression of CXCL12 in CAFs in a GC microenvironment can affect the migration, invasion, and EMT of GC cells. Furthermore, it can cause poor prognosis in patients with GC.
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Affiliation(s)
- Yan Qin
- Department of Pathology, Medical College of Soochow University, Soochow University, Suzhou, China.,Department of Pathology, the Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Fang Wang
- Jiangnan University School of Medicine, Wuxi, China
| | - Hengli Ni
- Department of Pathology, Medical College of Soochow University, Soochow University, Suzhou, China
| | - Yao Liu
- Department of Pathology, Medical College of Soochow University, Soochow University, Suzhou, China
| | - Yuan Yin
- Wuxi Oncology Institute, the Affiliated Hospital of Jiangnan University, Wuxi China
| | - Xinyi Zhou
- Department of Pathology, the Affiliated Hospital of Jiangnan University, Wuxi, China.,Jiangnan University School of Medicine, Wuxi, China
| | - Guihua Gao
- Department of Pathology, the Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Qing Li
- Department of Oncology, The Second Affiliated Hospital of Soochow University Suzhou, China
| | - Xiaowei Qi
- Department of Pathology, the Affiliated Hospital of Jiangnan University, Wuxi, China.,Jiangnan University School of Medicine, Wuxi, China
| | - Jianming Li
- Department of Pathology, Medical College of Soochow University, Soochow University, Suzhou, China
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22
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Dietrich K, Fiedler IA, Kurzyukova A, López-Delgado AC, McGowan LM, Geurtzen K, Hammond CL, Busse B, Knopf F. Skeletal Biology and Disease Modeling in Zebrafish. J Bone Miner Res 2021; 36:436-458. [PMID: 33484578 DOI: 10.1002/jbmr.4256] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 01/15/2021] [Accepted: 01/20/2021] [Indexed: 12/13/2022]
Abstract
Zebrafish are teleosts (bony fish) that share with mammals a common ancestor belonging to the phylum Osteichthyes, from which their endoskeletal systems have been inherited. Indeed, teleosts and mammals have numerous genetically conserved features in terms of skeletal elements, ossification mechanisms, and bone matrix components in common. Yet differences related to bone morphology and function need to be considered when investigating zebrafish in skeletal research. In this review, we focus on zebrafish skeletal architecture with emphasis on the morphology of the vertebral column and associated anatomical structures. We provide an overview of the different ossification types and osseous cells in zebrafish and describe bone matrix composition at the microscopic tissue level with a focus on assessing mineralization. Processes of bone formation also strongly depend on loading in zebrafish, as we elaborate here. Furthermore, we illustrate the high regenerative capacity of zebrafish bones and present some of the technological advantages of using zebrafish as a model. We highlight zebrafish axial and fin skeleton patterning mechanisms, metabolic bone disease such as after immunosuppressive glucocorticoid treatment, as well as osteogenesis imperfecta (OI) and osteopetrosis research in zebrafish. We conclude with a view of why larval zebrafish xenografts are a powerful tool to study bone metastasis. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Kristin Dietrich
- Center for Regenerative Therapies TU Dresden (CRTD), Center for Healthy Aging TU Dresden, Dresden, Germany
| | - Imke Ak Fiedler
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anastasia Kurzyukova
- Center for Regenerative Therapies TU Dresden (CRTD), Center for Healthy Aging TU Dresden, Dresden, Germany
| | - Alejandra C López-Delgado
- Center for Regenerative Therapies TU Dresden (CRTD), Center for Healthy Aging TU Dresden, Dresden, Germany
| | - Lucy M McGowan
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Karina Geurtzen
- Center for Regenerative Therapies TU Dresden (CRTD), Center for Healthy Aging TU Dresden, Dresden, Germany
| | - Chrissy L Hammond
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Björn Busse
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Interdisciplinary Competence Center for Interface Research (ICCIR), Hamburg, Germany
| | - Franziska Knopf
- Center for Regenerative Therapies TU Dresden (CRTD), Center for Healthy Aging TU Dresden, Dresden, Germany
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23
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Colón-Marrero S, Jusino S, Rivera-Rivera Y, Saavedra HI. Mitotic kinases as drivers of the epithelial-to-mesenchymal transition and as therapeutic targets against breast cancers. Exp Biol Med (Maywood) 2021; 246:1036-1044. [PMID: 33601912 DOI: 10.1177/1535370221991094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Biological therapies against breast cancer patients with tumors positive for the estrogen and progesterone hormone receptors and Her2 amplification have greatly improved their survival. However, to date, there are no effective biological therapies against breast cancers that lack these three receptors or triple-negative breast cancers (TNBC). TNBC correlates with poor survival, in part because they relapse following chemo- and radio-therapies. TNBC is intrinsically aggressive since they have high mitotic indexes and tend to metastasize to the central nervous system. TNBCs are more likely to display centrosome amplification, an abnormal phenotype that results in defective mitotic spindles and abnormal cytokinesis, which culminate in aneuploidy and chromosome instability (known causes of tumor initiation and chemo-resistance). Besides their known role in cell cycle control, mitotic kinases have been also studied in different types of cancer including breast, especially in the context of epithelial-to-mesenchymal transition (EMT). EMT is a cellular process characterized by the loss of cell polarity, reorganization of the cytoskeleton, and signaling reprogramming (upregulation of mesenchymal genes and downregulation of epithelial genes). Previously, we and others have shown the effects of mitotic kinases like Nek2 and Mps1 (TTK) on EMT. In this review, we focus on Aurora A, Aurora B, Bub1, and highly expressed in cancer (Hec1) as novel targets for therapeutic interventions in breast cancer and their effects on EMT. We highlight the established relationships and interactions of these and other mitotic kinases, clinical trial studies involving mitotic kinases, and the importance that represents to develop drugs against these proteins as potential targets in the primary care therapy for TNBC.
