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Levati L, Tabolacci C, Facchiano A, Facchiano F, Alvino E, Antonini Cappellini GC, Scala E, Bonmassar L, Caporali S, Lacal PM, Bresin A, De Galitiis F, Russo G, D'Atri S. Circulating interleukin-8 and osteopontin are promising biomarkers of clinical outcomes in advanced melanoma patients treated with targeted therapy. J Exp Clin Cancer Res 2024; 43:226. [PMID: 39143551 PMCID: PMC11325673 DOI: 10.1186/s13046-024-03151-3] [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: 05/28/2024] [Accepted: 08/04/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Circulating cytokines can represent non-invasive biomarkers to improve prediction of clinical outcomes of cancer patients. Here, plasma levels of IL-8, CCL4, osteopontin, LIF and BDNF were determined at baseline (T0), after 2 months of therapy (T2) and, when feasible, at progression (TP), in 70 melanoma patients treated with BRAF and MEK inhibitors. The association of baseline cytokine levels with clinical response, progression-free survival (PFS) and overall survival (OS) was evaluated. METHODS Cytokine concentrations were measured using the xMAP technology. Their ability to discriminate between responding (Rs) and non-responding (NRs) patients was assessed by Receiver Operating Characteristics analysis. PFS and OS were estimated with the Kaplan-Meier method. The Cox proportional hazard model was used in the univariate and multivariate analyses to estimate crude and adjusted hazard ratios with 95% confidence intervals. RESULTS CCL4 and LIF were undetectable in the majority of samples. The median osteopontin concentration at T0 and T2 was significantly higher in NRs than in Rs. The median T0 and T2 values of IL-8 were also higher in NRs than in Rs, although the statistical significance was not reached. No differences were detected for BDNF. In 39 Rs with matched T0, T2, and TP samples, osteopontin and IL-8 significantly decreased from T0 to T2 and rose again at TP, while BDNF levels remained unchanged. In NRs, none of the cytokines showed a significant decrease at T2. Only osteopontin demonstrated a good ability to discriminate between Rs and NRs. A high IL-8 T0 level was associated with significantly shorter PFS and OS and higher risk of progression and mortality, and remained an independent negative prognostic factor for OS in multivariate analysis. An elevated osteopontin T0 concentration was also significantly associated with worse OS and increased risk of death. Patients with high IL-8 and high osteopontin showed the lowest PFS and OS, and in multivariate analysis this cytokine combination remained independently associated with a three- to six-fold increased risk of mortality. CONCLUSION Circulating IL-8 and osteopontin appear useful biomarkers to refine prognosis evaluation of patients undergoing targeted therapy, and deserve attention as potential targets to improve its clinical efficacy.
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Affiliation(s)
- Lauretta Levati
- Laboratory of Molecular Oncology, Istituto Dermopatico Dell'Immacolata, IDI-IRCCS, Via Dei Monti Di Creta 104, 00167, Rome, Italy
| | - Claudio Tabolacci
- Department of Oncology and Molecular Medicine, Istituto Superiore Di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
- Present Address: Research Coordination and Support Service, Istituto Superiore Di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Antonio Facchiano
- Laboratory of Molecular Oncology, Istituto Dermopatico Dell'Immacolata, IDI-IRCCS, Via Dei Monti Di Creta 104, 00167, Rome, Italy
| | - Francesco Facchiano
- Department of Oncology and Molecular Medicine, Istituto Superiore Di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Ester Alvino
- Institute of Translational Pharmacology, National Council of Research, Via Fosso del Cavaliere 100, 00133, Rome, Italy
| | - Gian Carlo Antonini Cappellini
- Department of Oncology and Dermatological Oncology, Istituto Dermopatico Dell'Immacolata, IDI-IRCCS, Via Dei Monti Di Creta 104, 00167, Rome, Italy
- Present Address: UOC Oncologia, Interpresidio ASL RM2, Via Dei Monti Tiburtini 387, 00157, Rome, Italy
| | - Enrico Scala
- Clinical and Laboratory Molecular Allergy Unit, Istituto Dermopatico Dell'Immacolata, IDI-IRCCS, Via Dei Monti Di Creta 104, 00167, Rome, Italy
| | - Laura Bonmassar
- Laboratory of Molecular Oncology, Istituto Dermopatico Dell'Immacolata, IDI-IRCCS, Via Dei Monti Di Creta 104, 00167, Rome, Italy
| | - Simona Caporali
- Laboratory of Molecular Oncology, Istituto Dermopatico Dell'Immacolata, IDI-IRCCS, Via Dei Monti Di Creta 104, 00167, Rome, Italy
- Present Address: Regional Transplant Center Lazio (CRTL), San Camillo Hospital, Circonvallazione Gianicolense 87, 00152, Rome, Italy
| | - Pedro Miguel Lacal
- Laboratory of Molecular Oncology, Istituto Dermopatico Dell'Immacolata, IDI-IRCCS, Via Dei Monti Di Creta 104, 00167, Rome, Italy
| | - Antonella Bresin
- Laboratory of Molecular Oncology, Istituto Dermopatico Dell'Immacolata, IDI-IRCCS, Via Dei Monti Di Creta 104, 00167, Rome, Italy
| | - Federica De Galitiis
- Department of Oncology and Dermatological Oncology, Istituto Dermopatico Dell'Immacolata, IDI-IRCCS, Via Dei Monti Di Creta 104, 00167, Rome, Italy
| | - Giandomenico Russo
- Laboratory of Molecular Oncology, Istituto Dermopatico Dell'Immacolata, IDI-IRCCS, Via Dei Monti Di Creta 104, 00167, Rome, Italy
| | - Stefania D'Atri
- Laboratory of Molecular Oncology, Istituto Dermopatico Dell'Immacolata, IDI-IRCCS, Via Dei Monti Di Creta 104, 00167, Rome, Italy.
