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Dastagir N, Liebsch C, Kutz J, Wronski S, Pich A, Obed D, Vogt PM, Bucan V, Strauß S. Identification of antimicrobial peptides from the Ambystoma mexicanum displaying antibacterial and antitumor activity. PLoS One 2025; 20:e0316257. [PMID: 40043049 PMCID: PMC11882074 DOI: 10.1371/journal.pone.0316257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 12/09/2024] [Indexed: 05/13/2025] Open
Abstract
Antibiotic resistance is a significant healthcare concern. Therefore, identifying target molecules that can serve as antibiotic substitutes is crucial. Among the promising candidates are antimicrobial peptides (AMPs). AMPs are defense mechanisms of the innate immune system which exist in almost all living organisms. Research on the AMPs of some amphibians has shown that, in addition to their antimicrobial effectiveness, AMPs also exhibit anti-inflammatory and anti-carcinogenic properties. In this study, we identify and characterize AMPs deriving from the skin mucus of the axolotl (Ambystoma mexicanum). Upon activity spectrum evaluation of the AMPs, we synthesized and ranked 22 AMPs according to antimicrobial efficacy by means of a prediction tool. To assess the AMPs' potential as antibacterial and anticarcinogenic compounds, we performed a minimum inhibitory concentration (MIC) assay for efficacy against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA), and an apoptosis assay on T-47D mammary carcinoma cells. We identified four AMPs that showed significant inhibition of MRSA, of which three also demonstrated anticarcinogenic activity. Gene expression analysis was performed on AMP-stimulated carcinoma cells using a breast cancer-specific RT-PCR array. In cells stimulated with the AMPs, gene expression analysis showed upregulation of tumor suppressor genes and downregulation of oncogenes. Overall, our work demonstrates the antimicrobial and anticarcinogenic activity of axolotl-derived AMPs. The results of this work serve as a basis to further investigate the mode of action and potential use of axolotl AMPs as therapeutic anticancer or antibiotic agents.
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Affiliation(s)
- Nadjib Dastagir
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Christina Liebsch
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Jaqueline Kutz
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Sabine Wronski
- Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
| | - Andreas Pich
- Hannover Medical School, Institute for Toxicology, Hannover, Germany
| | - Doha Obed
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Peter Maria Vogt
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Vesna Bucan
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Sarah Strauß
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
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Kinoshita J, Kinoshita Y, Nomura T, Inoue YH. Macrophage-like Blood Cells Are Involved in Inter-Tissue Communication to Activate JAK/STAT Signaling, Inducing Antitumor Turandot Proteins in Drosophila Fat Body via the TNF-JNK Pathway. Int J Mol Sci 2024; 25:13110. [PMID: 39684820 DOI: 10.3390/ijms252313110] [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: 10/06/2024] [Revised: 11/30/2024] [Accepted: 12/04/2024] [Indexed: 12/18/2024] Open
Abstract
Turandot (Tot) family proteins, which are induced via the JAK/STAT pathway after infection, also suppress lymph gland tumors in Drosophila mxcmbn1 mutant larvae. We investigated the potential role of hemocytes in Tot induction in tumor-bearing mutants via immunostaining and RNAi experiments. Normal hemocytes transplanted into mutant larvae were recruited to the tumor and fat body (FB), suggesting that these cells transmit tumor-related information. The transplanted hemocytes ectopically expressed Unpaired3 (Upd3), which is necessary for the activation of JAK/STAT. Eiger, a Drosophila tumor necrosis factor (TNF) ortholog, was highly expressed in tumors. Depletion of the Eiger receptor in hemocytes reduced Tot levels and eventually enhanced tumor growth. The c-Jun N-terminal kinase (JNK) pathway, acting downstream of the receptor, was also activated in the hemocytes of mutants. Downregulation of the JNK pathway in hemocytes inhibited Tot induction, leading to enhanced tumor growth. These results suggest that upd3 expression in hemocytes depends on the Eiger-JNK pathway. We propose that after Eiger activates the JNK pathway in hemocytes present on the tumor, cells expressing Upd3 are recruited to the FB. Upd3 then activates JAK/STAT to induce the expression of antitumor proteins. This study highlights the intricate communication between tissues via blood cells during tumor suppression.
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Affiliation(s)
- Juri Kinoshita
- Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo, Kyoto 606-0962, Japan
- Graduate School of Science and Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo, Kyoto 606-8585, Japan
| | - Yuriko Kinoshita
- Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo, Kyoto 606-0962, Japan
| | - Tadashi Nomura
- Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo, Kyoto 606-0962, Japan
- Graduate School of Science and Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo, Kyoto 606-8585, Japan
| | - Yoshihiro H Inoue
- Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo, Kyoto 606-0962, Japan
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Brem S. Vagus nerve stimulation: Novel concept for the treatment of glioblastoma and solid cancers by cytokine (interleukin-6) reduction, attenuating the SASP, enhancing tumor immunity. Brain Behav Immun Health 2024; 42:100859. [PMID: 39512605 PMCID: PMC11541944 DOI: 10.1016/j.bbih.2024.100859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/31/2024] [Accepted: 09/07/2024] [Indexed: 11/15/2024] Open
Abstract
Immuno-oncology, specifically immune checkpoint inhibitors (ICIs), has revolutionized cancer care with dramatic, long-term responses and increased survival, including patients with metastatic cancer to the brain. Glioblastomas, and other primary brain tumors, are refractory to ICIs as monotherapy or in combination with standard therapy. The tumor microenvironment (TME) poses multiple biological hurdles: blood-brain barrier, immune suppression, heterogeneity, and tumor infiltration. Genomic analysis of the senescence-associated secretory phenotype (SASP) and preclinical models of glioma suggest that an exciting approach would entail reprogramming of the glioma microenvironment, attenuating the pro-inflammatory, pro-tumorigenic cytokines of the SASP, especially interleukin-6 (IL-6). A testable hypothesis now proposed is to modulate the immune system by harnessing the body's 'inflammatory reflex' to reduce cytokines. Vagus nerve stimulation can activate T cell immunity by the cholinergic, α7nicotinic acetylcholine receptor agonist (α7nAchR), and suppress IL-6 systemically, as well as other pro-inflammatory cytokines of the SASP, interleukin -1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). The hypothesis predicts that electrical activation of the vagus nerve, with cytokine reduction, in combination with ICIs, would convert an immune resistant ("cold") tumor to an immune responsive ("hot") tumor, and halt glioma progression. The hypothesis also envisions cancer as an immune "dysautonomia" whereby a therapeutic intervention, vagus nerve stimulation (VNS), resets the systemic and local cytokine levels. A prospective, randomized, phase II clinical trial, to confirm the hypothesis, is a logical, exigent, next step. Cytokine reduction by VNS could also be useful for other forms of human cancer, e.g., breast, colorectal, head and neck, lung, melanoma, ovarian, pancreatic, and prostate cancer, as the emerging field of "cancer neuroscience" shows a role for neural regulation of multiple tumor types. Because IL-6, and companion pro-inflammatory cytokines, participate in the initiation, progression, spread and recurrence of cancer, minimally invasive VNS could be employed to suppress glioma or cancer progression, while also mitigating depression and/or seizures, thereby enhancing quality of life. The current hypothesis reimagines glioma pathophysiology as a dysautonomia with the therapeutic objective to reset the autonomic nervous system and form an immune responsive state to halt tumor progression and prevent recurrence. VNS, as a novel method to control cancer, can be administered with ICIs, standard therapy, or in clinical trials, combined with emerging immunotherapy: dendritic cell, mRNA, or chimeric antigen receptor (CAR) T cell vaccines.
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Affiliation(s)
- Steven Brem
- University of Pennsylvania, Department of Neurosurgery, Perelman Center for Advanced Medicine, 15-141, 3400 Civic Center Blvd., Philadelphia, PA, 19104, United States
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, 19104, United States
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Shakeri A, Najm L, Khan S, Tian L, Ladouceur L, Sidhu H, Al-Jabouri N, Hosseinidoust Z, Didar TF. Noncontact 3D Bioprinting of Proteinaceous Microarrays for Highly Sensitive Immunofluorescence Detection within Clinical Samples. ACS NANO 2024; 18:31506-31523. [PMID: 39468857 DOI: 10.1021/acsnano.4c12460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/30/2024]
Abstract
Immunofluorescence assays are extensively used for the detection of disease-associated biomarkers within patient samples for direct diagnosis. Unfortunately, these 2D microarrays suffer from low repeatability and fail to attain the low limits of detection (LODs) required to accurately discern disease progression for clinical monitoring. While three-dimensional microarrays with increased biorecognition molecule density stand to circumvent these limitations, their viscous component materials are not compatible with current microarray fabrication protocols. Herein, we introduce a platform for 3D microarray bioprinting, wherein a two-step printing approach enables the high-throughput fabrication of immunosorbent hydrogels. The hydrogels are composed entirely of cross-linked proteins decorated with clinically relevant capture antibodies. Compared to two-dimensional microarrays, these proteinaceous microarrays offer 3-fold increases in signal intensity. When tested with clinically relevant biomarkers, ultrasensitive single-plex and multiplex detection of interleukin-6 (LOD 0.3 pg/mL) and tumor necrosis factor receptor 1 (LOD 1 pg/mL) is observed. When challenged with clinical samples, these hydrogel microarrays consistently discern elevated levels of interleukin-6 in blood plasma derived from patients with systemic blood infections. Given their easy-to-implement, high-throughput fabrication, and ultrasensitive detection, these three-dimensional microarrays will enable better clinical monitoring of disease progression, yielding improved patient outcomes.