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Affiliation(s)
- Stephanie Colón-Marrero
- Department of Basic Sciences, Division of Pharmacology and Cancer Biology, 6650Ponce Health Sciences University/Ponce Research Institute, Ponce, PR 00732, USA
| | - Shirley Jusino
- Department of Basic Sciences, Division of Pharmacology and Cancer Biology, 6650Ponce Health Sciences University/Ponce Research Institute, Ponce, PR 00732, USA
| | - Yainyrette Rivera-Rivera
- Department of Basic Sciences, Division of Pharmacology and Cancer Biology, 6650Ponce Health Sciences University/Ponce Research Institute, Ponce, PR 00732, USA
| | - Harold I Saavedra
- Department of Basic Sciences, Division of Pharmacology and Cancer Biology, 6650Ponce Health Sciences University/Ponce Research Institute, Ponce, PR 00732, USA
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24
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Samaržija I. Post-Translational Modifications That Drive Prostate Cancer Progression. Biomolecules 2021; 11:247. [PMID: 33572160 PMCID: PMC7915076 DOI: 10.3390/biom11020247] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/04/2021] [Accepted: 02/06/2021] [Indexed: 02/07/2023] Open
Abstract
While a protein primary structure is determined by genetic code, its specific functional form is mostly achieved in a dynamic interplay that includes actions of many enzymes involved in post-translational modifications. This versatile repertoire is widely used by cells to direct their response to external stimuli, regulate transcription and protein localization and to keep proteostasis. Herein, post-translational modifications with evident potency to drive prostate cancer are explored. A comprehensive list of proteome-wide and single protein post-translational modifications and their involvement in phenotypic outcomes is presented. Specifically, the data on phosphorylation, glycosylation, ubiquitination, SUMOylation, acetylation, and lipidation in prostate cancer and the enzymes involved are collected. This type of knowledge is especially valuable in cases when cancer cells do not differ in the expression or mutational status of a protein, but its differential activity is regulated on the level of post-translational modifications. Since their driving roles in prostate cancer, post-translational modifications are widely studied in attempts to advance prostate cancer treatment. Current strategies that exploit the potential of post-translational modifications in prostate cancer therapy are presented.
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Affiliation(s)
- Ivana Samaržija
- Laboratory for Epigenomics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
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25
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Hagaman DE, Damasco JA, Perez JVD, Rojo RD, Melancon MP. Recent Advances in Nanomedicine for the Diagnosis and Treatment of Prostate Cancer Bone Metastasis. Molecules 2021; 26:E384. [PMID: 33450939 PMCID: PMC7828457 DOI: 10.3390/molecules26020384] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/07/2021] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Patients with advanced prostate cancer can develop painful and debilitating bone metastases. Currently available interventions for prostate cancer bone metastases, including chemotherapy, bisphosphonates, and radiopharmaceuticals, are only palliative. They can relieve pain, reduce complications (e.g., bone fractures), and improve quality of life, but they do not significantly improve survival times. Therefore, additional strategies to enhance the diagnosis and treatment of prostate cancer bone metastases are needed. Nanotechnology is a versatile platform that has been used to increase the specificity and therapeutic efficacy of various treatments for prostate cancer bone metastases. In this review, we summarize preclinical research that utilizes nanotechnology to develop novel diagnostic imaging tools, translational models, and therapies to combat prostate cancer bone metastases.
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Affiliation(s)
- Daniel E. Hagaman
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.E.H.); (J.A.D.); (J.V.D.P.); (R.D.R.)
| | - Jossana A. Damasco
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.E.H.); (J.A.D.); (J.V.D.P.); (R.D.R.)
| | - Joy Vanessa D. Perez
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.E.H.); (J.A.D.); (J.V.D.P.); (R.D.R.)
- College of Medicine, University of the Philippines, Manila NCR 1000, Philippines
| | - Raniv D. Rojo
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.E.H.); (J.A.D.); (J.V.D.P.); (R.D.R.)
- College of Medicine, University of the Philippines, Manila NCR 1000, Philippines
| | - Marites P. Melancon
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.E.H.); (J.A.D.); (J.V.D.P.); (R.D.R.)
- UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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Singh AK, Roy NK, Bordoloi D, Padmavathi G, Banik K, Khwairakpam AD, Kunnumakkara AB, Sukumar P. Orai-1 and Orai-2 regulate oral cancer cell migration and colonisation by suppressing Akt/mTOR/NF-κB signalling. Life Sci 2020; 261:118372. [PMID: 32882268 DOI: 10.1016/j.lfs.2020.118372] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 08/17/2020] [Accepted: 08/28/2020] [Indexed: 12/24/2022]
Abstract
Despite remarkable progress in understanding and treating oral cancer (OC), it still remains one of the life-threatening diseases and predominant cancers in the world. Therefore, deciphering the molecular mechanisms of this disease would help us to develop highly efficacious therapies. Multiple lines of evidence suggest that calcium and its dysregulation play significant role in the development of various cancers. As an adaptation of survival mechanism, upon depletion of ER calcium stores, store-operated calcium entry (SOCE) has been induced via SOCE channels (SOCC) in various mammalian cells. SOCC are regulated by Orai-1, Orai-2 and Orai-3 located on plasma membrane and two calcium-sensing ER membrane proteins known as stromal interaction molecules (STIM-1 and STIM-2). Hence, the present study was aimed at analysing the role of Orai-1 and Orai-2 in oral cancer and the underlying mechanism. Our results suggest that both Orai-1 and Orai-2 proteins were overexpressed in oral cancer tissues and cell lines (SAS) compared to normal epithelial tissues and cell lines respectively. In addition, silencing of Orai-1 and Orai-2 via chemical SOCE inhibitors and siRNAs inhibited calcium uptake and suppressed oral cancer cell proliferation, colony formation and migration. Furthermore, silencing of Orai-1 and Orai-2 inhibited Akt/mTOR/NF-κB pathway in oral cancer cells. Interestingly, tobacco carcinogen NNN and synthetic carcinogen 4-NQO, enhanced the expression of Orai-1 and Orai-2 in SAS cells. Therefore, we conclude that Orai-1 and Orai-2 have significant role in oral cancer and can be further explored to develop novel therapies for the treatment of this disease.
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Affiliation(s)
- Anuj Kumar Singh
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Nand Kishor Roy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Devivasha Bordoloi
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Ganesan Padmavathi
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Kishore Banik
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Amrita Devi Khwairakpam
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India.
| | - Piruthivi Sukumar
- Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
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Cellular and Molecular Progression of Prostate Cancer: Models for Basic and Preclinical Research. Cancers (Basel) 2020; 12:cancers12092651. [PMID: 32957478 PMCID: PMC7563251 DOI: 10.3390/cancers12092651] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/10/2020] [Accepted: 09/11/2020] [Indexed: 02/08/2023] Open
Abstract
Simple Summary The molecular progression of prostate cancer is complex and elusive. Biological research relies heavily on in vitro and in vivo models that can be used to examine gene functions and responses to the external agents in laboratory and preclinical settings. Over the years, several models have been developed and found to be very helpful in understanding the biology of prostate cancer. Here we describe these models in the context of available information on the cellular and molecular progression of prostate cancer to suggest their potential utility in basic and preclinical prostate cancer research. The information discussed herein should serve as a hands-on resource for scholars engaged in prostate cancer research or to those who are making a transition to explore the complex biology of prostate cancer. Abstract We have witnessed noteworthy progress in our understanding of prostate cancer over the past decades. This basic knowledge has been translated into efficient diagnostic and treatment approaches leading to the improvement in patient survival. However, the molecular pathogenesis of prostate cancer appears to be complex, and histological findings often do not provide an accurate assessment of disease aggressiveness and future course. Moreover, we also witness tremendous racial disparity in prostate cancer incidence and clinical outcomes necessitating a deeper understanding of molecular and mechanistic bases of prostate cancer. Biological research heavily relies on model systems that can be easily manipulated and tested under a controlled experimental environment. Over the years, several cancer cell lines have been developed representing diverse molecular subtypes of prostate cancer. In addition, several animal models have been developed to demonstrate the etiological molecular basis of the prostate cancer. In recent years, patient-derived xenograft and 3-D culture models have also been created and utilized in preclinical research. This review is an attempt to succinctly discuss existing information on the cellular and molecular progression of prostate cancer. We also discuss available model systems and their tested and potential utility in basic and preclinical prostate cancer research.