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Peil J, Vossen C, Bock F, Clahsen T, Schiller P, Heindl LM, Bosch JJ, Wunderlich FT, Cursiefen C, Schlereth SL. Combined Osteopontin Blockade and Type 2 Classical Dendritic Cell Vaccination as Effective Synergetic Therapy for Conjunctival Melanoma. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:487-499. [PMID: 38099710 DOI: 10.4049/jimmunol.2300063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 11/20/2023] [Indexed: 01/18/2024]
Abstract
Angiogenesis and immune protection are essential at the onset of tumorigenesis. Angiogenesis serves to nourish the tumor, and prevention of immune defenses, for example, by dendritic cells (DCs), allows tumor growth. In this study, we investigated whether there are factors with dual functions that are both angiogenic and immunomodulatory and represent a therapeutic target. We analyzed 1) innate immune responses intratumorally and in draining lymph nodes and 2) angiogenic factors in conjunctival melanoma (CM), a potentially lethal malignant tumor at the ocular surface whose immune and vascular responses are largely unknown. For this purpose, an HGF-Cdk4R24C model in immunocompetent C57BL/6 mice was used and revealed that CD103- type 2 classical DC (cDC2s) were the most abundant DC subtype in healthy conjunctiva, whereas in CM, CD103- cDC2s, CD103+ type 1 cDCs, monocyte-derived DCs, and plasmacytoid DCs were significantly increased. In our analysis of angiogenic factors in CM, the examination of 53 angiogenesis-related factors that might interact with DCs identified osteopontin (OPN) as a major tumor-derived protein that interacts with DCs. Consistent with these findings, 3) a dual therapeutic strategy that inhibited tumor cell function by an OPN blocking Ab while enhancing the immune response by cDC2 vaccination resulted in 35% failure of tumor development. Moreover, tumor progression, monocyte-derived DC infiltration, and intratumoral angiogenesis were significantly reduced, whereas survival and CD8+ T cell infiltration were increased in treated mice compared with the control group. Therefore, we identified OPN blockade in combination with cDC2 vaccination as a potential future therapeutic intervention for early stages of CM by combining antiangiogenic and host immune stimulating effects.
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Affiliation(s)
- Jennifer Peil
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | | | - Felix Bock
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Thomas Clahsen
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Petra Schiller
- Faculty of Medicine and University Hospital Cologne, Institute of Medical Statistics and Computational Biology, University of Cologne, Cologne, Germany
| | - Ludwig M Heindl
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Jacobus J Bosch
- Centre for Human Drug Research and Leiden University Medical Center, Leiden, the Netherlands
| | - F Thomas Wunderlich
- MPI for Metabolism Research, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Simona L Schlereth
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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Várvölgyi T, Janka EA, Szász I, Koroknai V, Toka-Farkas T, Szabó IL, Ványai B, Szegedi A, Emri G, Balázs M. Combining Biomarkers for the Diagnosis of Metastatic Melanoma. J Clin Med 2023; 13:174. [PMID: 38202181 PMCID: PMC10779676 DOI: 10.3390/jcm13010174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/12/2023] [Accepted: 12/26/2023] [Indexed: 01/12/2024] Open
Abstract
The early detection of melanoma relapse can improve patient survival; thus, there is a great need for easily accessible biomarkers that facilitate the diagnosis of metastatic disease. We investigated the diagnostic effect of blood biomarkers such as lactate dehydrogenase (LDH), S100B, and osteopontin in the detection of metastases. Clinical data and peripheral blood samples of 206 melanoma patients were collected (no metastasis, N = 120; metastasis, N = 86). The discriminative power of blood biomarkers, patient demographics, and clinicopathological parameters of primary melanomas were evaluated using univariate and multivariate logistic regression models and receiver operating characteristic (ROC) analysis to determine the area under the curve (AUC). Plasma osteopontin levels showed a significant and independent effect on the probability of metastasis, similar to serum S100B levels. In addition, the location of the primary tumor on the lower extremities and the American Joint Committee on Cancer (AJCC) categories pT2b-3a, pT3b-4a, and pT4b were associated with the diagnosis of metastasis. Importantly, the combination of the three blood biomarkers and primary tumor localization and AJCC pT category yielded excellent discrimination (AUC: training set: 0.803; validation set: 0.822). In conclusion, plasma osteopontin can be classified as a melanoma biomarker; moreover, by combining clinicopathological prognostic variables, the diagnostic effect of blood biomarkers in the detection of metastatic melanoma can be improved.
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Affiliation(s)
- Tünde Várvölgyi
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.V.); (E.A.J.); (T.T.-F.); (I.L.S.); (B.V.); (A.S.); (G.E.)
| | - Eszter Anna Janka
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.V.); (E.A.J.); (T.T.-F.); (I.L.S.); (B.V.); (A.S.); (G.E.)
- HUN-REN-UD Allergology Research Group, University of Debrecen, 4032 Debrecen, Hungary
| | - István Szász
- HUN-REN-UD Public Health Research Group, University of Debrecen, 4028 Debrecen, Hungary; (I.S.); (V.K.)
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4028 Debrecen, Hungary
| | - Viktória Koroknai
- HUN-REN-UD Public Health Research Group, University of Debrecen, 4028 Debrecen, Hungary; (I.S.); (V.K.)
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4028 Debrecen, Hungary
| | - Tünde Toka-Farkas
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.V.); (E.A.J.); (T.T.-F.); (I.L.S.); (B.V.); (A.S.); (G.E.)
| | - Imre Lőrinc Szabó
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.V.); (E.A.J.); (T.T.-F.); (I.L.S.); (B.V.); (A.S.); (G.E.)
- HUN-REN-UD Allergology Research Group, University of Debrecen, 4032 Debrecen, Hungary
| | - Beatrix Ványai
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.V.); (E.A.J.); (T.T.-F.); (I.L.S.); (B.V.); (A.S.); (G.E.)
| | - Andrea Szegedi
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.V.); (E.A.J.); (T.T.-F.); (I.L.S.); (B.V.); (A.S.); (G.E.)
- HUN-REN-UD Allergology Research Group, University of Debrecen, 4032 Debrecen, Hungary
| | - Gabriella Emri
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.V.); (E.A.J.); (T.T.-F.); (I.L.S.); (B.V.); (A.S.); (G.E.)
- HUN-REN-UD Allergology Research Group, University of Debrecen, 4032 Debrecen, Hungary
| | - Margit Balázs
- HUN-REN-UD Public Health Research Group, University of Debrecen, 4028 Debrecen, Hungary; (I.S.); (V.K.)