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Affiliation(s)
- Amid Shakeri
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada M5S 3G9
| | - Lubna Najm
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
| | - Shadman Khan
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
| | - Lei Tian
- Department of Chemical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
| | - Liane Ladouceur
- Department of Mechanical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
| | - Hareet Sidhu
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1
| | - Nadine Al-Jabouri
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1
| | - Zeinab Hosseinidoust
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
- Department of Chemical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
- Institute for Infectious Disease Research (IIDR), 1280 Main St W, McMaster University, Hamilton, Ontario, Canada L8S 4L8
- Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1
| | - Tohid F Didar
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
- Department of Mechanical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
- Institute for Infectious Disease Research (IIDR), 1280 Main St W, McMaster University, Hamilton, Ontario, Canada L8S 4L8
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Ray CMP, Yang H, Spangler JB, Mac Gabhann F. Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors. PLoS Comput Biol 2024; 20:e1012157. [PMID: 38848446 PMCID: PMC11189202 DOI: 10.1371/journal.pcbi.1012157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 06/20/2024] [Accepted: 05/10/2024] [Indexed: 06/09/2024] Open
Abstract
The spread of cancer from organ to organ (metastasis) is responsible for the vast majority of cancer deaths; however, most current anti-cancer drugs are designed to arrest or reverse tumor growth without directly addressing disease spread. It was recently discovered that tumor cell-secreted interleukin-6 (IL-6) and interleukin-8 (IL-8) synergize to enhance cancer metastasis in a cell-density dependent manner, and blockade of the IL-6 and IL-8 receptors (IL-6R and IL-8R) with a novel bispecific antibody, BS1, significantly reduced metastatic burden in multiple preclinical mouse models of cancer. Bispecific antibodies (BsAbs), which combine two different antigen-binding sites into one molecule, are a promising modality for drug development due to their enhanced avidity and dual targeting effects. However, while BsAbs have tremendous therapeutic potential, elucidating the mechanisms underlying their binding and inhibition will be critical for maximizing the efficacy of new BsAb treatments. Here, we describe a quantitative, computational model of the BS1 BsAb, exhibiting how modeling multivalent binding provides key insights into antibody affinity and avidity effects and can guide therapeutic design. We present detailed simulations of the monovalent and bivalent binding interactions between different antibody constructs and the IL-6 and IL-8 receptors to establish how antibody properties and system conditions impact the formation of binary (antibody-receptor) and ternary (receptor-antibody-receptor) complexes. Model results demonstrate how the balance of these complex types drives receptor inhibition, providing important and generalizable predictions for effective therapeutic design.
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Affiliation(s)
- Christina M. P. Ray
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Medical-Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Huilin Yang
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Jamie B. Spangler
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America
- Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Feilim Mac Gabhann
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
- Institute for Nano Biotechnology (INBT), Johns Hopkins University, Baltimore, Maryland, United States of America
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6
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Lujan DA, Ochoa JL, Beswick EJ, Howard TA, Hathaway HJ, Perrone-Bizzozero NI, Hartley RS. Cold-Inducible RNA Binding Protein Impedes Breast Tumor Growth in the PyMT Murine Model for Breast Cancer. Biomedicines 2024; 12:340. [PMID: 38397942 PMCID: PMC10886683 DOI: 10.3390/biomedicines12020340] [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: 12/15/2023] [Revised: 01/21/2024] [Accepted: 01/22/2024] [Indexed: 02/25/2024] Open
Abstract
RNA binding proteins (RBPs) post-transcriptionally regulate gene expression by associating with regulatory sequences in the untranslated regions of mRNAs. Cold-inducible RBP (CIRP) is a stress-induced RBP that was recently shown to modulate inflammation in response to cellular stress, where it increases or decreases pro-tumorigenic (proinflammatory) cytokines in different contexts. CIRP expression is altered in several cancers, including breast cancer, but the effects of CIRP on inflammation in breast cancer is not known. Here, we investigate if CIRP alters growth and the inflammatory profile of breast tumors. Transgenic mice overexpressing CIRP in the mammary epithelium were crossed with the PyMT mouse model of breast cancer, and the effects on both early and late tumorigenesis and inflammation were assessed. The effects of CIRP knockdown were also assessed in Py2T cell grafts. Overexpression of CIRP led to decreased tumorigenesis in the PyMT mouse model. Conversely, the knockdown of CIRP in Py2T cell grafts led to increased tumor growth. Luminex cytokine assays assessed the effects on the inflammatory environment. CIRP/PyMT mammary glands/mammary tumors and serum had decreased cytokines that promote inflammation, angiogenesis, and metastasis compared to PyMT mammary glands and serum, documenting a shift towards an environment less supportive of tumorigenesis. CIRP overexpression also decreased CD4+ helper T cells and increased CD8+ cytotoxic T cells in mammary tumors. Overall, these data support a role for CIRP as a potent antitumor molecule that suppresses both local and systemic pro-tumorigenic inflammation.
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Affiliation(s)
- Daniel A. Lujan
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA; (D.A.L.); (J.L.O.); (T.A.H.); (H.J.H.)
| | - Joey L. Ochoa
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA; (D.A.L.); (J.L.O.); (T.A.H.); (H.J.H.)
| | - Ellen J. Beswick
- Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY 40506, USA;
| | - Tamara A. Howard
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA; (D.A.L.); (J.L.O.); (T.A.H.); (H.J.H.)
| | - Helen J. Hathaway
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA; (D.A.L.); (J.L.O.); (T.A.H.); (H.J.H.)
| | - Nora I. Perrone-Bizzozero
- Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA;
| | - Rebecca S. Hartley
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA; (D.A.L.); (J.L.O.); (T.A.H.); (H.J.H.)
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7
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Lynce F, Stevens LE, Li Z, Brock JE, Gulvady A, Huang Y, Nakhlis F, Patel A, Force JM, Haddad TC, Ueno N, Stearns V, Wolff AC, Clark AS, Bellon JR, Richardson ET, Balko JM, Krop IE, Winer EP, Lange P, Hwang ES, King TA, Tolaney SM, Thompson A, Gupta GP, Mittendorf EA, Regan MM, Overmoyer B, Polyak K. TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer. Breast Cancer Res 2024; 26:20. [PMID: 38297352 PMCID: PMC10829369 DOI: 10.1186/s13058-024-01774-0] [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: 09/14/2023] [Accepted: 01/18/2024] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC. METHODS We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR). RESULTS Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells. CONCLUSION In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target. TRIAL REGISTRATION www. CLINICALTRIALS gov , NCT02876302. Registered 23 August 2016.
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Affiliation(s)
- Filipa Lynce
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA.
- Harvard Medical School, Boston, MA, USA.
- Brigham and Women's Hospital, Boston, MA, USA.
| | - Laura E Stevens
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Zheqi Li
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Jane E Brock
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Anushree Gulvady
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Ying Huang
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Faina Nakhlis
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Ashka Patel
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | | | | | - Naoto Ueno
- MD Anderson Cancer Center, Houston, TX, USA
| | | | | | - Amy S Clark
- University of Pennsylvania, Philadelphia, PA, USA
| | - Jennifer R Bellon
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Edward T Richardson
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Justin M Balko
- Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ian E Krop
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
- Yale Cancer Center, New Haven, CT, USA
| | - Eric P Winer
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
- Yale Cancer Center, New Haven, CT, USA
| | - Paulina Lange
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
| | | | - Tari A King
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Sara M Tolaney
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | | | | | - Elizabeth A Mittendorf
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Meredith M Regan
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Beth Overmoyer
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Kornelia Polyak
- Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA.
- Harvard Medical School, Boston, MA, USA.
- Brigham and Women's Hospital, Boston, MA, USA.
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8
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Azizi A, Mansouri N, Tarlan M, Sadeghi M. Analysis of Interleukin-6 Gene Variants ( rs1800795, rs1800796, rs1554606, rs1800797, rs2069840, rs12700386, and rs2069861) as Prognostic Markers in Breast Cancer: A Systematic Review, Meta-Analysis, and Network Analysis. J Interferon Cytokine Res 2024; 44:3-15. [PMID: 38029374 DOI: 10.1089/jir.2023.0090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023] Open
Abstract
Interleukin-6 (IL-6) has obviously tumor-promoting and tumor-inhibitory effects and can induce an epithelial-mesenchymal transition phenotype in human breast cancer (BC) cells and implicate its potential to promote BC metastasis. Herein, we aimed to evaluate the association of IL-6 variants (rs1800795, rs1800796, rs1554606, rs1800797, rs2069840, rs12700386, and rs2069861) with the susceptibility to BC. The databases of PubMed/Medline, Web of Science, Scopus, and Cochrane Library were searched until December 19, 2022, without any restrictions. The quality assessment of each study was performed based on the Newcastle-Ottawa Scale tool. The Review Manager 5.3 software presented the effect sizes including odds ratio (OR) along with a 95% confidence interval (CI). Both publication bias and sensitivity analyses were carried out by the Comprehensive Meta-Analysis version 2.0 software. A total of 2,508 records were identified among databases and at last, 27 articles were entered into the meta-analysis. Seven polymorphisms of IL-6 were entered into the analyses. Just rs1800797 polymorphism in the dominant model (OR = 1.51; 95% CI = 1.15-2.00; P = 0.003) and rs2069840 polymorphism in heterozygous (OR = 0.89; 95% CI = 0.81-0.97; P = 0.008) and dominant (OR = 0.91; 95% CI = 0.84-0.99; P = 0.02) models had a significant association with the BC risk. In conclusion, among 7 polymorphisms and despite a few included cases, the present meta-analysis recommended that the AA+GA genotype of rs1800797 polymorphism had a significantly elevated risk and the GC and the CC+GC genotypes of rs2069840 polymorphism had a protective role in the BC patients.