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Powell IJ, Chinni SR, Reddy SS, Zaslavsky A, Gavande N. Pro-inflammatory cytokines and chemokines initiate multiple prostate cancer biologic pathways of cellular proliferation, heterogeneity and metastasis in a racially diverse population and underlie the genetic/biologic mechanism of racial disparity: Update. Urol Oncol 2020; 39:34-40. [PMID: 32900629 DOI: 10.1016/j.urolonc.2020.08.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/24/2020] [Accepted: 08/10/2020] [Indexed: 01/27/2023]
Abstract
Pro-inflammatory cytokine and chemokines genes drive prostate cancer progression and metastasis: molecular mechanism update and the science that underlies racial disparity. comprehensive review article. Isaac J. Powell, S. Chinni, S.S. Reddy, Alexander Zaslavsky, Navnath Gavande Introduction: In 2013 we reported that with the use of bioinformatics and ingenuity pathway network analysis we were able to identify functional driver genes that were differentially expressed among a large population of African American men (AAM) and European American men (EAM). Pro-inflammatory cytokine genes were found to be more interactive and more expressed among AAM and have been found to be functional drivers of aggressive prostate cancer (CaP) and aggressiveness in other solid tumors. We examined these genes and biological pathways initiated by these cytokines in primary CaP tissue. Method We unravel the gene network and identified biologic pathways that impacted activation of the androgen receptor, mesenchymal epithelial transition (invasion) and chemokines associated with metastasis in the CaP tissue from 639 radical prostatectomy specimens. Results Biologic pathways identified by unraveling pro-inflammatory genes from our network, more expressed among AAM compared to EAM, were tumor necrosis factor (TNF), IL1b, IL6, and IL8. IL6 and IL8 are downstream of TNF activity and are known activators of androgen receptor and through mediators promote CaP cell proliferation. TNF and IL1b mediate tumor cell invasiveness through the activation of MMP (matrix metalloproteinase) which down regulates E-Cadherin to initiate epithelial mesenchymal transition which allows cells to become invasive in the microenvironment. Ultimately our network analysis indicates that TNF and IL1b activate CXCR4 receptor on CaP cells, which facilitates metastatic progression reportedly by binding to CXCL12 on lipid rafts and tumor implantation in the bone marrow. Conclusion Our retrospective biologic mechanistic model reveals a set of pro-inflammatory cytokines and chemokines that drive CaP aggressiveness, tumor heterogeneity, progression and metastasis. A prospective multi-institutional study needs to be conducted for clinical validation as well consideration of targeted therapy.
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Affiliation(s)
- Isaac J Powell
- Department of Urology, Wayne State University, Detroit, Mi. USA.
| | | | - Sunil S Reddy
- Department of Urology, Wayne State University, Detroit, Mi. USA
| | | | - Navnath Gavande
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI. USA
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Wang M, Xia F, Wei Y, Wei X. Molecular mechanisms and clinical management of cancer bone metastasis. Bone Res 2020; 8:30. [PMID: 32793401 PMCID: PMC7391760 DOI: 10.1038/s41413-020-00105-1] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 09/03/2019] [Accepted: 10/23/2019] [Indexed: 02/05/2023] Open
Abstract
As one of the most common metastatic sites of malignancies, bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish. The fenestrated capillaries in the bone, bone matrix, and bone cells, including osteoblasts and osteoclasts, together maintain the homeostasis of the bone microenvironment. In contrast, tumor-derived factors act on bone components, leading to subsequent bone resorption or excessive bone formation. The various pathways involved also provide multiple targets for therapeutic strategies against bone metastases. In this review, we summarize the current understanding of the mechanism of bone metastases. Based on the general process of bone metastases, we specifically highlight the complex crosstalk between tumor cells and the bone microenvironment and the current management of cancer bone metastases.
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Affiliation(s)
- Manni Wang
- Laboratory of Aging Research and Cancer Drug Targets, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan P.R. China
| | - Fan Xia
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan P.R. China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Targets, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan P.R. China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Targets, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan P.R. China
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Identification of Matrine as a Novel Regulator of the CXCR4 Signaling Axis in Tumor Cells. Int J Mol Sci 2020; 21:ijms21134731. [PMID: 32630806 PMCID: PMC7370290 DOI: 10.3390/ijms21134731] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/29/2020] [Accepted: 06/30/2020] [Indexed: 12/22/2022] Open
Abstract
Matrine, a quinolizidine alkaloid, is commonly employed for treating various viral and inflammatory disorders. Here, we have evaluated matrine for its activity on C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinases (MMP-9/2) expression, and its potential to affect tumor metastasis and invasion. The effects of matrine on CXCR4, MMP-9/2, and nuclear factor κB (NF-κB) activation in lung (A549), prostate (DU145), and pancreas (MIA PaCa-2) cells were investigated by diverse techniques. The expression level of CXCR4 and MMP-9/2 was analyzed by western blot analysis and reverse transcription polymerase chain reaction. NF-κB activation was also evaluated by western blot analysis, electrophoretic mobility shift assay as well as immunocytochemical experiments. Furthermore, we monitored cell invasion and metastasis activities by wound healing and Boyden chamber assays. We noted that matrine induced a down-regulation of CXCR4 and MMP-9/2 at both protein and mRNA levels. In addition, matrine negatively regulated human epidermal growth factor receptor 2 (HER2) and C-X-C Motif Chemokine Ligand 12 (CXCL12)-induced CXCR4 expression. Moreover, NF-κB suppression by matrine led to inhibition of metastatic potential of tumor cells. Our results suggest that matrine can block the cancer metastasis through the negative regulation of CXCR4 and MMP-9/2 and consequently it can be considered as a potential candidate for cancer therapy.