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4028 Debrecen, Hungary
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Leung LL, Myles T, Morser J. Thrombin Cleavage of Osteopontin and the Host Anti-Tumor Immune Response. Cancers (Basel) 2023; 15:3480. [PMID: 37444590 PMCID: PMC10340489 DOI: 10.3390/cancers15133480] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/28/2023] [Accepted: 07/01/2023] [Indexed: 07/15/2023] Open
Abstract
Osteopontin (OPN) is a multi-functional protein that is involved in various cellular processes such as cell adhesion, migration, and signaling. There is a single conserved thrombin cleavage site in OPN that, when cleaved, yields two fragments with different properties from full-length OPN. In cancer, OPN has tumor-promoting activity and plays a role in tumor growth and metastasis. High levels of OPN expression in cancer cells and tumor tissue are found in various types of cancer, including breast, lung, prostate, ovarian, colorectal, and pancreatic cancer, and are associated with poor prognosis and decreased survival rates. OPN promotes tumor progression and invasion by stimulating cell proliferation and angiogenesis and also facilitates the metastasis of cancer cells to other parts of the body by promoting cell adhesion and migration. Furthermore, OPN contributes to immune evasion by inhibiting the activity of immune cells. Thrombin cleavage of OPN initiates OPN's tumor-promoting activity, and thrombin cleavage fragments of OPN down-regulate the host immune anti-tumor response.
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Affiliation(s)
- Lawrence L. Leung
- Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA; (L.L.L.); (T.M.)
- Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA
| | - Timothy Myles
- Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA; (L.L.L.); (T.M.)
- Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA
| | - John Morser
- Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA; (L.L.L.); (T.M.)
- Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA
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Saup R, Nair N, Shen J, Schmaus A, Thiele W, Garvalov BK, Sleeman JP. Increased Circulating Osteopontin Levels Promote Primary Tumour Growth, but Do Not Induce Metastasis in Melanoma. Biomedicines 2023; 11:biomedicines11041038. [PMID: 37189656 DOI: 10.3390/biomedicines11041038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/21/2023] [Accepted: 03/25/2023] [Indexed: 03/30/2023] Open
Abstract
Osteopontin (OPN) is a phosphoprotein with diverse functions in various physiological and pathological processes. OPN expression is increased in multiple cancers, and OPN within tumour tissue has been shown to promote key stages of cancer development. OPN levels are also elevated in the circulation of cancer patients, which in some cases has been correlated with enhanced metastatic propensity and poor prognosis. However, the precise impact of circulating OPN (cOPN) on tumour growth and progression remains insufficiently understood. To examine the role of cOPN, we used a melanoma model, in which we stably increased the levels of cOPN through adeno-associated virus-mediated transduction. We found that increased cOPN promoted the growth of primary tumours, but did not significantly alter the spontaneous metastasis of melanoma cells to the lymph nodes or lungs, despite an increase in the expression of multiple factors linked to tumour progression. To assess whether cOPN has a role at later stages of metastasis formation, we employed an experimental metastasis model, but again could not detect any increase in pulmonary metastasis in animals with elevated levels of cOPN. These results demonstrate that increased levels of OPN in the circulation play distinct roles during different stages of melanoma progression.
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Ding L, Gosh A, Lee DJ, Emri G, Huss WJ, Bogner PN, Paragh G. Prognostic biomarkers of cutaneous melanoma. PHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE 2022; 38:418-434. [PMID: 34981569 DOI: 10.1111/phpp.12770] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/02/2021] [Accepted: 12/30/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND/PURPOSE Melanomas account for only approximately 4% of diagnosed skin cancers in the United States but are responsible for the majority of deaths caused by skin cancer. Both genetic factors and ultraviolet (UV) radiation exposure play a role in the development of melanoma. Although melanomas have a strong propensity to metastasize when diagnosed late, melanomas that are diagnosed and treated early pose a low mortality risk. In particular, the identification of patients with increased metastatic risk, who may benefit from early adjuvant therapies, is crucial, especially given the advent of new melanoma treatments. However, the accuracy of classic clinical and histological variables, including the Breslow thickness, presence of ulceration, and lymph node status, might not be sufficient to identify such individuals. Thus, there is a need for the development of additional prognostic melanoma biomarkers that can improve early attempts to stratify melanoma patients and reliably identify high-risk subgroups with the aim of providing effective personalized therapies. METHODS In our current work, we discuss and assess emerging primary melanoma tumor biomarkers and prognostic circulating biomarkers. RESULTS Several promising biomarkers show prognostic value (eg, exosomal MIA (ie, melanoma inhibitory activity), serum S100B, AMLo signatures, and mRNA signatures); however, the scarcity of reliable data precludes the use of these biomarkers in current clinical applications. CONCLUSION Further research is needed on several promising biomarkers for melanoma. Large-scale studies are warranted to facilitate the clinical translation of prognostic biomarker applications for melanoma in personalized medicine.
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Affiliation(s)
- Liang Ding
- Department of Dermatology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Pathology, Buffalo General Medical Center, State University of New York, Buffalo, New York, USA
| | - Alexandra Gosh
- Department of Dermatology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Delphine J Lee
- Division of Dermatology, Department of Medicine, Harbor-UCLA Medical Center, Torrance, California, USA
- Division of Dermatology, Department of Medicine, The Lundquist Institute, Torrance, California, USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Gabriella Emri
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Wendy J Huss
- Department of Dermatology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Paul N Bogner
- Department of Dermatology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Gyorgy Paragh
- Department of Dermatology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
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Jámbor K, Koroknai V, Kiss T, Szász I, Pikó P, Balázs M. Gene Expression Patterns of Osteopontin Isoforms and Integrins in Malignant Melanoma. PATHOLOGY AND ONCOLOGY RESEARCH 2022; 28:1610608. [PMID: 36091936 PMCID: PMC9448871 DOI: 10.3389/pore.2022.1610608] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/11/2022] [Indexed: 11/30/2022]
Abstract
Osteopontin (OPN) is a multifunctional glycoprotein that physiologically interacts with different types of integrins. It is considered to be a possible prognostic biomarker in certain tumor types; however, various splicing isoforms exist, which have not been investigated in melanoma. We aimed to define the relative expression pattern of five OPN isoforms and clarify the prognostic significance of the splice variants in melanoma. We also aimed to investigate the expression pattern of eight integrins in the same tumors. Gene expression analyses revealed that the relative expression of OPNa, OPNb, and OPNc is significantly higher in metastatic tumors compared to primary lesions (p < 0.01), whereas the expression of OPN4 and OPN5 was low in both. The more aggressive nodular melanomas had higher expression levels compared to the superficial spreading subtype (p ≤ 0.05). The relative expression of the eight tested integrins was low, with only the expression of ITGB3 being detectable in nodular melanoma (Medianlog2 = 1.274). A positive correlation was found between Breslow thickness and the expression of OPNc variant, whereby thicker tumors (>4 mm) had significantly higher expression (p ≤ 0.05). The Breslow thickness was negatively correlated with the expression of OPN4, and similarly with ITGA2. OPNc also exhibited significant positive correlation with the presence of metastasis. Our data show that high expression of OPNa, OPNb, and especially OPNc and low expression of OPN4 and ITGA2 are associated with an advanced stage of tumor progression and poor prognosis in melanoma.