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Affiliation(s)
- Ali Azizi
- Social Development and Health Promotion Research Center, Department of Family and Community Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nasrin Mansouri
- Department of Obstetrics and Gynecology, Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mitra Tarlan
- Department of Physiology, Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Sadeghi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
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9
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Zhu S, Jaffiol R, Crunteanu A, Vézy C, Chan ST, Yuan W, Ho HP, Zeng S. Label-free biosensing with singular-phase-enhanced lateral position shift based on atomically thin plasmonic nanomaterials. LIGHT, SCIENCE & APPLICATIONS 2024; 13:2. [PMID: 38161210 PMCID: PMC10757996 DOI: 10.1038/s41377-023-01345-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 11/18/2023] [Accepted: 11/24/2023] [Indexed: 01/03/2024]
Abstract
Rapid plasmonic biosensing has attracted wide attention in early disease diagnosis and molecular biology research. However, it was still challenging for conventional angle-interrogating plasmonic sensors to obtain higher sensitivity without secondary amplifying labels such as plasmonic nanoparticles. To address this issue, we developed a plasmonic biosensor based on the enhanced lateral position shift by phase singularity. Such singularity presents as a sudden phase retardation at the dark point of reflection from resonating plasmonic substrate, leading to a giant position shift on reflected beam. Herein, for the first time, the atomically thin layer of Ge2Sb2Te5 (GST) on silver nanofilm was demonstrated as a novel phase-response-enhancing plasmonic material. The GST layer was not only precisely engineered to singularize phase change but also served as a protective layer for active silver nanofilm. This new configuration has achieved a record-breaking largest position shift of 439.3 μm measured in calibration experiments with an ultra-high sensitivity of 1.72 × 108 nm RIU-1 (refractive index unit). The detection limit was determined to be 6.97 × 10-7 RIU with a 0.12 μm position resolution. Besides, a large figure of merit (FOM) of 4.54 × 1011 μm (RIU∙°)-1 was evaluated for such position shift interrogation, enabling the labelfree detection of trace amounts of biomolecules. In targeted biosensing experiments, the optimized sensor has successfully detected small cytokine biomarkers (TNF-α and IL-6) with the lowest concentration of 1 × 10-16 M. These two molecules are the key proinflammatory cancer markers in clinical diagnosis, which cannot be directly screened by current clinical techniques. To further validate the selectivity of our sensing systems, we also measured the affinity of integrin binding to arginylglycylaspartic acid (RGD) peptide (a key protein interaction in cell adhesion) with different Mn2+ ion concentrations, ranging from 1 nM to 1 mM.
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Affiliation(s)
- Shaodi Zhu
- Light, Nanomaterials & Nanotechnologies (L2n), CNRS-EMR 7004, University of Technology of Troyes, 10000, Troyes, France
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Rodolphe Jaffiol
- Light, Nanomaterials & Nanotechnologies (L2n), CNRS-EMR 7004, University of Technology of Troyes, 10000, Troyes, France
| | - Aurelian Crunteanu
- XLIM Research Institute, UMR 7252 CNRS/University of Limoges, 123, Avenue Albert Thomas, Limoges, France
| | - Cyrille Vézy
- Light, Nanomaterials & Nanotechnologies (L2n), CNRS-EMR 7004, University of Technology of Troyes, 10000, Troyes, France
| | - Sik-To Chan
- Light, Nanomaterials & Nanotechnologies (L2n), CNRS-EMR 7004, University of Technology of Troyes, 10000, Troyes, France
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Wu Yuan
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Ho-Pui Ho
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
| | - Shuwen Zeng
- Light, Nanomaterials & Nanotechnologies (L2n), CNRS-EMR 7004, University of Technology of Troyes, 10000, Troyes, France.
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10
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Ray CMP, Yang H, Spangler JB, Mac Gabhann F. Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.18.570445. [PMID: 38187701 PMCID: PMC10769311 DOI: 10.1101/2023.12.18.570445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
The spread of cancer from organ to organ (metastasis) is responsible for the vast majority of cancer deaths; however, most current anti-cancer drugs are designed to arrest or reverse tumor growth without directly addressing disease spread. It was recently discovered that tumor cell-secreted interleukin-6 (IL-6) and interleukin-8 (IL-8) synergize to enhance cancer metastasis in a cell-density dependent manner, and blockade of the IL-6 and IL-8 receptors (IL-6R and IL-8R) with a novel bispecific antibody, BS1, significantly reduced metastatic burden in multiple preclinical mouse models of cancer. Bispecific antibodies (BsAbs), which combine two different antigen-binding sites into one molecule, are a promising modality for drug development due to their enhanced avidity and dual targeting effects. However, while BsAbs have tremendous therapeutic potential, elucidating the mechanisms underlying their binding and inhibition will be critical for maximizing the efficacy of new BsAb treatments. Here, we describe a quantitative, computational model of the BS1 BsAb, exhibiting how modeling multivalent binding provides key insights into antibody affinity and avidity effects and can guide therapeutic design. We present detailed simulations of the monovalent and bivalent binding interactions between different antibody constructs and the IL-6 and IL-8 receptors to establish how antibody properties and system conditions impact the formation of binary (antibody-receptor) and ternary (receptor-antibody-receptor) complexes. Model results demonstrate how the balance of these complex types drives receptor inhibition, providing important and generalizable predictions for effective therapeutic design.
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Affiliation(s)
- Christina MP Ray
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Medical-Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Huilin Yang
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Jamie B Spangler
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America
- Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Feilim Mac Gabhann
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
- Institute for Nano Biotechnology (INBT), Johns Hopkins University, Baltimore, Maryland, United States of America
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11
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Berger K, Persson E, Gregersson P, Ruiz-Martínez S, Jonasson E, Ståhlberg A, Rhost S, Landberg G. Interleukin-6 Induces Stem Cell Propagation through Liaison with the Sortilin-Progranulin Axis in Breast Cancer. Cancers (Basel) 2023; 15:5757. [PMID: 38136303 PMCID: PMC10741783 DOI: 10.3390/cancers15245757] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 10/25/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Unraveling the complex network between cancer cells and their tumor microenvironment is of clinical importance, as it might allow for the identification of new targets for cancer treatment. Cytokines and growth factors secreted by various cell types present in the tumor microenvironment have the potential to affect the challenging subpopulation of cancer stem cells showing treatment-resistant properties as well as aggressive features. By using various model systems, we investigated how the breast cancer stem cell-initiating growth factor progranulin influenced the secretion of cancer-associated proteins. In monolayer cultures, progranulin induced secretion of several inflammatory-related cytokines, such as interleukin (IL)-6 and -8, in a sortilin-dependent manner. Further, IL-6 increased the cancer stem fraction similarly to progranulin in the breast cancer cell lines MCF7 and MDA-MB-231 monitored by the surrogate mammosphere-forming assay. In a cohort of 63 patient-derived scaffold cultures cultured with breast cancer cells, we observed significant correlations between IL-6 and progranulin secretion, clearly validating the association between IL-6 and progranulin also in human-based microenvironments. In conclusion, the interplay between progranulin and IL-6 highlights a dual breast cancer stem cell-promoting function via sortilin, further supporting sortilin as a highly relevant therapeutic target for aggressive breast cancer.
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Affiliation(s)
- Karoline Berger
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Emma Persson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Pernilla Gregersson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Santiago Ruiz-Martínez
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Emma Jonasson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Anders Ståhlberg
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
- Wallenberg Center for Molecular and Translational Medicine, University of Gothenburg, 41390 Gothenburg, Sweden
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, 41346 Gothenburg, Sweden
| | - Sara Rhost
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Göran Landberg
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
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12
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Afshari H, Noori S, Zarghi A. Curcumin potentiates the anti-inflammatory effects of Tehranolide by modulating the STAT3/NF-κB signaling pathway in breast and ovarian cancer cell lines. Inflammopharmacology 2023; 31:2541-2555. [PMID: 37452228 DOI: 10.1007/s10787-023-01281-2] [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: 01/17/2023] [Accepted: 06/09/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND Studies have demonstrated that natural products, such as curcumin and artemisinin, possess anti-inflammatory effects, which can be beneficial for cancer treatment. Tehranolide, as a novel natural product, has a wide range of biological activities, including anti-cancer effects. However, many properties of Tehranolide, like its anti-inflammatory activity and its combination with curcumin, have not been investigated yet. This investigation examined the anti-inflammatory activity of Tehranolide, either alone or in combination with curcumin, via modulating the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and STAT3 (signal transducer and activator of transcription 3) signaling pathways in MDA-MB-231 and SKOV3, breast and ovarian cancer cell lines. METHODS ELISA-based methods were employed to measure the pro-inflammatory cytokine levels and the NF-κB activity in lipopolysaccharide (LPS)-induced cells. The real-time PCR experiment and Griess test were performed to evaluate inducible nitric oxide synthase (iNOS) gene expression and nitrite levels, respectively. The STAT3 and NF-κB signaling pathways were investigated by Western blotting analysis. Tehranolide's anti-cancer activity was also assessed in a mouse model of breast cancer using the TUNEL (terminal deoxynucleotidyl transferase nick-end labeling) assay. RESULTS Tehranolide diminished levels of pro-inflammatory cytokines in cancer cells. Additionally, it suppressed NF-κB DNA binding and STAT3 phosphorylation, reducing iNOS gene expression and nitrite production. Moreover, Western blotting showed that Tehranolide enhanced the inhibitory κB (IκBα) and Bcl-2 (B-cell lymphoma 2)-associated X (BAX) expression, and downregulated the expression of Bcl-2 proteins. Furthermore, the TUNEL assay demonstrated that Tehranolide induced apoptosis in a breast cancer mouse model. Curcumin potentiated all the anti-inflammatory effects of Tehranolide. CONCLUSION This investigation indicated for the first time that Tehranolide, either alone or in combination with curcumin, exerted its anti-inflammatory effects by suppressing NF-κB and STAT3 signaling pathways in SKOV3 and MDA-MB-231 cells.
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Affiliation(s)
- Havva Afshari
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shokoofe Noori
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Afshin Zarghi
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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13
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Rahman MA, Pal RK, Islam N, Freeman R, Berthiaume F, Mazzeo A, Ashraf A. A Facile Graphene Conductive Polymer Paper Based Biosensor for Dopamine, TNF-α, and IL-6 Detection. SENSORS (BASEL, SWITZERLAND) 2023; 23:8115. [PMID: 37836943 PMCID: PMC10575219 DOI: 10.3390/s23198115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/20/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023]
Abstract
Paper-based biosensors are a potential paradigm of sensitivity achieved via microporous spreading/microfluidics, simplicity, and affordability. In this paper, we develop decorated paper with graphene and conductive polymer (herein referred to as graphene conductive polymer paper-based sensor or GCPPS) for sensitive detection of biomolecules. Planetary mixing resulted in uniformly dispersed graphene and conductive polymer ink, which was applied to laser-cut Whatman filter paper substrates. Scanning electron microscopy and Raman spectroscopy showed strong attachment of conductive polymer-functionalized graphene to cellulose fibers. The GCPPS detected dopamine and cytokines, such as tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) in the ranges of 12.5-400 µM, 0.005-50 ng/mL, and 2 pg/mL-2 µg/mL, respectively, using a minute sample volume of 2 µL. The electrodes showed lower detection limits (LODs) of 3.4 µM, 5.97 pg/mL, and 9.55 pg/mL for dopamine, TNF-α, and IL-6 respectively, which are promising for rapid and easy analysis for biomarkers detection. Additionally, these paper-based biosensors were highly selective (no serpin A1 detection with IL-6 antibody) and were able to detect IL-6 antigen in human serum with high sensitivity and hence, the portable, adaptable, point-of-care, quick, minute sample requirement offered by our fabricated biosensor is advantageous to healthcare applications.