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31
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Barillari G. The Impact of Matrix Metalloproteinase-9 on the Sequential Steps of the Metastatic Process. Int J Mol Sci 2020; 21:ijms21124526. [PMID: 32630531 PMCID: PMC7350258 DOI: 10.3390/ijms21124526] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/20/2020] [Accepted: 06/23/2020] [Indexed: 02/07/2023] Open
Abstract
In industrialized countries, cancer is the second leading cause of death after cardiovascular disease. Most cancer patients die because of metastases, which consist of the self-transplantation of malignant cells in anatomical sites other than the one from where the tumor arose. Disseminated cancer cells retain the phenotypic features of the primary tumor, and display very poor differentiation indices and functional regulation. Upon arrival at the target organ, they replace preexisting, normal cells, thereby permanently compromising the patient's health; the metastasis can, in turn, metastasize. The spread of cancer cells implies the degradation of the extracellular matrix by a variety of enzymes, among which the matrix metalloproteinase (MMP)-9 is particularly effective. This article reviews the available published literature concerning the important role that MMP-9 has in the metastatic process. Additionally, information is provided on therapeutic approaches aimed at counteracting, or even preventing, the development of metastasis via the use of MMP-9 antagonists.
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Affiliation(s)
- Giovanni Barillari
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 1 via Montpellier, 00133 Rome, Italy
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32
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Cytokines and Chemokines as Mediators of Prostate Cancer Metastasis. Int J Mol Sci 2020; 21:ijms21124449. [PMID: 32585812 PMCID: PMC7352203 DOI: 10.3390/ijms21124449] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/19/2020] [Accepted: 06/21/2020] [Indexed: 12/16/2022] Open
Abstract
The consequences of prostate cancer metastasis remain severe, with huge impact on the mortality and overall quality of life of affected patients. Despite the convoluted interplay and cross talk between various cell types and secreted factors in the metastatic process, cytokine and chemokines, along with their receptors and signaling axis, constitute important factors that help drive the sequence of events that lead to metastasis of prostate cancer. These proteins are involved in extracellular matrix remodeling, epithelial-mesenchymal-transition, angiogenesis, tumor invasion, premetastatic niche creation, extravasation, re-establishment of tumor cells in secondary organs as well as the remodeling of the metastatic tumor microenvironment. This review presents an overview of the main cytokines/chemokines, including IL-6, CXCL12, TGFβ, CXCL8, VEGF, RANKL, CCL2, CX3CL1, IL-1, IL-7, CXCL1, and CXCL16, that exert modulatory roles in prostate cancer metastasis. We also provide extensive description of their aberrant expression patterns in both advanced disease states and metastatic sites, as well as their functional involvement in the various stages of the prostate cancer metastatic process.
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Hryniewicz-Jankowska A, Augoff K, Sikorski AF. The role of cholesterol and cholesterol-driven membrane raft domains in prostate cancer. Exp Biol Med (Maywood) 2020; 244:1053-1061. [PMID: 31573840 DOI: 10.1177/1535370219870771] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Membrane rafts are heterogeneous and dynamic domains that are characterized by tight packing of lipids. They are enriched in cholesterol, sphingolipids, and certain types of proteins. Among these are various cell signaling proteins, which indicate that rafts play an important role in cell signal transduction pathways, including some involved in cancer development, progression, and invasiveness. Due to their increased cholesterol content, raft domains exhibit lower fluidity than the surrounding membrane. The cell membranes of some solid tumors, such as breast and prostate cancer, contain higher levels of cholesterol, which means larger raft domain can form in those membranes. This may stimulate signaling pathways to promote tumor growth and progression. This review focuses on the known raft-dependent regulatory mechanisms that promote prostate cancer progression.Impact statementProstate cancer remains the most common malignancy and second most frequent cause of cancer-related death in men. Cholesterol levels are usually higher in prostate cancer cells. This affects the cell membrane composition, with cholesterol and sphingolipid-containing raft membrane domains becoming a greater component. In addition to polar lipids, these domains recruit and regulate certain types of protein, including various cell signaling proteins that are critical to cancer cell survival and invasiveness. This suggests that membrane rafts have a regulatory role in tumor progression, making them a potential target in prostate cancer treatment.
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Affiliation(s)
| | - Katarzyna Augoff
- Department of Surgical Education, Wrocław Medical University, Wroclaw 50-369, Poland
| | - Aleksander F Sikorski
- Department of Cytobiochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw 50-383, Poland
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Shirjang S, Mansoori B, Mohammadi A, Shajari N, H G Duijf P, Najafi S, Abedi Gaballu F, Nofouzi K, Baradaran B. miR-330 Regulates Colorectal Cancer Oncogenesis by Targeting BACH1. Adv Pharm Bull 2020; 10:444-451. [PMID: 32665904 PMCID: PMC7335988 DOI: 10.34172/apb.2020.054] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 11/28/2019] [Accepted: 12/08/2019] [Indexed: 12/24/2022] Open
Abstract
Purpose: Based on WHO report, colorectal cancer (CRC) is the second cause of death among patients with cancer worldwide. Dysregulation of miRNAs expressions has been demonstrated in different human cancers, especially CRC. Studies have shown that miR-330 could act as both TS-miR and/or oncomiR in different types of cancers. BACH1 is also identified as a transcription factor, which is involved in ontogenesis. In this study, we evaluated the CRC suppression via silencing of BACH1 by small silencer molecule called miR-330. Methods: Firstly, we analyzed the BACH1, miR-330-3p and miR-330-5p expressions according to the colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) project established from a patient of the colon and rectal cancer patients in The Cancer Genome Atlas (TCGA) database. The targeting of BACH1 via miR-330 in human CRC cells was evaluated by Vejnar bioinformatics methods, and confirmed by qRT-PCR and western blot analysis. Proliferation was performed by MTT assay. The MMP9, CXCR4, and VEGFR proteins were measured by western blotting. Results: The analysis of BACH1, miR-330-3p, and miR-330-5p expressions according to the COAD and READ projects showed that BACH1 was overexpressed, but miR-330-3p and miR330-5p were reduced in CRC tumors compared to normal controls. The miR-330 induction prevented proliferation of CRC cell by targeting BACH1 mRNA, which represses MMP9, C-X-C chemokine receptor type 4 (CXCR4), and vascular endothelial growth factor receptor (VEGFR) proteins expressions. Conclusion: Our results suggested that BACH1 is a potential target for miR-330 in CRC cells. The miR-330 induction inhibits CRC cells proliferation by suppressing BACH1 expression in posttranscriptional level. It was suggested that targeting of BACH1 via miRNA such as miR-330 could be a valid strategy in the field of CRC targeted therapy via modulating the oncogenic signaling pathway.