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Affiliation(s)
- Krisztina Jámbor
- Doctoral School of Health Sciences, University of Debrecen, Debrecen, Hungary
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Viktória Koroknai
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- ELKH-DE Public Health Research Group, University of Debrecen, Debrecen, Hungary
| | - Tímea Kiss
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - István Szász
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- ELKH-DE Public Health Research Group, University of Debrecen, Debrecen, Hungary
| | - Péter Pikó
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- ELKH-DE Public Health Research Group, University of Debrecen, Debrecen, Hungary
| | - Margit Balázs
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- ELKH-DE Public Health Research Group, University of Debrecen, Debrecen, Hungary
- *Correspondence: Margit Balázs,
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Raineri D, Cappellano G, Vilardo B, Maione F, Clemente N, Canciani E, Boggio E, Gigliotti CL, Monge C, Dianzani C, Boldorini R, Dianzani U, Chiocchetti A. Inducible T-Cell Costimulator Ligand Plays a Dual Role in Melanoma Metastasis upon Binding to Osteopontin or Inducible T-Cell Costimulator. Biomedicines 2021; 10:biomedicines10010051. [PMID: 35052731 PMCID: PMC8772802 DOI: 10.3390/biomedicines10010051] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 12/23/2022] Open
Abstract
Recently, we demonstrated that inducible T-cell costimulator (ICOS) shares its unique ligand (ICOSL) with osteopontin (OPN), and OPN/ICOSL binding promotes tumor metastasis and angiogenesis in the 4T1 breast cancer model. Literature showed that OPN promotes melanoma metastasis by suppressing T-cell activation and recruiting myeloid suppressor cells (MDSC). On the opposite, ICOS/ICOSL interaction usually sustains an antitumor response. Here, we engineered murine B16F10 melanoma cells, by transfecting or silencing ICOSL. In vitro data showed that loss of ICOSL favors anchorage-independent growth and induces more metastases in vivo, compared to ICOSL expressing cells. To dissect individual roles of the three molecules, we compared data from C57BL/6 with those from OPN-KO, ICOS-KO, and ICOSL-KO mice, missing one partner at a time. We found that OPN produced by the tumor microenvironment (TME) favors the metastasis by interacting with stromal ICOSL. This activity is dominantly inhibited by ICOS expressed on TME by promoting Treg expansion. Importantly, we also show that OPN and ICOSL highly interact in human melanoma metastases compared to primary tumors. Interfering with this binding may be explored in immunotherapy either for nonresponding or patients resistant to conventional therapies.
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Affiliation(s)
- Davide Raineri
- Dipartimento di Scienze della Salute, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, Università del Piemonte Orientale, 28100 Novara, Italy; (D.R.); (G.C.); (B.V.); (F.M.); (N.C.); (E.C.); (E.B.); (C.L.G.); (A.C.)
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy
| | - Giuseppe Cappellano
- Dipartimento di Scienze della Salute, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, Università del Piemonte Orientale, 28100 Novara, Italy; (D.R.); (G.C.); (B.V.); (F.M.); (N.C.); (E.C.); (E.B.); (C.L.G.); (A.C.)
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy
| | - Beatrice Vilardo
- Dipartimento di Scienze della Salute, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, Università del Piemonte Orientale, 28100 Novara, Italy; (D.R.); (G.C.); (B.V.); (F.M.); (N.C.); (E.C.); (E.B.); (C.L.G.); (A.C.)
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy
| | - Federica Maione
- Dipartimento di Scienze della Salute, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, Università del Piemonte Orientale, 28100 Novara, Italy; (D.R.); (G.C.); (B.V.); (F.M.); (N.C.); (E.C.); (E.B.); (C.L.G.); (A.C.)
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy
| | - Nausicaa Clemente
- Dipartimento di Scienze della Salute, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, Università del Piemonte Orientale, 28100 Novara, Italy; (D.R.); (G.C.); (B.V.); (F.M.); (N.C.); (E.C.); (E.B.); (C.L.G.); (A.C.)
| | - Elena Canciani
- Dipartimento di Scienze della Salute, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, Università del Piemonte Orientale, 28100 Novara, Italy; (D.R.); (G.C.); (B.V.); (F.M.); (N.C.); (E.C.); (E.B.); (C.L.G.); (A.C.)
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy
| | - Elena Boggio
- Dipartimento di Scienze della Salute, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, Università del Piemonte Orientale, 28100 Novara, Italy; (D.R.); (G.C.); (B.V.); (F.M.); (N.C.); (E.C.); (E.B.); (C.L.G.); (A.C.)
| | - Casimiro Luca Gigliotti
- Dipartimento di Scienze della Salute, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, Università del Piemonte Orientale, 28100 Novara, Italy; (D.R.); (G.C.); (B.V.); (F.M.); (N.C.); (E.C.); (E.B.); (C.L.G.); (A.C.)
| | - Chiara Monge
- Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, 10125 Torino, Italy; (C.M.); (C.D.)
| | - Chiara Dianzani
- Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, 10125 Torino, Italy; (C.M.); (C.D.)
| | - Renzo Boldorini
- Divisione di Anatomia Patologica, Dipartimento di Scienze della Salute, AOU Maggiore della Carità, Università del Piemonte Orientale, 28100 Novara, Italy;
| | - Umberto Dianzani
- Dipartimento di Scienze della Salute, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, Università del Piemonte Orientale, 28100 Novara, Italy; (D.R.); (G.C.); (B.V.); (F.M.); (N.C.); (E.C.); (E.B.); (C.L.G.); (A.C.)