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Affiliation(s)
- Md Ashiqur Rahman
- Department of Mechanical Engineering, Purdue University, West Lafayette, IN 47906, USA;
| | - Ramendra Kishor Pal
- Hyderabad Campus, Birla Institute of Technology and Science Pilani, Hyderabad 500078, Telangana, India;
| | - Nazmul Islam
- Department of Electrical and Computer Engineering, University of Texas Rio Grande Valley, Edinburg, TX 78539, USA;
| | - Robert Freeman
- Department of Mechanical Engineering, University of Texas Rio Grande Valley, Edinburg, TX 78539, USA;
| | - Francois Berthiaume
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA;
| | - Aaron Mazzeo
- Department of Mechanical & Aerospace Engineering, Rutgers University, Piscataway, NJ 08854, USA
| | - Ali Ashraf
- Department of Mechanical Engineering, University of Texas Rio Grande Valley, Edinburg, TX 78539, USA;
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Schmid T, Wegener F, Hotfiel T, Hoppe MW. Moderate evidence exists for four microRNAs as potential biomarkers for tendinopathies and degenerative tendon ruptures at the upper extremity in elderly patients: conclusion of a systematic review with best-evidence synthesis. J Exp Orthop 2023; 10:81. [PMID: 37563331 PMCID: PMC10415244 DOI: 10.1186/s40634-023-00645-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 07/22/2023] [Indexed: 08/12/2023] Open
Abstract
PURPOSE The aim of this systematic review was to investigate tendon-specific microRNAs (miRNAs) as biomarkers for the detection of tendinopathies or degenerative tendon ruptures. Also, their regulatory mechanisms within the tendon pathophysiology were summarized. METHODS A systematic literature research was performed using the PRISMA guidelines. The search was conducted in the Pubmed database. The SIGN checklist was used to assess the study quality of the included original studies. To determine the evidence and direction of the miRNA expression rates, a best-evidence synthesis was carried out, whereby only studies with at least a borderline methodological quality were considered for validity purposes. RESULTS Three thousand three hundred seventy studies were reviewed from which 22 fulfilled the inclusion criteria. Moderate evidence was found for miR-140-3p and miR-425-5p as potential biomarkers for tendinopathies as well as for miR-25-3p, miR-29a-3p, miR-140-3p, and miR-425-5p for the detection of degenerative tendon ruptures. This evidence applies to tendons at the upper extremity in elderly patients. All miRNAs were associated with inflammatory cytokines as interleukin-6 or interleukin-1ß and tumor necrosis factor alpha. CONCLUSIONS Moderate evidence exists for four miRNAs as potential biomarkers for tendinopathies and degenerative tendon ruptures at the upper extremity in elderly patients. The identified miRNAs are associated with inflammatory processes.
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Affiliation(s)
- Tristan Schmid
- Movement and Training Science, Leipzig University, Jahnallee 59, 04109, Leipzig, Germany.
| | - Florian Wegener
- Movement and Training Science, Leipzig University, Jahnallee 59, 04109, Leipzig, Germany
| | - Thilo Hotfiel
- Center for Musculoskeletal Surgery Osnabrück (OZMC), Klinikum Osnabrück, Am Finkenhügel 1, 49076, Osnabrueck, Germany
| | - Matthias W Hoppe
- Movement and Training Science, Leipzig University, Jahnallee 59, 04109, Leipzig, Germany
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15
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Shakir N, Sharif A, Ali S, Akhtar B, Akhtar MF, Muhammad F, Saleem A, Akhtar K, Tariq I, Khan MI. Pirarubicin loaded biodegradable nanoparticles downregulate IL-6, COX-II and TNF-α along with oxidative stress markers in comparison to conventional pirarubicin in healthy albino rats. J Drug Deliv Sci Technol 2023; 84:104498. [DOI: 10.1016/j.jddst.2023.104498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
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16
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Tarek A, Mohamed HT, El-Sharkawy AA, El-Sayed SK, Hirshon JM, Woodward WA, El-Shinawi M, Mohamed MM. Differential Gene Expression of fresh tissue and patient-derived explants' matricellular proteins augment inflammatory breast cancer metastasis: the possible role of IL-6 and MCP-1. QJM 2023; 116:345-354. [PMID: 36592055 PMCID: PMC10226750 DOI: 10.1093/qjmed/hcac284] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/25/2022] [Accepted: 12/22/2022] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Matricellular proteins comprising matrisome and adhesome are responsible for structure integrity and interactions between cells in the tumour microenvironment of breast cancer. Changes in the gene expression of matrisome and adhesome augment metastasis. Since inflammatory breast cancer (IBC) is characterized by high metastatic behaviour. Herein, we compared the gene expression profile of matrisome and adhesome in non-IBC and IBC in fresh tissue and ex vivo patient-derived explants (PDEs) and we also compared the secretory inflammatory mediators of PDEs in non-IBC and IBC to identify secretory cytokines participate in cross-talk between cells via interactions with matrisome and adhisome. METHODS Fifty patients (31 non-IBC and 19 IBC) were enrolled in the present study. To test their validation in clinical studies, PDEs were cultured as an ex vivo model. Gene expression and cytokine array were used to identify candidate genes and cytokines contributing to metastasis in the examined fresh tissues and PDEs. Bioinformatics analysis was applied on identified differentially expressed genes using GeneMANIA and Metascape gene annotation and analysis resource to identify pathways involved in IBC metastasis. RESULTS Normal and cancer fresh tissues and PDEs of IBC were characterized by overexpression of CDH1 and MMP14 and downregulation of CTNNA1 and TIMP1 compared with non-IBC. The secretome of IBC cancer PDEs is characterized by significantly high expression of interleukin 6 and monocyte chemoattractant protein-1 (CCL2) compared with non-IBC. CONCLUSION Genes expressed by adhisome and matrisome play a significant role in IBC metastasis and should be considered novel target therapy.
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Affiliation(s)
- Alshaimaa Tarek
- From the Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Hossam Taha Mohamed
- From the Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
- Faculty of Biotechnology, October University for Modern Sciences and Arts, Giza 12451, Egypt
| | - Aya Ali El-Sharkawy
- From the Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | | | - Jon Mark Hirshon
- School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - Wendy A Woodward
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mohamed El-Shinawi
- Faculty of Medicine, Galala University, Suez 43511, Egypt
- Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Mona Mostafa Mohamed
- From the Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
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17
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Huang R, Wang H, Hong J, Wang Z, Wu J, Huang O, He J, Chen W, Li Y, Chen X, Shen K. A senescence-associated signature refines the classification of different modification patterns and characterization of tumor immune microenvironment infiltration in triple-negative breast cancer. Front Pharmacol 2023; 14:1191910. [PMID: 37251343 PMCID: PMC10213971 DOI: 10.3389/fphar.2023.1191910] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 04/17/2023] [Indexed: 05/31/2023] Open
Abstract
Background: Recent studies have found that senescence-associated genes play a significant role in cancer biological processes. We aimed to analyze the characteristics and role of senescence-associated genes in triple-negative breast cancer (TNBC). Methods: We systematically screened senescence-associated secretory phenotype (SASP) genes based on the gene expression information in the TCGA database. According to the expression levels of senescence-associated genes, TNBC was classified into two subtypes, namely, TNBCSASP1 and TNBCSASP2, using an unsupervised cluster algorithm. We then performed gene expression, enrichment pathway, immune infiltration, mutational profile characterization, drug sensitivity and prognostic value analyses for the two subtypes. The reliability and prognostic predictive utility of this classification model were validated. The most prognostically relevant gene, FAM3B, was comprehensively identified and validated by tissue microarray in TNBC. Results: TNBC was classified into two senescence-associated subtypes, TNBCSASP1 and TNBCSASP2, based on the set of senescence-associated secretory phenotype genes, among which the TNBCSASP1 subtype had a poor prognosis. The TNBCSASP1 subtype was immunosuppressed, with suppressed immune-related signaling pathways and low immune cell infiltration. The effect of the mutation on the TP53 and TGF-β pathways could be related to the poor prognosis of the TNBCSASP1 subtype. Drug sensitivity analysis showed that AMG.706, CCT007093, and CHIR.99021 were potential targeted drugs for the TNBCSASP1 subtype. Finally, FAM3B was a key biomarker affecting the prognosis of patients with triple-negative breast cancer. Compared to normal breast tissue, the expression of FAM3B was reduced in triple-negative breast cancer. Survival analysis showed that overall survival was significantly shorter in triple-negative breast cancer patients with high FAM3B expression. Conclusion: A senescence-associated signature with different modification patterns has critical potential for providing a better understanding of TNBC biological processes, and FAM3B might serve as an applicable target for TNBC therapy.