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Affiliation(s)
- Solmaz Shirjang
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Shajari
- Department of Immunology, School of Medicine, Shiraz University of Medical Science, Shiraz, Iran
| | - Pascal H G Duijf
- University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Katayoon Nofouzi
- Department of Pathobiology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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35
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Aghajani M, Mokhtarzadeh A, Aghebati-Maleki L, Mansoori B, Mohammadi A, Safaei S, Asadzadeh Z, Hajiasgharzadeh K, Khaze Shahgoli V, Baradaran B. CD133 suppression increases the sensitivity of prostate cancer cells to paclitaxel. Mol Biol Rep 2020; 47:3691-3703. [PMID: 32246247 DOI: 10.1007/s11033-020-05411-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 03/26/2020] [Indexed: 12/18/2022]
Abstract
One of the major barriers in cancer therapy is the resistance to conventional therapies and cancer stem cells (CSCs) are among the main causes of this problem. CD133 as a CSC marker displays stem cell-like properties, tumorigenic capacity, and drug resistance in various cancers. However, the molecular mechanism behind CD133 function in prostate cancer (PC) still remains unclear. This research aimed to illustrate the probabilistic mechanism of CD133-siRNA and paclitaxel in the reduction of chemoresistance in PC cells. To measure the cell viability, migratory capacity, CSCs properties, invasive potential, apoptosis and cell cycle progression of the cells, the MTT, wound healing, spheroid assay, colony formation assay, DAPI staining and flow cytometry assays were applied in the LNCaP cell line, respectively. Also, quantitative real-time PCR (qRT-PCR) and western blot method were used for measuring the expression of CD133 and the effects of CD133 silencing on the AKT/mTOR/c-myc axis and pro-metastatic genes expression. We showed that the CD133-siRNA considerably decreased the CD133 expression. Moreover, CD133-siRNA and paclitaxel treatment significantly decreased cell proliferation and also inhibited the ability of cell migration and invasion and reduced pro-metastatic genes expression. Additionally, we found that the simultaneous use of CD133-siRNA and paclitaxel increased the paclitaxel-induced apoptosis. Our results confirmed that CD133 silencing combined with paclitaxel synergistically could suppress cell migration, invasion, and proliferation and enhance the chemosensitivity compared with mono treatment. Therefore, CD133 silencing therapy could be viewed as a promising and efficient strategy in PC targeted therapies.
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Affiliation(s)
- Marjan Aghajani
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran
| | - Leili Aghebati-Maleki
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran
| | - Behzad Mansoori
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Ali Mohammadi
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran
| | - Khalil Hajiasgharzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran
| | - Vahid Khaze Shahgoli
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran.
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Lu W, He Z, Shi J, Wang Z, Wu W, Liu J, Kang H, Li F, Liang S. AMD3100 Attenuates Post-Traumatic Osteoarthritis by Maintaining Transforming Growth Factor-β1-Induced Expression of Tissue Inhibitor of Metalloproteinase-3 via the Phosphatidylinositol 3-Kinase/Akt Pathway. Front Pharmacol 2020; 10:1554. [PMID: 32038242 PMCID: PMC6987846 DOI: 10.3389/fphar.2019.01554] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 12/02/2019] [Indexed: 12/20/2022] Open
Abstract
AMD3100 is a small-molecule inhibitor of the C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4 (CXCL12/CXCR4) axis, while its role in aggrecan metabolism is unclear. We hypothesized that the AMD3100 modulates the transforming growth factor-β1 (TGF-β1)-induced expression of tissue inhibitor of metalloproteinase-3 (TIMP-3) in chondrocytes. We evaluated expression of CXCL12/CXCR4 and TIMP-3 in the knee joints of rats with and without osteoarthritis (OA) by immunohistochemistry, immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay (ELISA). The rats were divided into sham control, destabilization of the medial meniscus/AMD3100-treated (DMM/AMD3100-treated), and DMM/phosphate-buffered saline (PBS)-treated groups. After 6 weeks, the rats were euthanized and subjected to histological and immunohistochemical analyses. Also, interleukin (IL)-1-pretreated primary chondrocytes were cultured in the presence of empty control (−, −), CXCL12a (+,−), CXCL12a + small interfering RNA (siRNA) CXCR4 (+,+), or CXCL12a + siNC (+NC), and the expression levels of target markers were evaluated by Western blotting and real-time reverse transcription PCR (RT-PCR). The CXCL12/CXCR4 levels were higher, and the expression of TIMP-3 was lower, in the OA rats compared to the healthy control rats. The rats in the DMM/AMD3100-treated group revealed a markedly decreased immunological response and mild pathology. Treatment with CXCL12a increased expression of aggrecan and disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) and suppressed that of TIMP-3 in IL-1-pretreated primary chondrocytes. TGF-β1 increased expression of TIMP-3, and this increase was reversed by CXCL12a via the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Moreover, these effects were inhibited by the CXCR4 antagonist AMD3100 and the PI3K inhibitor LY303511. In conclusion, inhibition of the CXCL12a/CXCR4 signaling axis maintained TIMP-3 expression via the PI3K/Akt pathway. Our findings provide insight into the mechanism by which AMD3100 prevents OA.
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Affiliation(s)
- Weiwei Lu
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiyi He
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Shi
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenggang Wang
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wu
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Liu
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Kang
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Li
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuang Liang
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Yu L, Pham Q, Yu LL, Wang TTY. Modulation of CXC-motif chemokine receptor 7, but not 4, expression is related to migration of the human prostate cancer cell LNCaP: regulation by androgen and inflammatory stimuli. Inflamm Res 2019; 69:167-178. [PMID: 31865399 DOI: 10.1007/s00011-019-01305-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 11/08/2019] [Accepted: 12/05/2019] [Indexed: 01/23/2023] Open
Abstract
OBJECTIVE To elucidate the regulation, function of the chemokine CXC-motif ligand 12 (CXCL12) and its receptors (CXCR) 4 and 7 in prostate cancer tumor microenvironment. MATERIAL In-silico-analysis of expression in prostate cancer tissues. In-vitro comparison, testing of regulation in human prostate cancer cells LNCaP, DU145, and PC3. TREATMENT Dihydrotestosterone (DHT) treatments (0-10 nM) were for 0-48 h. The inflammatory agent Flagellin treatment (20 ng/ml) was for 2 h. Migration assays were performed for 24 h using 10 ng/ml CXCL12. METHODS Real-time PCR, western analysis, and migration assays were used to determine mRNA, protein, and functional changes, respectively. RESULTS Malignant prostate cancer tissues exhibit higher CXCR4/7 mRNA ratio, and higher CXCR7 mRNA levels were detected in the androgen-responsive LNCaP cells. Putative androgen-responsive elements were identified in CXCR4, 7 gene, and exposure to DHT, flagellin increased CXCR4 mRNA but decreased CXCR7 mRNA levels in LNCaP cells. Androgen receptor siRNA significantly attenuated the effects of DHT on CXCR4, 7 mRNA in LNCaP cells. However, DHT and flagellin only decrease CXCR7 protein and additively increased migration of LNCaP cells towards CXCL12. CONCLUSIONS Down regulation of CXCR7 protein by DHT and flagellin increased migration, supporting CXCR7 as decoy receptor counteracting CXCL12/CXCR4-mediated migration in prostate cancer cells.