- Laboratorio di Biochimica Clinica, Dipartimento di Scienze della Salute, AOU Maggiore della Carità, Università del Piemonte Orientale, Corso Mazzini 18, 28100 Novara, Italy
- Correspondence:
| | - Annalisa Chiocchetti
- Dipartimento di Scienze della Salute, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, Università del Piemonte Orientale, 28100 Novara, Italy; (D.R.); (G.C.); (B.V.); (F.M.); (N.C.); (E.C.); (E.B.); (C.L.G.); (A.C.)
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy
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Olszańska J, Pietraszek-Gremplewicz K, Nowak D. Melanoma Progression under Obesity: Focus on Adipokines. Cancers (Basel) 2021; 13:cancers13092281. [PMID: 34068679 PMCID: PMC8126042 DOI: 10.3390/cancers13092281] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/01/2021] [Accepted: 05/05/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Obesity is a rapidly growing public health problem and the reason for numerous diseases in the human body, including cancer. This article reviews the current knowledge of the effect of molecules secreted by adipose tissue-adipokines on melanoma progression. We also discuss the role of these factors as markers of incidence, metastasis, and melanoma patient survival. Understanding the functions of adipokines will lead to knowledge of whether and how obesity promotes melanoma growth. Abstract Obesity is a growing problem in the world and is one of the risk factors of various cancers. Among these cancers is melanoma, which accounts for the majority of skin tumor deaths. Current studies are looking for a correlation between obesity and melanoma. They suspect that a potential cause of its development is connected to the biology of adipokines, active molecules secreted by adipose tissue. Under physiological conditions, adipokines control many processes, including lipid and glucose homeostasis, insulin sensitivity, angiogenesis, and inflammations. However, when there is an increased amount of fat in the body, their secretion is dysregulated. This article reviews the current knowledge of the effect of adipokines on melanoma growth. This work focuses on the molecular pathways by which adipose tissue secreted molecules modify the angiogenesis, migration, invasion, proliferation, and death of melanoma cells. We also discuss the role of these factors as markers of incidence, metastasis, and melanoma patient survival. Understanding the functions of adipokines will lead to knowledge of whether and how obesity promotes melanoma growth. Further studies may contribute to the innovations of therapies and the use of adipokines as predictive and/or prognostic biomarkers.
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Malecka K, Mikuła E, Ferapontova EE. Design Strategies for Electrochemical Aptasensors for Cancer Diagnostic Devices. SENSORS 2021; 21:s21030736. [PMID: 33499136 PMCID: PMC7866130 DOI: 10.3390/s21030736] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/12/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023]
Abstract
Improved outcomes for many types of cancer achieved during recent years is due, among other factors, to the earlier detection of tumours and the greater availability of screening tests. With this, non-invasive, fast and accurate diagnostic devices for cancer diagnosis strongly improve the quality of healthcare by delivering screening results in the most cost-effective and safe way. Biosensors for cancer diagnostics exploiting aptamers offer several important advantages over traditional antibodies-based assays, such as the in-vitro aptamer production, their inexpensive and easy chemical synthesis and modification, and excellent thermal stability. On the other hand, electrochemical biosensing approaches allow sensitive, accurate and inexpensive way of sensing, due to the rapid detection with lower costs, smaller equipment size and lower power requirements. This review presents an up-to-date assessment of the recent design strategies and analytical performance of the electrochemical aptamer-based biosensors for cancer diagnosis and their future perspectives in cancer diagnostics.
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Affiliation(s)
- Kamila Malecka
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima Str. 10, 10-748 Olsztyn, Poland; (K.M.); (E.M.)
| | - Edyta Mikuła
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima Str. 10, 10-748 Olsztyn, Poland; (K.M.); (E.M.)
| | - Elena E. Ferapontova
- Interdisciplinary Nanoscience Center (iNANO), Faculty of Science and Technology, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark
- Correspondence: ; Tel.: +45-87156703
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Deng G, Zeng F, Su J, Zhao S, Hu R, Zhu W, Hu S, Chen X, Yin M. BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway. Am J Cancer Res 2020; 10:11428-11443. [PMID: 33052224 PMCID: PMC7546000 DOI: 10.7150/thno.47432] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 08/30/2020] [Indexed: 12/12/2022] Open
Abstract
Background: Bromodomain and extra-terminal domain (BET) inhibitors have shown profound efficacy against hematologic malignancies and solid tumors in preclinical studies. However, the underlying molecular mechanism in melanoma is not well understood. Here we identified secreted phosphoprotein 1 (SPP1) as a melanoma driver and a crucial target of BET inhibitors in melanoma. Methods: Bioinformatics analysis and meta-analysis were used to evaluate the SPP1 expression in normal tissues, primary melanoma, and metastatic melanoma. Real-time PCR (RT-PCR) and Western blotting were employed to quantify SPP1 expression in melanoma cells and tissues. Cell proliferation, wound healing, and Transwell assays were carried out to evaluate the effects of SPP1 and BET inhibitors in melanoma cells in vitro. A xenograft mouse model was used to investigate the effect of SPP1 and BET inhibitors on melanoma in vivo. Chromatin immunoprecipitation (ChIP) assay was performed to evaluate the regulatory mechanism of BET inhibitors on SPP1. Results: SPP1 was identified as a melanoma driver by bioinformatics analysis, and meta-analysis determined it to be a diagnostic and prognostic biomarker for melanoma. SPP1 overexpression was associated with poor melanoma prognosis, and silencing SPP1 suppressed melanoma cell proliferation, migration, and invasion. Through a pilot drug screen, we identified BET inhibitors as ideal therapeutic agents that suppressed SPP1 expression. Also, SPP1 overexpression could partially reverse the suppressive effect of BET inhibitors on melanoma. We further demonstrated that bromodomain-containing 4 (BRD4) regulated SPP1 expression. Notably, BRD4 did not bind directly to the SPP1 promoter but regulated SPP1 expression through NFKB2. Silencing of NFKB2 resembled the phenotype of BET inhibitors treatment and SPP1 silencing in melanoma. Conclusion: Our findings highlight SPP1 as an essential target of BET inhibitors and provide a novel mechanism by which BET inhibitors suppress melanoma progression via the noncanonical NF-κB/SPP1 pathway.