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Affiliation(s)
| | | | | | - Zheng Wang
- *Correspondence: Zheng Wang, ; Xiaosong Chen, ; Kunwei Shen,
| | | | | | | | | | | | - Xiaosong Chen
- *Correspondence: Zheng Wang, ; Xiaosong Chen, ; Kunwei Shen,
| | - Kunwei Shen
- *Correspondence: Zheng Wang, ; Xiaosong Chen, ; Kunwei Shen,
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Nada H, Sivaraman A, Lu Q, Min K, Kim S, Goo JI, Choi Y, Lee K. Perspective for Discovery of Small Molecule IL-6 Inhibitors through Study of Structure–Activity Relationships and Molecular Docking. J Med Chem 2023; 66:4417-4433. [PMID: 36971365 DOI: 10.1021/acs.jmedchem.2c01957] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
Interleukin-6 (IL-6) is a proinflammatory cytokine that plays a key role in the pathogenesis and physiology of inflammatory and autoimmune diseases, such as coronary heart disease, cancer, Alzheimer's disease, asthma, rheumatoid arthritis, and most recently COVID-19. IL-6 and its signaling pathway are promising targets in the treatment of inflammatory and autoimmune diseases. Although, anti-IL-6 monoclonal antibodies are currently being used in clinics, huge unmet medical needs remain because of the high cost, administration-related toxicity, lack of opportunity for oral dosing, and potential immunogenicity of monoclonal antibody therapy. Furthermore, nonresponse or loss of response to monoclonal antibody therapy has been reported, which increases the importance of optimizing drug therapy with small molecule drugs. This work aims to provide a perspective for the discovery of novel small molecule IL-6 inhibitors by the analysis of the structure-activity relationships and computational studies for protein-protein inhibitors targeting the IL-6/IL-6 receptor/gp130 complex.
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CoNet: Efficient Network Regression for Survival Analysis in Transcriptome-Wide Association Studies—With Applications to Studies of Breast Cancer. Genes (Basel) 2023; 14:genes14030586. [PMID: 36980857 PMCID: PMC10048118 DOI: 10.3390/genes14030586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/23/2023] [Accepted: 02/23/2023] [Indexed: 03/02/2023] Open
Abstract
Transcriptome-wide association studies (TWASs) aim to detect associations between genetically predicted gene expression and complex diseases or traits through integrating genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) mapping studies. Most current TWAS methods analyze one gene at a time, ignoring the correlations between multiple genes. Few of the existing TWAS methods focus on survival outcomes. Here, we propose a novel method, namely a COx proportional hazards model for NEtwork regression in TWAS (CoNet), that is applicable for identifying the association between one given network and the survival time. CoNet considers the general relationship among the predicted gene expression as edges of the network and quantifies it through pointwise mutual information (PMI), which is under a two-stage TWAS. Extensive simulation studies illustrate that CoNet can not only achieve type I error calibration control in testing both the node effect and edge effect, but it can also gain more power compared with currently available methods. In addition, it demonstrates superior performance in real data application, namely utilizing the breast cancer survival data of UK Biobank. CoNet effectively accounts for network structure and can simultaneously identify the potential effecting nodes and edges that are related to survival outcomes in TWAS.
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Habanjar O, Bingula R, Decombat C, Diab-Assaf M, Caldefie-Chezet F, Delort L. Crosstalk of Inflammatory Cytokines within the Breast Tumor Microenvironment. Int J Mol Sci 2023; 24:4002. [PMID: 36835413 PMCID: PMC9964711 DOI: 10.3390/ijms24044002] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/10/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023] Open
Abstract
Several immune and immunocompetent cells, including dendritic cells, macrophages, adipocytes, natural killer cells, T cells, and B cells, are significantly correlated with the complex discipline of oncology. Cytotoxic innate and adaptive immune cells can block tumor proliferation, and others can prevent the immune system from rejecting malignant cells and provide a favorable environment for tumor progression. These cells communicate with the microenvironment through cytokines, a chemical messenger, in an endocrine, paracrine, or autocrine manner. These cytokines play an important role in health and disease, particularly in host immune responses to infection and inflammation. They include chemokines, interleukins (ILs), adipokines, interferons, colony-stimulating factors (CSFs), and tumor necrosis factor (TNF), which are produced by a wide range of cells, including immune cells, such as macrophages, B-cells, T-cells, and mast cells, as well as endothelial cells, fibroblasts, a variety of stromal cells, and some cancer cells. Cytokines play a crucial role in cancer and cancer-related inflammation, with direct and indirect effects on tumor antagonistic or tumor promoting functions. They have been extensively researched as immunostimulatory mediators to promote the generation, migration and recruitment of immune cells that contribute to an effective antitumor immune response or pro-tumor microenvironment. Thus, in many cancers such as breast cancer, cytokines including leptin, IL-1B, IL-6, IL-8, IL-23, IL-17, and IL-10 stimulate while others including IL-2, IL-12, and IFN-γ, inhibit cancer proliferation and/or invasion and enhance the body's anti-tumor defense. Indeed, the multifactorial functions of cytokines in tumorigenesis will advance our understanding of cytokine crosstalk pathways in the tumor microenvironment, such as JAK/STAT, PI3K, AKT, Rac, MAPK, NF-κB, JunB, cFos, and mTOR, which are involved in angiogenesis, cancer proliferation and metastasis. Accordingly, targeting and blocking tumor-promoting cytokines or activating and amplifying tumor-inhibiting cytokines are considered cancer-directed therapies. Here, we focus on the role of the inflammatory cytokine system in pro- and anti-tumor immune responses, discuss cytokine pathways involved in immune responses to cancer and some anti-cancer therapeutic applications.
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Affiliation(s)
- Ola Habanjar
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Rea Bingula
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Caroline Decombat
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Mona Diab-Assaf
- Equipe Tumorigénèse Pharmacologie Moléculaire et Anticancéreuse, Faculté des Sciences II, Université Libanaise Fanar, Beyrouth 1500, Lebanon
| | - Florence Caldefie-Chezet
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Laetitia Delort
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
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Zhang D, Li Y, Liang M, Liang Y, Tian J, He Q, Yang B, Jin J, Zhu W. LC-MS/MS based metabolomics and proteomics reveal candidate biomarkers and molecular mechanism of early IgA nephropathy. Clin Proteomics 2022; 19:51. [PMID: 36572849 PMCID: PMC9793667 DOI: 10.1186/s12014-022-09387-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 12/07/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN), a globally common primary chronic glomerulopathy, is one of the leading causes of end-stage renal disease. However, the underlying mechanisms of IgAN have yet to be demonstrated. There were no adequate and reliable plasma biomarkers for clinical diagnosis, especially at the early stage. In the present study, integrative proteomics and metabolomics were aimed at exploring the mechanism of IgAN and identifying potential biomarkers. METHODS Plasma from IgAN and healthy individuals were collected and analyzed in a randomized controlled manner. Data-independent acquisition quantification proteomics and mass spectrometry based untargeted metabolomics techniques were used to profile the differentially expressed proteins (DEPs) and differentially abundant metabolites (DAMs) between two groups and identify potential biomarkers for IgAN from health at the early stage. Disease-related pathways were screened out by clustering and function enrichment analyses of DEPs and DAMs. And the potential biomarkers for IgAN were identified through the machine learning approach. Additionally, an independent cohort was used to validate the priority candidates by enzyme-linked immunosorbent assay (ELISA). RESULTS Proteomic and metabolomic analyses of IgAN plasma showed that the complement and the immune system were activated, while the energy and amino acid metabolism were disordered in the IgAN patients. PRKAR2A, IL6ST, SOS1, and palmitoleic acid have been identified as potential biomarkers. Based on the AUC value for the training and test sets, the classification performance was 0.994 and 0.977, respectively. The AUC of the external validation of the four biomarkers was 0.91. CONCLUSION In this study, we combined proteomics and metabolomics techniques to analyze the plasma of IgAN patients and healthy individuals, constructing a biomarker panel, which could provide new insights and provide potential novel molecular diagnoses for IgAN.
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Affiliation(s)
- Di Zhang
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
| | - Yaohan Li
- grid.13402.340000 0004 1759 700XCollege of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, 310027 Zhejiang China ,grid.410726.60000 0004 1797 8419The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310002 Zhejiang China
| | - Mingzhu Liang
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
| | - Yan Liang
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
| | - Jingkui Tian
- grid.410726.60000 0004 1797 8419The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310002 Zhejiang China
| | - Qiang He
- grid.417400.60000 0004 1799 0055Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, 310000 Zhejiang China
| | - Bingxian Yang
- grid.413273.00000 0001 0574 8737College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018 China
| | - Juan Jin
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
| | - Wei Zhu
- grid.410726.60000 0004 1797 8419The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310002 Zhejiang China
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22
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McGovern KA, Durham WJ, Wright TJ, Dillon EL, Randolph KM, Danesi CP, Urban RJ, Sheffield-Moore M. Impact of Adjunct Testosterone on Cancer-Related Fatigue: An Ancillary Analysis from a Controlled Randomized Trial. Curr Oncol 2022; 29:8340-8356. [PMID: 36354718 PMCID: PMC9689748 DOI: 10.3390/curroncol29110658] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/29/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
Many cancer patients undergoing treatment experience cancer-related fatigue (CRF). Inflammatory markers are correlated with CRF but are not routinely targeted for treatment. We previously demonstrated in an NIH-funded placebo-controlled, double-blind, randomized clinical trial (NCT00878995, closed to follow-up) that seven weekly injections of 100 mg adjunct testosterone preserved lean body mass in cancer patients undergoing standard-of-care treatment in a hospital setting. Because testosterone therapy can reduce circulating proinflammatory cytokines, we conducted an ancillary analysis to determine if this testosterone treatment reduced inflammatory burden and improved CRF symptoms and health-related quality of life. Randomization was computer-generated and managed by the pharmacy, which dispensed testosterone and placebo in opaque syringes to the administering study personnel. A total of 24 patients were randomized (14 placebo, 10 testosterone), and 21 were included in the primary analysis (11 placebo, 10 testosterone). Testosterone therapy did not ameliorate CRF symptoms (placebo to testosterone difference in predicted mean multidimensional fatigue symptom inventory scores: -5.6, 95% CI: -24.6 to 13.3), improve inflammatory markers, or preserve health-related quality of life and functional measures of performance in late-stage cancer patients.