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Affiliation(s)
- Lu Yu
- Department of Nutrition and Food Science, University of Maryland, College Park, MD, 20742, USA
| | - Quynhchi Pham
- Diet, Genomics and Immunology Laboratory, Beltsville Human Nutrition Research Center, ARS, USDA, 10300 Baltimore Ave., Bldg. 307C, Rm 132, Beltsville, MD, 20705, USA
| | - Liangli Lucy Yu
- Department of Nutrition and Food Science, University of Maryland, College Park, MD, 20742, USA
| | - Thomas T Y Wang
- Diet, Genomics and Immunology Laboratory, Beltsville Human Nutrition Research Center, ARS, USDA, 10300 Baltimore Ave., Bldg. 307C, Rm 132, Beltsville, MD, 20705, USA.
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Baci D, Bruno A, Cascini C, Gallazzi M, Mortara L, Sessa F, Pelosi G, Albini A, Noonan DM. Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:464. [PMID: 31718684 PMCID: PMC6852951 DOI: 10.1186/s13046-019-1461-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 10/21/2019] [Indexed: 01/04/2023]
Abstract
Background Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. Methods The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. Results We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. Conclusions Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible “repurposed agent’ for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.
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Affiliation(s)
- Denisa Baci
- School of Medicine and Surgery, University of Milano-Bicocca, Building U8, Via Cadore 48, 20900, Monza, Italy
| | - Antonino Bruno
- Science and Technology Pole (PST), IRCCS MultiMedica, Milan, Italy
| | - Caterina Cascini
- Science and Technology Pole (PST), IRCCS MultiMedica, Milan, Italy
| | - Matteo Gallazzi
- Science and Technology Pole (PST), IRCCS MultiMedica, Milan, Italy
| | - Lorenzo Mortara
- Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Fausto Sessa
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Giuseppe Pelosi
- Science and Technology Pole (PST), IRCCS MultiMedica, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Adriana Albini
- School of Medicine and Surgery, University of Milano-Bicocca, Building U8, Via Cadore 48, 20900, Monza, Italy. .,Science and Technology Pole (PST), IRCCS MultiMedica, Milan, Italy.
| | - Douglas M Noonan
- Science and Technology Pole (PST), IRCCS MultiMedica, Milan, Italy.,Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
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Yang XW, Huang HX, Wang F, Zhou QL, Huang YQ, Qin RZ. Elevated plasma CXCL12/SDF-1 levels are linked with disease severity of postmenopausal osteoporosis. Innate Immun 2019; 26:222-230. [PMID: 31640442 PMCID: PMC7144032 DOI: 10.1177/1753425919883365] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
This study was designed to determine whether plasma CXCL12 levels in postmenopausal osteoporosis (PMOP) patients are related to disease severity. A total of 91 PMOP females were recruited, and 88 postmenopausal non-osteoporotic (PMNOP) women and 90 healthy females were incorporated as controls. Dual-energy X-ray absorptiometry was utilised to explore bone-mineral density (BMD). The Genant semi-quantitative grading scale was used for vertebral fractures, and plasma CXCL12/SDF-1 levels were investigated by ELISA. Plasma TNF-α and C-telopeptide cross-linked collagen type 1 (CTX-1) were also tested. The Oswestry Disability Index (ODI) and a visual analogue scale (VAS) were completed in order to assess clinical severity. Plasma CXCL12 levels were considerably elevated in PMOP females compared to PMNOP women and healthy controls. Plasma CXCL12 concentrations were positively correlated with the Genant grading system. We observed significant and negative correlations of plasma CXCL12 levels with lumbar spine, femoral neck and total hip BMD. Moreover, plasma CXCL12 concentrations were positively correlated to VAS and ODI, as well as plasma TNF-α and CTX-1 levels. In conclusion, elevated plasma CXCL12 levels are correlated with disease severity in PMOP females.
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Affiliation(s)
- Xian-Wen Yang
- Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, PR China.,The Third Affiliated Hospital of GuangZhou University of Chinese Medicine, PR China
| | - Hong-Xing Huang
- The Third Affiliated Hospital of GuangZhou University of Chinese Medicine, PR China
| | - Fei Wang
- Air Force General Hospital, PR China
| | - Qi-Lin Zhou
- Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, PR China
| | - Yan-Qiang Huang
- Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, PR China
| | - Ru-Zi Qin
- Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, PR China
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Isali I, Al-Sadawi MAA, Qureshi A, Khalifa AO, Agrawal MK, Shukla S. Growth factors involve in cellular proliferation, differentiation and migration during prostate cancer metastasis. INTERNATIONAL JOURNAL OF CELL BIOLOGY AND PHYSIOLOGY 2019; 2:1-13. [PMID: 32259163 PMCID: PMC7133721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Growth factors play active role in cells proliferation, embryonic development regulation and cellular differentiation. Altered level growth factors promote malignant transformation of normal cells. There has been significant progress made in form of drugs, inhibitors and monoclonal antibodies against altered growth factor to treat the malignant form of cancer. Moreover, these altered growth factors in prostate cancer increases steroidal hormone levels, which promotes progression. Though this review we are highlighting the majorly involved growth factors in prostate carcinogenesis, this will enable to better design the therapeutic strategies to inhibit prostate cancer progression.
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Affiliation(s)
- Ilaha Isali
- Department of Urology, Case Western Reserve University, Cleveland, OH
| | | | - Arshna Qureshi
- Department of Anesthesiology, Case Western Reserve University, Cleveland, OH
| | - Ahmad O. Khalifa
- Department of Urology, Case Western Reserve University, Cleveland, OH
- Department of Urology, Menofia University, Shebin Al kom, Egypt
| | | | - Sanjeev Shukla
- Department of Urology, Case Western Reserve University, Cleveland, OH
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Xi Y, Qi Z, Ma J, Chen Y. PTEN loss activates a functional AKT/CXCR4 signaling axis to potentiate tumor growth and lung metastasis in human osteosarcoma cells. Clin Exp Metastasis 2019; 37:173-185. [PMID: 31571016 DOI: 10.1007/s10585-019-09998-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 09/24/2019] [Indexed: 12/17/2022]
Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Loss of the tumor suppressor PTEN or activation of chemokine receptor CXCR4 has been demonstrated to associate with OS respectively. However, the signaling mechanism underlying PTEN-mediated antitumor effect remains largely unknown, and the crosstalk between PTEN and CXCR4 in OS has not been investigated. Here, we uncover a PTEN/AKT/CXCR4 pathway nexus in highly tumorigenic and metastatic human 143B OS cells. Loss of PTEN activates AKT/CXCR4 signaling axis and regulates a series of tumor cell behaviors. Notably, ERK is inversely regulated by PTEN and its activation occurs downstream of AKT but upstream of CXCR4, suggesting this kinase to be an important mediator between AKT and CXCR4. In vivo studies show that overexpression of PTEN dramatically attenuates bone destruction, and this inhibition is associated with reduced CXCR4 expression in tumors. CXCR4 inhibitor AMD3100 also markedly suppresses tumor growth in the bone. In addition, PTEN overexpression or AMD3100 substantially inhibits tumor expansion in the lung. Our studies highlight a novel PTEN/AKT/CXCR4 signaling nexus in OS tumor growth and lung metastasis, and provide a strong rationale to consider PTEN restoration or CXCR4 blockade for the treatment of aggressive OS in humans.