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Molecular alterations associated with acquired resistance to BRAFV600E targeted therapy in melanoma cells. Melanoma Res 2020; 29:390-400. [PMID: 30741840 DOI: 10.1097/cmr.0000000000000588] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Selective inhibition of the mutant BRAF protein is a highly promising therapeutic approach for melanoma patients carrying the BRAF mutation. Despite the remarkable clinical response, most patients develop resistance and experience tumour regrowth. To clarify the molecular background of BRAF inhibitor resistance, we generated four drug-resistant melanoma cell lines from paired primary/metastatic cell lines using a vemurafenib analogue PLX4720. Three of the resistant cell lines showed decreased proliferation after drug withdrawal, but the proliferation of one cell line (WM278) increased notably. Furthermore, we observed opposite phenomena in which a 'drug holiday' could not only be beneficial but also contribute to tumour progression. Using genomic and proteomic approaches, we found significantly different alterations between the sensitive and resistant cell lines, some of which have not been reported previously. In addition to several other changes, copy number gains were observed in all resistant cell lines on 8q24.11-q24.12 and 8q21.2. Gene expression analysis showed that most genes upregulated in the resistant cell lines were associated with cell motility and angiogenesis. Increased expression of six proteins (ANGPLT4, EGFR, Endoglin, FGF2, SerpinE1 and VCAM-1) and decreased expression of two proteins (osteopontin and survivin) were observed consistently in all resistant cell lines. In summary, we identified new genomic alterations and characterized the protein expression patterns associated with the resistant phenotype. Although several proteins have been shown to be associated with BRAF resistance, our study is the first to describe the association of VCAM-1 and osteopontin with BRAF resistance.
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Biomarkers Predictive of Survival and Response to Immune Checkpoint Inhibitors in Melanoma. Am J Clin Dermatol 2020; 21:1-11. [PMID: 31602560 DOI: 10.1007/s40257-019-00475-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Immunotherapy has revolutionized the treatment of melanoma. Targeting of the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 has led to improved survival in a subset of patients. Unfortunately, the use of immune checkpoint inhibitors is associated with significant side effects and many patients do not respond to treatment. Thus, there is an urgent need both for prognostic biomarkers to estimate risk and for predictive biomarkers to determine which patients are likely to respond to therapy. In this review, prognostic and predictive biomarkers that are an active area of research are outlined. Of note, certain transcriptomic signatures are already used in the clinic, albeit not routinely, to prognosticate patients. In the predictive setting, programmed cell death protein ligand 1 expression has been shown to correlate with benefit but is not precise enough to be used as an exclusionary biomarker. Future investigation will need to focus on biomarkers that are easily reproducible, cost effective, and accurate. The use of readily available clinical material, such as serum or hematoxylin and eosin-stained images, may offer one such path forward.
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Wakamatsu K, Fukushima S, Minagawa A, Omodaka T, Hida T, Hatta N, Takata M, Uhara H, Okuyama R, Ihn H. Significance of 5- S-Cysteinyldopa as a Marker for Melanoma. Int J Mol Sci 2020; 21:E432. [PMID: 31936623 PMCID: PMC7013534 DOI: 10.3390/ijms21020432] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 01/07/2020] [Accepted: 01/07/2020] [Indexed: 12/18/2022] Open
Abstract
Melanoma is one of the most lethal and malignant cancers and its incidence is increasing worldwide, and Japan is not an exception. Although there are numerous therapeutic options for melanoma, the prognosis is still poor once it has metastasized. The main concern after removal of a primary melanoma is whether it has metastasized, and early detection of metastatic melanoma would be effective in improving the prognosis of patients. Thus, it is very important to identify reliable methods to detect metastases as early as possible. Although many prognostic biomarkers (mainly for metastases) of melanoma have been reported, there are very few effective for an early diagnosis. Serum and urinary biomarkers for melanoma diagnosis have especially received great interest because of the relative ease of sample collection and handling. Several serum and urinary biomarkers appear to have significant potential both as prognostic indicators and as targets for future therapeutic methods, but still there are no efficient serum and urinary biomarkers for early detection, accurate diagnosis and prognosis, efficient monitoring of the disease and reliable prediction of survival and recurrence. Levels of 5-S-cysteinyldopa (5SCD) in the serum or urine as biomarkers of melanoma have been found to be significantly elevated earlier and to reflect melanoma progression better than physical examinations, laboratory tests and imaging techniques, such as scintigraphy and echography. With recent developments in the treatment of melanoma, studies reporting combinations of 5SCD levels and new applications for the treatment of melanoma are gradually increasing. This review summarizes the usefulness of 5SCD, the most widely used and well-known melanoma marker in the serum and urine, compares 5SCD and other useful markers, and finally its application to other fields.
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Affiliation(s)
- Kazumasa Wakamatsu
- Department of Chemistry, Fujita Health University School of Medical Sciences, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan
| | - Satoshi Fukushima
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan; (S.F.); (H.I.)
| | - Akane Minagawa
- Department of Dermatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; (A.M.); (T.O.); (R.O.)
| | - Toshikazu Omodaka
- Department of Dermatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; (A.M.); (T.O.); (R.O.)
| | - Tokimasa Hida
- Department of Dermatology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo 060-8543, Japan; (T.H.); (H.U.)
| | - Naohito Hatta
- Department of Dermatology, Toyama Prefectural Central Hospital, 2-2-78 Nishinagae, Toyama, Toyama 930-8550, Japan;
| | - Minoru Takata
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikada-cho, Kita-Ku, Okayama 700-8558, Japan;
| | - Hisashi Uhara
- Department of Dermatology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo 060-8543, Japan; (T.H.); (H.U.)
| | - Ryuhei Okuyama
- Department of Dermatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; (A.M.); (T.O.); (R.O.)
| | - Hironobu Ihn
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan; (S.F.); (H.I.)