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Affiliation(s)
- Kristen A. McGovern
- Department of Internal Medicine, The University of Texas Medical Branch (UTMB), 301 University Blvd., Galveston, TX 77555, USA
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Villarreal-García V, Estupiñan-Jiménez JR, Vivas-Mejía PE, Gonzalez-Villasana V, Vázquez-Guillén JM, Reséndez-Pérez D. A vicious circle in breast cancer: The interplay between inflammation, reactive oxygen species, and microRNAs. Front Oncol 2022; 12:980694. [PMID: 36226048 PMCID: PMC9548555 DOI: 10.3389/fonc.2022.980694] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 09/05/2022] [Indexed: 11/28/2022] Open
Abstract
Breast cancer (BC) is the most common cancer in women worldwide. This highly heterogeneous disease is molecularly stratified into luminal A, luminal B, HER2, triple-negative/basal-like, and normal-like subtypes. An important aspect in BC progression is the activation of inflammatory processes. The activation of CD8+/Th1, NK, and M1 tumor associated macrophages (TAMs), leads to tumor destruction. In contrast, an anti-inflammatory response mediated by CD4+/Th2 and M2 TAMs will favor tumor progression. Inflammation also stimulates the production of inflammatory mediators like reactive oxygen species (ROS). In chronic inflammation, ROS activates oxidative stress and endothelial dysfunction. In cancer, ROS plays a dual role with anti-tumorigenic and pro-tumorigenic effects in cell signaling pathways that control proliferation, survival, apoptosis, and inflammation. MicroRNAs (miRNAs), which are known to be involved in BC progression and inflammation, can be regulated by ROS. At the same time, miRNAs regulate the expression of genes modulating oxidative stress. In this review, we will discuss the interplay between inflammation, ROS, and miRNAs as anticancer and tumor promoter molecules in BC. A clear understanding of the role of miRNAs in the regulation of ROS production and inflammation, may lead to new opportunities for therapy in BC.
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Affiliation(s)
- Valeria Villarreal-García
- Departmento de Biología Celular y Genética, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo León, Mexico
| | - José Roberto Estupiñan-Jiménez
- Departmento de Biología Celular y Genética, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo León, Mexico
| | - Pablo E. Vivas-Mejía
- Department of Biochemestry, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico
- Comprehensive Cancer Center, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico
| | - Vianey Gonzalez-Villasana
- Departmento de Biología Celular y Genética, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo León, Mexico
| | - José Manuel Vázquez-Guillén
- Departamento de Inmunología y Virología, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo León, Mexico
| | - Diana Reséndez-Pérez
- Departmento de Biología Celular y Genética, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo León, Mexico
- Departamento de Inmunología y Virología, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo León, Mexico
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Effect of Poly(methacrylic acid) on the Cytokine Level in an In Vivo Tumor Model. Molecules 2022; 27:molecules27144572. [PMID: 35889444 PMCID: PMC9316288 DOI: 10.3390/molecules27144572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 07/09/2022] [Accepted: 07/14/2022] [Indexed: 11/18/2022] Open
Abstract
Cancer is a leading cause of mortality globally. Despite remarkable improvements in cancer-treatment approaches, disease recurrence and progression remain major obstacles to therapy. While chemotherapy is still a first-line treatment for a variety of cancers, the focus has shifted to the development and application of new approaches to therapy. Nevertheless, the relationship between immune response, neoplastic diseases and treatment efficiency is not fully understood. Therefore, the aim of the study was to investigate the immunopharmacological effects of methacrylic acid homopolymer in an in vivo tumor model. Materials and methods: Monomeric methacrylic acid was used to synthesize polymers. Methacrylic acid was polymerized in dioxane in the presence of 4-Cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid. To study the molecular weight characteristics of PMAA by GPC, carboxyl groups were preliminarily methylated with diazomethane. An experimental cancer model was obtained by grafting RMK1 breast cancer cells. The serum levels of IL-6, IL-10, IL-17, transforming growth factor β1 (TGF-β1), and tumor necrosis factor α (TNF-α) were measured by ELISA. Results: The effect of PMAA on the serum concentrations of several cytokines was studied upon its single administration to laboratory animals in early neoplastic process. The IL-6, IL-17 and TGF-β1 concentrations were found to change significantly and reach the level observed in intact rats. The IL-10 concentration tended to normalize. Conclusion: The positive results obtained are the basis for further studies on the effect of methacrylic-acid polymers with different molecular-weight characteristics on the neoplastic process.
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25
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The effect of mesenchymal stromal cells ın the microenvironment on cancer development. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:114. [PMID: 35674854 DOI: 10.1007/s12032-022-01703-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 03/01/2022] [Indexed: 10/18/2022]
Abstract
Inflammatory signals secreted from the tumor microenvironment are thought to promote tumor growth and survival. It has been reported that stromal cells in the tumor microenvironment have similar characteristics to tumor-associated cells. In addition miRNAs play critical roles in various diseases, including cancer. In this study, we aimed to investigate the effects of co-culture of cancer cells and stromal cells isolated from normal and malignant breast tissue on each other and the possible effects of miRNAs on these interactions. The characterized stromal cells were co-cultured with an MDA-MB-231 cancer cell line. The proliferation capacity of the experimental groups was evaluated using the WST-1 assay. The expression of breast cancer-specific miRNAs and related genes were assessed by real-time PCR. ELISA assay was performed to determine the concentration of some cytokines and chemokines. We found that the microenvironment plays an important role in the development of cancer, confirming the changes in the expression of oncogenic and tumor suppressor miRNA and their target genes after co-culture with malignant stromal cells. As a result of the studies, specific gene expressions of related signaling pathways were detected in correlation with miRNA changes and the effects of tumor microenvironment on tumorigenesis were revealed in detail. miRNAs have been shown to play an important role in cancer development in recent studies. The idea that these small molecules can be used in diagnosis and treatment is becoming stronger day by day. We believe that new treatment approaches involving the tumor microenvironment and using miRNAs as markers are promising.
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26
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Stanimirovic J, Radovanovic J, Banjac K, Obradovic M, Essack M, Zafirovic S, Gluvic Z, Gojobori T, Isenovic ER. Role of C-Reactive Protein in Diabetic Inflammation. Mediators Inflamm 2022; 2022:3706508. [PMID: 35620114 PMCID: PMC9129992 DOI: 10.1155/2022/3706508] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/20/2022] [Accepted: 04/29/2022] [Indexed: 01/08/2023] Open
Abstract
Even though type 2 diabetes mellitus (T2DM) represents a worldwide chronic health issue that affects about 462 million people, specific underlying determinants of insulin resistance (IR) and impaired insulin secretion are still unknown. There is growing evidence that chronic subclinical inflammation is a triggering factor in the origin of T2DM. Increased C-reactive protein (CRP) levels have been linked to excess body weight since adipocytes produce tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), which are pivotal factors for CRP stimulation. Furthermore, it is known that hepatocytes produce relatively low rates of CRP in physiological conditions compared to T2DM patients, in which elevated levels of inflammatory markers are reported, including CRP. CRP also participates in endothelial dysfunction, the production of vasodilators, and vascular remodeling, and increased CRP level is closely associated with vascular system pathology and metabolic syndrome. In addition, insulin-based therapies may alter CRP levels in T2DM. Therefore, determining and clarifying the underlying CRP mechanism of T2DM is imperative for novel preventive and diagnostic procedures. Overall, CRP is one of the possible targets for T2DM progression and understanding the connection between insulin and inflammation may be helpful in clinical treatment and prevention approaches.
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Affiliation(s)
- Julijana Stanimirovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Jelena Radovanovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Katarina Banjac
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Milan Obradovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Magbubah Essack
- King Abdullah University of Science and Technology (KAUST), Computer, Electrical, and Mathematical Sciences and Engineering (CEMSE) Division, Computational Bioscience Research Center (CBRC), Thuwal, Saudi Arabia
| | - Sonja Zafirovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran Gluvic
- University Clinical-Hospital Centre Zemun-Belgrade, Clinic of Internal Medicine, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Takashi Gojobori
- King Abdullah University of Science and Technology (KAUST), Computer, Electrical, and Mathematical Sciences and Engineering (CEMSE) Division, Computational Bioscience Research Center (CBRC), Thuwal, Saudi Arabia
| | - Esma R. Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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Radharani NNV, Yadav AS, Nimma R, Kumar TVS, Bulbule A, Chanukuppa V, Kumar D, Patnaik S, Rapole S, Kundu GC. Tumor-associated macrophage derived IL-6 enriches cancer stem cell population and promotes breast tumor progression via Stat-3 pathway. Cancer Cell Int 2022; 22:122. [PMID: 35300689 PMCID: PMC8932105 DOI: 10.1186/s12935-022-02527-9] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 02/21/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) play crucial role in tumor progression, drug resistance and relapse in various cancers. CSC niche is comprised of various stromal cell types including Tumor-associated macrophages (TAMs). Extrinsic ques derived from these cells help in maintenance of CSC phenotype. TAMs have versatile roles in tumor progression however their function in enrichment of CSC is poorly explored. METHODS Mouse macrophages (RAW264.7) cells were activated by interaction with conditioned media (CM) of murine breast cancer cells (4T1) into TAMs and the effect of activated macrophage (TAM) derived factors was examined on enrichment of cancer stem cells (CSCs) and tumor growth using in vitro and in vivo models. RESULTS In this study, we report that macrophages upon interaction with breast cancer cells activate tumor promoting function and exhibit differential expression of various proteins as shown by secretome analysis using proteomics studies. Based on secretome data, we found that Interleukin-6 (IL-6) is one of the up-regulated genes expressed in activated macrophages. Further, we confirm that TAMs produce high levels of IL-6 and breast cancer cell derived factors induce IL-6 production in activated macrophages via p38-MAPK pathway. Furthermore, we demonstrate that tumor activated macrophages induce enrichment of CSCs and expression of CSC specific transcription factors such as Sox-2, Oct-3/4 and Nanog in breast cancer cells. We further prove that TAM derived IL-6 plays a key role in TAM mediated CSC enrichment through activation of Signal transducer and activator of transcription 3 (STAT-3) signaling. TAM derived IL-6 influences breast cancer cell migration and angiogenesis. Moreover, our in vivo findings indicated that TAM derived IL-6 induces CSC population and resulting tumor growth in breast cancer. CONCLUSION These finding provide evidence that TAM derived IL-6 plays a major role in CSC enrichment and tumor progression in breast cancer and IL-6 and its regulated signalling network may act as potential therapeutic target for management of breast cancer.