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Affiliation(s)
- Yongming Xi
- Department of Orthopaedics, Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, China.
| | - Zonghua Qi
- Department of Orthopaedics, Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, China
| | - Jinfeng Ma
- Department of Orthopaedics, Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, China
| | - Yan Chen
- Division in Signaling Biology, Princess Margaret Cancer Center, University Health Network, Rm 13-301, TMDT Bldg, 101 College St., Toronto, Canada.
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Jang YG, Go RE, Hwang KA, Choi KC. Resveratrol inhibits DHT-induced progression of prostate cancer cell line through interfering with the AR and CXCR4 pathway. J Steroid Biochem Mol Biol 2019; 192:105406. [PMID: 31185279 DOI: 10.1016/j.jsbmb.2019.105406] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 06/06/2019] [Accepted: 06/07/2019] [Indexed: 12/20/2022]
Abstract
Prostate cancer (PCa) is one of the most common malignancies and the second most common cause of cancer-related deaths in men world-wide and is known to be affected by the action of dihydrotestosterone (DHT) via androgen receptor (AR). Resveratrol (Res) as a phytochemical in grapes and red wine has diverse biological effects such as anti-inflammation, anti-oxidation and anti-cancer. CXCR4 as a chemokine receptor has been found to be upregulated in cancer metastasis and has been used as a prognostic marker in various types of cancer, including leukemia, breast cancer, and prostate cancer. In this study, we focused on the role of DHT in the induction of prostate cancer progression by affecting the AR and CXCR4 pathway. Also, we investigated the inhibition effect of resveratrol on DHT-induced prostate cancer metastasis. In cell viability assay, DHT increased the cell viability of LNCaP prostate cancer cells, on the other hand, Res and its combination with bicalutamide (BCT) as an AR-antagonist or AMD3100 as a CXCR4 inhibitor significantly reduced the cell viability promoted by DHT. Trans-well migration assay and wound healing assay represented the similar results with cell viability assay. According to the results of TUNEL assay, the apoptotic activity was induced by treatment of Res. As results of western blot analysis, the expression of AR, CXCR4, p-PI3K, and p-AKT and the downstream genes related with cell cycle progression and epithelial-mesenchymal transition (EMT) were decreased and the expression of the apoptosis-related genes was increased by treatment of Res and its combination with BCT or AMD3100. This study would suggest that Res and its combination with AR and CXCR4 antagonists can be used in order to suppress the metastatic behaviors of prostate cancer.
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Affiliation(s)
- Yin-Gi Jang
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Ryu-Eun Go
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyung-A Hwang
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
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Yao X, Ning LJ, He SK, Cui J, Hu RN, Zhang Y, Zhang YJ, Luo JC, Ding W, Qin TW. Stem Cell Extracellular Matrix-Modified Decellularized Tendon Slices Facilitate the Migration of Bone Marrow Mesenchymal Stem Cells. ACS Biomater Sci Eng 2019; 5:4485-4495. [DOI: 10.1021/acsbiomaterials.9b00064] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Li Z, Shen Y, Wang Y, Zhu L, Zhu C, Qian C, Sun M, Oupicky D. Perfluorocarbon Nanoemulsions for Combined Pulmonary siRNA Treatment of Lung Metastatic Osteosarcoma. ADVANCED THERAPEUTICS 2019. [DOI: 10.1002/adtp.201900039] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Zhaoting Li
- State Key Laboratory of Natural MedicinesDepartment of PharmaceuticsChina Pharmaceutical University Nanjing 210009 China
| | - Yuexin Shen
- State Key Laboratory of Natural MedicinesDepartment of PharmaceuticsChina Pharmaceutical University Nanjing 210009 China
| | - Yixin Wang
- State Key Laboratory of Natural MedicinesDepartment of PharmaceuticsChina Pharmaceutical University Nanjing 210009 China
| | - Lianghan Zhu
- State Key Laboratory of Natural MedicinesDepartment of PharmaceuticsChina Pharmaceutical University Nanjing 210009 China
| | - Chenfei Zhu
- State Key Laboratory of Natural MedicinesDepartment of PharmaceuticsChina Pharmaceutical University Nanjing 210009 China
| | - Chenggen Qian
- State Key Laboratory of Natural MedicinesDepartment of PharmaceuticsChina Pharmaceutical University Nanjing 210009 China
| | - Minjie Sun
- State Key Laboratory of Natural MedicinesDepartment of PharmaceuticsChina Pharmaceutical University Nanjing 210009 China
| | - David Oupicky
- State Key Laboratory of Natural MedicinesDepartment of PharmaceuticsChina Pharmaceutical University Nanjing 210009 China
- Center for Drug Delivery and NanomedicineDepartment of Pharmaceutical SciencesUniversity of Nebraska Medical Center Omaha, NE 68198 USA
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Perumal E, So Youn K, Sun S, Seung-Hyun J, Suji M, Jieying L, Yeun-Jun C. PTEN inactivation induces epithelial-mesenchymal transition and metastasis by intranuclear translocation of β-catenin and snail/slug in non-small cell lung carcinoma cells. Lung Cancer 2019; 130:25-34. [PMID: 30885348 DOI: 10.1016/j.lungcan.2019.01.013] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 12/26/2018] [Accepted: 01/27/2019] [Indexed: 12/11/2022]
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Miller D, Ingersoll MA, Lin MF. ErbB-2 signaling in advanced prostate cancer progression and potential therapy. Endocr Relat Cancer 2019; 26:R195-R209. [PMID: 31294537 PMCID: PMC6628717 DOI: 10.1530/erc-19-0009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Currently, prostate cancer (PCa) remains the most commonly diagnosed solid tumor and the second leading cause of cancer-related deaths in US men. Most of these deaths are attributed to the development of castration-resistant (CR) PCa. ErbB-2 and ErbB family members have been demonstrated to contribute to the progression of this lethal disease. In this review, we focus on updating the role of ErbB-2 in advanced PCa progression and its regulation, including its regulation via ligand activation, miRNAs and protein phosphorylation. We also discuss its downstream signaling pathways, including AKT, ERK1/2 and STATs, involved in advanced PCa progression. Additionally, we evaluate the potential of ErbB-2, focusing on its protein hyper-phosphorylation status, as a biomarker for aggressive PCa as well as the effectiveness of ErbB-2 as a target for the treatment of CR PCa via a multitude of approaches, including orally available inhibitors, intratumoral expression of cPAcP, vaccination and immunotherapy.