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Valenti MT, Dalle Carbonare L, Mottes M. Ectopic expression of the osteogenic master gene RUNX2 in melanoma Maria Teresa Valenti, Luca Dalle Carbonare, Monica Mottes. World J Stem Cells 2018; 10:78-81. [PMID: 30079129 PMCID: PMC6068731 DOI: 10.4252/wjsc.v10.i7.78] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 06/11/2018] [Accepted: 06/28/2018] [Indexed: 02/06/2023] Open
Abstract
The transcription factor RUNX2 is the osteogenic master gene expressed in mesenchymal stem cells during osteogenic commitment as well as in pre-osteoblasts and early osteoblasts. However, RUNX2 is also ectopically expressed in melanoma and other cancers. Malignant melanoma (MM) is a highly metastatic skin cancer. The incidence of MM has increased considerably in the past half-century. The expression levels and mutation rates of genes such as BRAF, KIT, NRAS, PTEN, P53, TERT and MITF are higher in melanoma than in other solid malignancies. Additionally, transcription factors can affect cellular processes and induce cellular transformation since they control gene expression. Recently, several studies have identified alterations in RUNX2 expression. In particular, the regulation of KIT by RUNX2 and the increased expression of RUNX2 in melanoma specimens have been shown. Melanocytes, whose transformation results in melanoma, arise from the neural crest and therefore show “stemness” features. RUNX2 plays an important role in the re-activation of the MAPK and PI3K/AKT pathways, thus endowing melanoma cells with a high metastatic potential. In melanoma, the most frequent metastatic sites are the lung, liver, brain and lymph nodes. In addition, bone metastatic melanoma has been described. Notably, studies focusing on RUNX2 may contribute to the identification of an appropriate oncotarget in melanoma.
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Affiliation(s)
| | | | - Monica Mottes
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona 37100, Italy
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Osteopontin at the Crossroads of Inflammation and Tumor Progression. Mediators Inflamm 2017; 2017:4049098. [PMID: 28769537 PMCID: PMC5523273 DOI: 10.1155/2017/4049098] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 06/04/2017] [Indexed: 12/13/2022] Open
Abstract
Complex interactions between tumor and host cells regulate systemic tumor dissemination, a process that begins early at the primary tumor site and goes on until tumor cells detach themselves from the tumor mass and start migrating into the blood or lymphatic vessels. Metastatic cells colonize the target organs and are capable of surviving and growing at distant sites. In this context, osteopontin (OPN) appears to be a key determinant of the crosstalk between cancer cells and the host microenvironment, which in turn modulates immune evasion. OPN is overexpressed in several human carcinomas and has been implicated in inflammation, tumor progression, and metastasis. Thus, it represents one of the most attracting targets for cancer therapy. Within the tumor mass, OPN is secreted in various forms either by the tumor itself or by stroma cells, and it can exert either pro- or antitumorigenic effects according to the cell type and tumor microenvironment. Thus, targeting OPN for therapeutic purposes needs to take into account the heterogeneous functions of the multiple OPN forms with regard to cancer formation and progression. In this review, we will describe the role of systemic, tumor-derived, and stroma-derived OPN, highlighting its pivotal role at the crossroads of inflammation and tumor progression.
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Hao C, Cui Y, Owen S, Li W, Cheng S, Jiang WG. Human osteopontin: Potential clinical applications in cancer (Review). Int J Mol Med 2017; 39:1327-1337. [PMID: 28440483 PMCID: PMC5428945 DOI: 10.3892/ijmm.2017.2964] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 04/10/2017] [Indexed: 12/11/2022] Open
Abstract
Human osteopontin (OPN) is a glycosylated phosphoprotein which is expressed in a variety of tissues in the body. In recent years, accumulating evidence has indicated that the aberrant expression of OPN is closely associated with tumourigensis, progression and most prominently with metastasis in several tumour types. In this review, we present the current knowledge on the expression profiles of OPN and its main splice variants in human cancers, as well as the potential implications in patient outcome. We also discuss its putative clinical application as a cancer biomarker and as a therapeutic target.
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Affiliation(s)
- Chengcheng Hao
- Department of Biochemistry and Molecular Biology
- Beijing Key Laboratory of Cancer and Metastasis Research, Capital Medical University, Beijing 100069, P.R. China
| | - Yuxin Cui
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - Sionen Owen
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - Wenbin Li
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, P.R. China
| | - Shan Cheng
- Department of Biochemistry and Molecular Biology
- Beijing Key Laboratory of Cancer and Metastasis Research, Capital Medical University, Beijing 100069, P.R. China
| | - Wen G. Jiang
- Correspondence to: Professor Wen G. Jiang, Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Henry Wellcome Building, Heath Park Way, Cardiff CF14 4XN, UK, E-mail:
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Association of osteopontin with specific prognostic factors and survival in adjuvant breast cancer trials of the Hellenic Cooperative Oncology Group. J Transl Med 2017; 15:30. [PMID: 28193231 PMCID: PMC5304396 DOI: 10.1186/s12967-017-1134-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 02/03/2017] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The shift towards an earlier diagnosis of breast cancer (BC) highlights the need for biomarkers that would identify patients at risk for relapse and metastatic spread and indicate the potential value of additional treatment strategies. Osteopontin (OPN) is a matricellular protein that has been suggested to be a potential biomarker in BC. In the present study, we used archived BC patient samples to assess the clinical utility of OPN. METHODS Formalin-fixed paraffin-embedded tumor tissue samples from 975 patients were collected from two large phase III randomized adjuvant chemotherapy trials (HE10/97 and HE10/00) that included patients with high risk BC. All tissue samples were assessed for ER, PgR, Ki67 and HER2 protein expression. OPN protein and mRNA expression was evaluated using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction, respectively. RESULTS OPN mRNA expression data were available for 814 patients, whereas OPN protein expression data were available for 546 patients. The majority of patients were ER/PgR-positive (78.3%), HER2-negative (76.5%) and Ki67-positive (55.2%) and had received adjuvant radiation therapy (76.8%) and hormonal therapy (81.1%). OPN mRNA expression was significantly associated with age (60.9% in high OPN tumors vs. 54.1% in low OPN tumors, p = 0.047), ER/PgR-negative status (25.7 vs. 17.2%, p = 0.004) and BC subtypes (p = 0.021). In addition, high OPN mRNA expression was significantly associated with reduced DFS (HR 1.26, 95% CI 1.00-1.59, Wald's p = 0.050) and OS (HR 1.37, 95% CI 1.05-1.78, p = 0.019), while it retained its prognostic significance for both DFS (HR 1.39, 95% CI 1.10-1.77, p = 0.007) and OS (HR 1.54, 95% CI 1.61-2.05, p = 0.003) in the multivariate analysis. CONCLUSIONS We showed that high OPN mRNA expression is associated with decreased DFS and OS in a large cohort of BC patients treated with adjuvant chemotherapy in a clinical trial setting. Our results suggest that OPN may serve as a prognostic factor and a potential target for therapy. Trial registration Australian New Zealand Clinical Trials Registry; HE10/97 ACTRN12611000506998; HE10/00 ACTRN12609001036202.