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Affiliation(s)
- N N V Radharani
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), Pune, 411007, India.,School of Biotechnology, KIIT Deemed To Be University, Bhubaneswar, 751 024, India
| | - Amit S Yadav
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), Pune, 411007, India.,School of Biotechnology, KIIT Deemed To Be University, Bhubaneswar, 751 024, India
| | - Ramakrishna Nimma
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), Pune, 411007, India
| | - T V Santosh Kumar
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), Pune, 411007, India
| | - Anuradha Bulbule
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), Pune, 411007, India
| | - Venkatesh Chanukuppa
- Proteomics Laboratory, National Centre for Cell Science (NCCS), Pune, 411007, India
| | - Dhiraj Kumar
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA
| | - Srinivas Patnaik
- School of Biotechnology, KIIT Deemed To Be University, Bhubaneswar, 751 024, India
| | - Srikanth Rapole
- Proteomics Laboratory, National Centre for Cell Science (NCCS), Pune, 411007, India
| | - Gopal C Kundu
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), Pune, 411007, India. .,School of Biotechnology, KIIT Deemed To Be University, Bhubaneswar, 751 024, India. .,Kalinga Institute of Medical Sciences (KIMS), KIIT Deemed To Be University, Bhubaneswar, 751024, India.
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28
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Lee S, Lee A, Lim J, Lim JS. Regulation of tumor-associated macrophage (TAM) differentiation by NDRG2 expression in breast cancer cells. BMB Rep 2022. [PMID: 34743782 PMCID: PMC8891626 DOI: 10.5483/bmbrep.2022.55.2.114] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Macrophages are a major cellular component of innate immunity and are mainly known to have phagocytic activity. In the tumor microenvironment (TME), they can be differentiated into tumor-associated macrophages (TAMs). As the most abundant immune cells in the TME, TAMs promote tumor progression by enhancing angiogenesis, suppressing T cells and increasing immunosuppressive cytokine production. N-myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor gene, whose expression is down-regulated in various cancers. However, the effect of NDRG2 on the differentiation of macrophages into TAMs in breast cancer remains elusive. In this study, we investigated the effect of NDRG2 expression in breast cancer cells on the differentiation of macrophages into TAMs. Compared to tumor cell-conditioned medium (TCCM) from 4T1-mock cells, TCCM from NDRG2-overexpressing 4T1 mouse breast cancer cells did not significantly change the morphology of RAW 264.7 cells. However, TCCM from 4T1-NDRG2 cells reduced the mRNA levels of TAM-related genes, including MR1, IL-10, ARG1 and iNOS, in RAW 264.7 cells. In addition, TCCM from 4T1-NDRG2 cells reduced the expression of TAM-related surface markers, such as CD206, in peritoneal macrophages (PEM). The mRNA expression of TAM-related genes, including IL-10, YM1, FIZZ1, MR1, ARG1 and iNOS, was also downregulated by TCCM from 4T1-NDRG2 cells. Remarkably, TCCM from 4T1-NDRG2 cells reduced the expression of PD-L1 and Fra-1 as well as the production of GM-CSF, IL-10 and ROS, leading to the attenuation of T cell-inhibitory activity of PEM. These data showed that compared with TCCM from 4T1-mock cells, TCCM from 4T1-NDRG2 cells suppressed the TAM differentiation and activation. Collectively, these results suggest that NDRG2 expression in breast cancer may reduce the differentiation of macrophages into TAMs in the TME.
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Affiliation(s)
- Soyeon Lee
- Department of Biological Science and the Cellular Heterogeneity Research Center, Sookmyung Women’s University, Seoul 04310, Korea
| | - Aram Lee
- Department of Biological Science and the Cellular Heterogeneity Research Center, Sookmyung Women’s University, Seoul 04310, Korea
| | - Jihyun Lim
- Department of Biological Science and the Cellular Heterogeneity Research Center, Sookmyung Women’s University, Seoul 04310, Korea
| | - Jong-Seok Lim
- Department of Biological Science and the Cellular Heterogeneity Research Center, Sookmyung Women’s University, Seoul 04310, Korea
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29
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Grinshpun A, Cohen Y, Zick A, Kadouri L, Hamburger T, Nisman B, Allweis TM, Oprea G, Peretz T, Uziely B, Sonnenblick A. Potential Refinement of Recurrence Score by pSTAT3 Status. Genes (Basel) 2022; 13:genes13030438. [PMID: 35327992 PMCID: PMC8949499 DOI: 10.3390/genes13030438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/21/2022] [Accepted: 02/25/2022] [Indexed: 02/04/2023] Open
Abstract
The likelihood of recurrence in breast cancer patients with hormone receptor-positive (HR-positive) tumors is influenced by clinical, histopathological, and molecular features. Recent studies suggested that activated STAT3 (pSTAT3) might serve as a biomarker of outcome in breast cancer patients. In the present work, we have analyzed the added value of pSTAT3 to OncotypeDx Recurrence Score (RS) in patient prognostication. We have found that patients with low RS (<26) and low pSTAT3 might represent a population at a higher risk for cancer recurrence. Furthermore, we have observed that a positive pSTAT3 score alone can be a favorable marker for patients with HR-positive breast cancer under the age of 50. In an era of personalized medicine, these findings warrant further appraisal of chemotherapy benefit in this population.
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Affiliation(s)
- Albert Grinshpun
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; (A.G.); (Y.C.); (A.Z.); (L.K.); (T.H.); (B.N.); (T.P.); (B.U.)
- Faculty of Medicine, The Hebrew University, Jerusalem 9112102, Israel;
| | - Yogev Cohen
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; (A.G.); (Y.C.); (A.Z.); (L.K.); (T.H.); (B.N.); (T.P.); (B.U.)
- Faculty of Medicine, The Hebrew University, Jerusalem 9112102, Israel;
| | - Aviad Zick
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; (A.G.); (Y.C.); (A.Z.); (L.K.); (T.H.); (B.N.); (T.P.); (B.U.)
- Faculty of Medicine, The Hebrew University, Jerusalem 9112102, Israel;
| | - Luna Kadouri
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; (A.G.); (Y.C.); (A.Z.); (L.K.); (T.H.); (B.N.); (T.P.); (B.U.)
- Faculty of Medicine, The Hebrew University, Jerusalem 9112102, Israel;
| | - Tamar Hamburger
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; (A.G.); (Y.C.); (A.Z.); (L.K.); (T.H.); (B.N.); (T.P.); (B.U.)
| | - Benjamin Nisman
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; (A.G.); (Y.C.); (A.Z.); (L.K.); (T.H.); (B.N.); (T.P.); (B.U.)
| | - Tanir M. Allweis
- Faculty of Medicine, The Hebrew University, Jerusalem 9112102, Israel;
- Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Gabriela Oprea
- Department of pathology, Emory University, Atlanta, GA 30322, USA;
| | - Tamar Peretz
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; (A.G.); (Y.C.); (A.Z.); (L.K.); (T.H.); (B.N.); (T.P.); (B.U.)
- Faculty of Medicine, The Hebrew University, Jerusalem 9112102, Israel;
| | - Beatrice Uziely
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; (A.G.); (Y.C.); (A.Z.); (L.K.); (T.H.); (B.N.); (T.P.); (B.U.)
- Faculty of Medicine, The Hebrew University, Jerusalem 9112102, Israel;
| | - Amir Sonnenblick
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel
- Correspondence: ; Tel.: +972-3-6972061; Fax: +972-3-6974789
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Sparano JA, O’Neill A, Graham N, Northfelt DW, Dang CT, Wolff AC, Sledge GW, Miller KD. Inflammatory cytokines and distant recurrence in HER2-negative early breast cancer. NPJ Breast Cancer 2022; 8:16. [PMID: 35136076 PMCID: PMC8825796 DOI: 10.1038/s41523-021-00376-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 12/07/2021] [Indexed: 01/14/2023] Open
Abstract
Systemic inflammation is believed to contribute to the distant recurrence of breast cancer. We evaluated serum samples obtained at diagnosis from 249 case:control pairs with stage II-III Her2-negative breast cancer with or without subsequent distant recurrence. Conditional logistic regression analysis, with models fit via maximum likelihood, were used to estimate hazard ratios (HRs) and test for associations of cytokines with distant recurrence risk. The only biomarker associated with a significantly increased distant recurrence risk when adjusted for multiple testing was the proinflammatory cytokine IL-6 (HR 1.37, 95% confidence intervals [CI] 1.15, 1.65, p = 0.0006). This prospective-retrospective study provides evidence indicating that higher levels of the cytokine IL-6 at diagnosis are associated with a significantly higher distant recurrence risk.
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Affiliation(s)
- Joseph A. Sparano
- grid.59734.3c0000 0001 0670 2351Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY USA
| | - Anne O’Neill
- grid.65499.370000 0001 2106 9910Dana Farber Cancer Institute ECOG-ACRIN Biostatistics Center, Boston, MA USA
| | - Noah Graham
- grid.65499.370000 0001 2106 9910Dana Farber Cancer Institute ECOG-ACRIN Biostatistics Center, Boston, MA USA
| | | | - Chau T. Dang
- grid.51462.340000 0001 2171 9952Memorial Sloan Kettering Cancer Center, New York, NY USA
| | - Antonio C. Wolff
- grid.280502.d0000 0000 8741 3625Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD USA
| | - George W. Sledge
- grid.168010.e0000000419368956Stanford Cancer Center, Palo Alto, CA USA
| | - Kathy D. Miller
- grid.257413.60000 0001 2287 3919Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN USA
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Felcher CM, Bogni ES, Kordon EC. IL-6 Cytokine Family: A Putative Target for Breast Cancer Prevention and Treatment. Int J Mol Sci 2022; 23:ijms23031809. [PMID: 35163731 PMCID: PMC8836921 DOI: 10.3390/ijms23031809] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/11/2022] Open
Abstract
The IL-6 cytokine family is a group of signaling molecules with wide expression and function across vertebrates. Each member of the family signals by binding to its specific receptor and at least one molecule of gp130, which is the common transmembrane receptor subunit for the whole group. Signal transduction upon stimulation of the receptor complex results in the activation of multiple downstream cascades, among which, in mammary cells, the JAK-STAT3 pathway plays a central role. In this review, we summarize the role of the IL-6 cytokine family—specifically IL-6 itself, LIF, OSM, and IL-11—as relevant players during breast cancer progression. We have compiled evidence indicating that this group of soluble factors may be used for early and more precise breast cancer diagnosis and to design targeted therapy to treat or even prevent metastasis development, particularly to the bone. Expression profiles and possible therapeutic use of their specific receptors in the different breast cancer subtypes are also described. In addition, participation of these cytokines in pathologies of the breast linked to lactation and involution of the gland, as post-partum breast cancer and mastitis, is discussed.