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Affiliation(s)
- Dannah Miller
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Matthew A. Ingersoll
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE
| | - Ming-Fong Lin
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Section of Urology, Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Corresponding Author: Ming-Fong Lin, Ph. D., Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA, TEL: (402) 559-6658, FAX: (402) 559-6650, (MFL)
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CXCR3 expression in colorectal cancer cells enhanced invasion through preventing CXCR4 internalization. Exp Cell Res 2018; 371:162-174. [DOI: 10.1016/j.yexcr.2018.08.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 08/03/2018] [Accepted: 08/05/2018] [Indexed: 01/09/2023]
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A novel cross-talk between CXCR4 and PI4KIIIα in prostate cancer cells. Oncogene 2018; 38:332-344. [PMID: 30111818 PMCID: PMC6336684 DOI: 10.1038/s41388-018-0448-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 07/03/2018] [Accepted: 07/14/2018] [Indexed: 12/20/2022]
Abstract
Chemokine signaling regulates cell migration and tumor metastasis. CXCL12, a member of the chemokine family, and its receptor, CXCR4, a G protein coupled receptor (GPCR), are key mediators of prostate-cancer (PC) bone metastasis. In PC cells androgens activate CXCR4 gene expression and receptor signaling on lipid rafts, which induces protease expression and cancer cell invasion. To identify novel lipid-raft-associated CXCR4 regulators supporting invasion/metastasis, we performed a SILAC-based quantitative proteomic analysis of lipid-rafts derived from PC3 stable cell lines with overexpression or knockdown of CXCR4. This analysis identified the evolutionarily conserved phosphatidylinositol 4-kinase IIIα (PI4KIIIα), and SAC1 phosphatase that dephosphorylates phosphatidylinositol-4-phosphate as potential candidate CXCR4 regulators. CXCR4 interacted with PI4KIIIα membrane targeting machinery recruiting them to the plasma membrane for PI4P production. Consistent with this interaction, PI4KIIIα was found tightly linked to the CXCR4 induced PC cell invasion. Thus, ablation of PI4KIIIα in CXCR4-expressing PC3 cells reduced cellular invasion in response to a variety of chemokines. Immunofluorescence microscopy in CXCR4 expressing cells revealed localized production of PI4P on the invasive projections. Human tumor studies documented increased PI4KIIIα expression in metastatic tumors vs. the primary tumor counterparts, further supporting the PI4KIIIα role in tumor metastasis. Furthermore, we also identified an unexpected function of PI4KIIIα in GPCR signaling where CXCR4 regulates PI4KIIIα activity and mediate tumor metastasis. Together, our study identifies a novel cross-talk between PI4KIIIα and CXCR4 in promoting tumor metastasis and suggests that PI4KIIIα pharmacological targeting may have therapeutic benefit for advanced prostate cancer patients.
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Wang Y, Song Y, Che X, Zhang L, Wang Q, Zhang X, Qu J, Li Z, Xu L, Zhang Y, Fan Y, Hou K, Liu Y, Qu X. Caveolin‑1 enhances RANKL‑induced gastric cancer cell migration. Oncol Rep 2018; 40:1287-1296. [PMID: 30015970 PMCID: PMC6072394 DOI: 10.3892/or.2018.6550] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 06/21/2018] [Indexed: 12/16/2022] Open
Abstract
The classical pathway involving receptor activator of nuclear factor‑κB (RANK) and its ligand (RANKL) induces the activation of osteoclasts and the migration of a variety of tumor cells, including breast and lung cancer. In our previous study, the expression of RANK was identified on the surface of gastric cancer cells, however, whether the RANKL/RANK pathway is involved in the regulation of gastric cancer cell migration remains to be fully elucidated. Lipid rafts represent a major platform for the regulation of cancer signaling; however, their involvement in RANKL‑induced migration remains to be elucidated. To investigate the potential roles and mechanism of RANKL/RANK in gastric cancer migration and metastasis, the present study examined the expression of RANK by western blot analysis and the expression of caveolin‑1 (Cav‑1) in gastric cancer tissues by immunohistochemistry, in addition to cell migration which is measured by Transwell migration assay. The aggregation of lipid reft was observed by fluorescence microscopy and western blotting was used to measure signaling changes in associated pathways. The results showed that RANKL induced gastric cancer cell migration, accompanied by the activation of Cav‑1 and aggregation of lipid rafts. Nystatin, a lipid raft inhibitor, inhibited the activation of Cav‑1 and markedly reversed RANKL‑induced gastric cancer cell migration. The RANKL‑induced activation of Cav‑1 has been shown to occur with the activation of proto‑oncogene tyrosine‑protein kinase Src (c‑Src). The c‑Src inhibitor, PP2, inhibited the activation of Cav‑1 and lipid raft aggregation, and reversed RANKL‑induced gastric cancer cell migration. Furthermore, it was demonstrated that Cav‑1 was involved in RANKL‑induced cell migration in lung, renal and breast cancer cells. These results suggested that RANKL induced gastric cancer cell migration, likely through mechanisms involving the c‑Src/Cav‑1 pathway and lipid raft aggregation.
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Affiliation(s)
- Yan Wang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yongxi Song
- Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Lingyun Zhang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Qian Wang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiaomeng Zhang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Jinglei Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Zhi Li
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Ling Xu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Ye Zhang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yibo Fan
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Kezuo Hou
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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Park SH, Keller ET, Shiozawa Y. Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis. Calcif Tissue Int 2018; 102:152-162. [PMID: 29094177 PMCID: PMC5807175 DOI: 10.1007/s00223-017-0350-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 10/19/2017] [Indexed: 12/13/2022]
Abstract
Bone is the most common site of prostate cancer metastasis. Once prostate cancer cells metastasize to bone, the mortality rate of prostate cancer patients increases significantly. Furthermore, bone metastases produce multiple skeletal complications, including bone pain that impairs the patients' quality of life. Effective therapies for bone metastatic disease are underdeveloped with most current therapies being primarily palliative with modest survival benefit. Although the exact mechanisms through which prostate cancer metastasizes to bone are unclear, growing evidence suggests that the bone marrow microenvironment, particularly its hematopoietic activity, is a significant mediator of prostate cancer bone tropism. Moreover, the bone microenvironment may regulate metastatic prostate cancer cells between dormant and proliferative states. In this review, we discuss (1) how prostate cancer cells interact with the bone microenvironment to establish bone metastases and (2) current and future potential treatments for prostate cancer patients with bone metastases.
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Affiliation(s)
- Sun H Park
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA
| | - Evan T Keller
- Departments of Urology and Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
| | - Yusuke Shiozawa
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
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