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Guarneri C, Bevelacqua V, Polesel J, Falzone L, Cannavò PS, Spandidos DA, Malaponte G, Libra M. NF‑κB inhibition is associated with OPN/MMP‑9 downregulation in cutaneous melanoma. Oncol Rep 2017; 37:737-746. [PMID: 28075446 PMCID: PMC5355753 DOI: 10.3892/or.2017.5362] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 12/20/2016] [Indexed: 01/21/2023] Open
Abstract
The development of cutaneous melanoma is influenced by genetic factors, including BRAF mutations and environmental factors, such as ultraviolet exposure. Its progression has been also associated with the involvement of several tumour microenvironmental molecules. Among these, nuclear factor‑κB (NF‑κB) has been indicated as a key player of osteopontin (OPN) and matrix metalloproteinase‑9 (MMP‑9) activation. However, whether NF‑κB plays a role in the development and progression of melanoma in association with the OPN/MMP‑9 axis according to the BRAFV600E mutation status has not been investigated in detail to date. Thus, in the present study, in order to shed light on this matter, 148 patients with melanoma and 53 healthy donors were recruited for the analysis of OPN, MMP‑9 and NF‑κB. Significantly higher circulating levels of OPN and MMP‑9 were observed in the patients with melanoma when compared to the healthy donors. Similar data were obtained for NF‑κB p65 activity. The OPN levels did not differ significantly between melanomas with or without BRAFV600E mutation. However, as regards NF‑κB and MMP‑9, significant differences were observed between the melanomas with or without BRAFV600E mutation. To determine whether NF‑κB inhibition is associated with a decrease in the levels of OPN and MMP‑9, peripheral blood mononuclear cells from 29 patients with melanoma were treated with the NF‑κB inhibitor, dehydroxymethylepoxyquinomycin (DHMEQ), with or without OPN. As expected, the inhibition of NF‑κB induced a marked decrease in both the OPN and MMP‑9 levels. Furthermore, the decrease in MMP‑9 levels was higher among melanomas harbouring the BRAFV600E mutation. Overall, our data suggest that the activation of MMP‑9 is associated with the BRAFV600E mutation status. Furthermore, such an activation is mediated by NF‑κB, suggesting its role as therapeutic target in patients with melanoma.
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Affiliation(s)
- Claudio Guarneri
- Department of Clinical and Experimental Medicine, Section of Dermatology, University of Messina, I-98125 Messina, Italy
| | - Valentina Bevelacqua
- Department of Biomedical and Biotechnological Sciences, Section of General and Clinical Pathology and Oncology, University of Catania, I-95124 Catania, Italy
| | - Jerry Polesel
- Unit of Cancer Epidemiology, CRO Aviano National Cancer Institute, IRCCS, I-33081 Aviano, Italy
| | - Luca Falzone
- Department of Biomedical and Biotechnological Sciences, Section of General and Clinical Pathology and Oncology, University of Catania, I-95124 Catania, Italy
| | - Patrizia S. Cannavò
- Department of Clinical and Experimental Medicine, Section of Dermatology, University of Messina, I-98125 Messina, Italy
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion 71003, Greece
| | - Grazia Malaponte
- Department of Biomedical and Biotechnological Sciences, Section of General and Clinical Pathology and Oncology, University of Catania, I-95124 Catania, Italy
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, Section of General and Clinical Pathology and Oncology, University of Catania, I-95124 Catania, Italy
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Khan Z, Marshall JF. The role of integrins in TGFβ activation in the tumour stroma. Cell Tissue Res 2016; 365:657-73. [PMID: 27515461 PMCID: PMC5010607 DOI: 10.1007/s00441-016-2474-y] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 07/07/2016] [Indexed: 12/27/2022]
Abstract
TGFβ1 is the most pleiotropic of all known cytokines and thus, to avoid uncontrolled TGFβ-activated processes, its activity is tightly regulated. Studies in fibrosis have led to the discovery that αv integrins are the major regulators of the local activation of latent TGFβ in our tissues. Since all cells can express one or more types of αv integrins, this raises the possibility that, in the complex milieu of a developing cancer, multiple cell types including both cancer cells and stromal cells activate TGFβ. In normal tissues, TGFβ1 is a tumour suppressor through its ability to suppress epithelial cell division, whereas in cancer, in which tumour cells develop genetic escape mechanisms to become resistant to TGFβ growth suppression, TGFβ signalling creates a tumour-permissive environment by activating fibroblast-to-myofibroblast transition, by promoting angiogenesis, by suppressing immune cell populations and by promoting the secretion of both matrix proteins and proteases. In addition, TGFβ drives epithelial-to-mesenchymal transition (EMT) increasing the potential for metastasis. Since αv integrins activate TGFβ, they almost certainly drive TGFβ-dependent cancer progression. In this review, we discuss the data that are helping to develop this hypothesis and describe the evidence that αv integrins regulate the TGFβ promotion of cancer. Graphical Abstract Mechanisms of integrin-mediated transforming growth factor beta (TGFβ) activation and its effect on stromal processes. 1 Matrix-bound latent LAP-TGFβ1 binds αv integrins expressed by epithelial cells or fibroblasts (LAP latency-associated peptide). TGFβ1 becomes exposed. 2 Active TGFβ1 binds the TGFβ receptor in an autocrine or paracrine fashion. 3 TGFβ1 signalling increases integrin expression, LAP-TGFβ1 secretion and trans-differentiation of fibroblasts into contractile cells that secrete collagens and collagen cross-linking proteins. By contracting the matrix, latent TGFβ1 is stretched making the activation of latent TGFβ1 easier and creating a continuous cycle of TGFβ1 signalling. TGFβ1 promotes cancer progression by promoting angiogenesis, immune suppression and epithelial-to-mesenchymal transition (EMT).
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Affiliation(s)
- Zareen Khan
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - John F. Marshall
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
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Song K, Liu N, Yang Y, Qiu X. Regulation of osteosarcoma cell invasion through osteopontin modification by miR-4262. Tumour Biol 2015; 37:6493-9. [DOI: 10.1007/s13277-015-4530-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 11/26/2015] [Indexed: 11/30/2022] Open
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