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Affiliation(s)
- Carla M. Felcher
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Universidad de Buenos Aires—Consejo Nacional de Investigaciones Científicas y Técnicas (IFIBYNE-UBA-CONICET), Ciudad Autónoma de Buenos Aires (CABA) 1428, Argentina; (C.M.F.); (E.S.B.)
| | - Emilia S. Bogni
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Universidad de Buenos Aires—Consejo Nacional de Investigaciones Científicas y Técnicas (IFIBYNE-UBA-CONICET), Ciudad Autónoma de Buenos Aires (CABA) 1428, Argentina; (C.M.F.); (E.S.B.)
| | - Edith C. Kordon
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Universidad de Buenos Aires—Consejo Nacional de Investigaciones Científicas y Técnicas (IFIBYNE-UBA-CONICET), Ciudad Autónoma de Buenos Aires (CABA) 1428, Argentina; (C.M.F.); (E.S.B.)
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires (CABA) 1428, Argentina
- Correspondence:
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Usman M, Hameed Y, Ahmad M, Jalil Ur Rehman, Ahmed H, Hussain MS, Asif R, Murtaza MG, Jawad MT, Iqbal MJ. Breast Cancer Risk and Human Papillomavirus Infection: A Bradford Hill Criteria Based Evaluation. Infect Disord Drug Targets 2022; 22:e200122200389. [PMID: 35048811 DOI: 10.2174/1573401318666220120105931] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 10/20/2021] [Accepted: 11/17/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The association between human papillomavirus (HPV) and human breast cancer (BC) has already been thoroughly studied worldwide with contradictory findings. Although the researchers have tried to minimize the conflict using statistical meta-analysis, because of its shortcomings, there is still a need to evaluate the correlation between HPV and BC using any additional method. OBJECTIVES This study was launched to investigate the correlation between HPV and BC through the application of Bradford Hill criteria postulates. METHODS Population-wide studies associating HPV with BC were searched using the PubMed database. Then, the information of HPV burden in BC, normal/benign samples was analyzed, and ultimately Bradford Hill criteria postulates were applied on the collected evidence to explore the relationship between HPV and BC. In addition, to make the outcomes more authentic, we also reviewed the methodologies of previous studies to address the propensity of false results. RESULTS After a careful evaluation of the obtained data against major Bradford Hill criteria postulates, it was noted that all these postulates including strength, consistency, biological gradient, temporality, plausibility, experiment, specificity, and analogy were not fulfilled. CONCLUSION The results of the present study have failed to establish a casual association between HPV and BC rather suggested HPV as a cause-effective agent or at least a co-participant in the pathogenesis of BC. The weakness of association especially the low level of consistency across studies, and the lack of specificity of effect, there is a need for more experiments concerning Bradford Hill criteria postulates.
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Affiliation(s)
- Muhammad Usman
- Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Yasir Hameed
- Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Mukhtiar Ahmad
- Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Jalil Ur Rehman
- Department of Eastern Medicine, Qarshi University, Lahore, Pakistan
| | - Hamad Ahmed
- Department of Eastern Medicine, Government College University Faisalabad, Pakistan
| | - Muhammad Safdar Hussain
- Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Rizwan Asif
- Department of Microbiology, Government College University Faisalabad, Pakistan
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The effect of mindfulness-based interventions on immunity-related biomarkers: a comprehensive meta-analysis of randomised controlled trials. Clin Psychol Rev 2022; 92:102124. [DOI: 10.1016/j.cpr.2022.102124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 12/17/2021] [Accepted: 01/09/2022] [Indexed: 11/21/2022]
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Socioeconomic Status and Inflammation in Women with Early-stage Breast Cancer: Mediation by Body Mass Index. Brain Behav Immun 2022; 99:307-316. [PMID: 34673177 PMCID: PMC9802182 DOI: 10.1016/j.bbi.2021.10.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 10/05/2021] [Accepted: 10/13/2021] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Breast cancer is the most common cancer among women in the US, and women of low socioeconomic status (SES) show markedly poorer outcomes than those of high SES. SES may influence health through inflammation, although links between SES and inflammatory biomarkers have not been investigated in women with breast cancer. This study tested the hypothesis that breast cancer patients of lower SES would show higher levels of inflammation than those of higher SES. BMI was examined as a mediator of this association. METHODS Women recently diagnosed with early-stage breast cancer (N = 194) were recruited before neoadjuvant or adjuvant therapy. Participants completed questionnaires and provided blood samples for immune assessment. SES was indexed by participants' self-reported education and annual household income, BMI was determined by height and weight measurements, and blood was assayed for inflammatory biomarkers linked with cancer outcomes: IL-6, CRP, TNF-α, and sTNF-RII. General linear models tested associations between SES and inflammation, and mediation models examined indirect effects through BMI. RESULTS Consistent with hypotheses, education status was associated with CRP, (F(2,185) = 4.72, p = 0.001), and sTNF-RII, (F(2,185) = 4.19, p = 0.02), such that lower education was associated with higher levels of both biomarkers. Further, BMI mediated the associations between education and CRP, (95% CIs [-0.62, -0.11; -0.76, -0.21]), sTNF-RII, (95% CIs [-0.09, -0.01; -0.10, -0.02]), and IL-6, (95% CIs [-0.32, -0.05; -0.38, -0.09]). Annual household income was not significantly associated with inflammation (ps > 0.25), and indirect effects on inflammation through BMI were not significant. CONCLUSIONS Lower education was associated with higher levels of inflammation in this sample, which may presage poor breast cancer-related and clinical outcomes. SES should inform the development of interventions targeting BMI and inflammation in breast cancer.
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IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells. NPJ Syst Biol Appl 2021; 7:42. [PMID: 34853340 PMCID: PMC8636565 DOI: 10.1038/s41540-021-00204-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 11/01/2021] [Indexed: 12/13/2022] Open
Abstract
Inflammatory stimuli triggers the degradation of three inhibitory κB (IκB) proteins, allowing for nuclear translocation of nuclear factor-κB (NFκB) for transcriptional induction of its target genes. Of these three, IκBα is a well-known negative feedback regulator that limits the duration of NFκB activity. We sought to determine whether IκBα's role in enabling or limiting NFκB activation is important for tumor necrosis factor (TNF)-induced gene expression in human breast cancer cells (MCF-7). Contrary to our expectations, many more TNF-response genes showed reduced induction than enhanced induction in IκBα knockdown cells. Mathematical modeling was used to investigate the underlying mechanism. We found that the reduced activation of some NFκB target genes in IκBα-deficient cells could be explained by the incoherent feedforward loop (IFFL) model. In addition, for a subset of genes, prolonged NFκB activity due to loss of negative feedback control did not prolong their transient activation; this implied a multi-state transcription cycle control of gene induction. Genes encoding key inflammation-related transcription factors, such as JUNB and KLF10, were found to be best represented by a model that contained both the IFFL and the transcription cycle motif. Our analysis sheds light on the regulatory strategies that safeguard inflammatory gene expression from overproduction and repositions the function of IκBα not only as a negative feedback regulator of NFκB but also as an enabler of NFκB-regulated stimulus-responsive inflammatory gene expression. This study indicates the complex involvement of IκBα in the inflammatory response to TNF that is induced by radiation therapy in breast cancer.
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Barek MA, Begum M, Noor F, Aziz MA, Islam MS. The link between IL-6 rs2069840 SNP and cancer risk: Evidence from a systematic review and meta-analysis. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100972] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Zhao Y, Cui L, Yang XX, Sun X, Liu Y, Yang Z, Zhu L, Peng C, Li D, Cai J, Ma Y. Sinoacutine inhibits inflammatory responses to attenuates acute lung injury by regulating NF-κB and JNK signaling pathways. BMC Complement Med Ther 2021; 21:284. [PMID: 34801005 PMCID: PMC8605577 DOI: 10.1186/s12906-021-03458-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 11/03/2021] [Indexed: 12/22/2022] Open
Abstract
Background Stephania yunnanensis H. S. Lo is widely used as an antipyretic, analgesic and anti-inflammatory herbal medicine in SouthWest China. In this study, we investigated the anti-inflammatory activity and mechanism of sinoacutine (sino), one of the primary components extracted from this plant. Methods A RAW264.7 cell model was established using lipopolysaccharide (LPS) induced for estimation of cytokines in vitro, qPCR was used to estimate gene expression, western blot analysis was used to estimate protein level and investigate the regulation of NF- κB, JNK and MAPK signal pathway. In addition, an acute lung injury model was established to determine lung index and levels of influencing factors. Results Using the RAW264.7 model, we found that sino reduced levels of nitric oxide (NO), tumour necrosis factor-α (TNF-α), interleukin (IL)-1β and prostaglandin E2 (PGE2) but increased levels of IL-6. qPCR analysis revealed that sino (50, 25 μg/ml) inhibited gene expression of nitric oxide synthase (iNOS). western blot analysis showed that sino significantly inhibited protein levels of both iNOS and COX-2. Further signalling pathway analysis validated that sino also inhibited phosphorylation of p65 in the NF-κB and c-Jun NH2 terminal kinase (JNK) signalling pathways but promoted the phosphorylation of extracellular signal regulated kinase (ERK) and p38 in the MAPK signalling pathway. In addition, in a mouse model induced by LPS, we determined that sino reduced the lung index and the levels of myeloperoxidase (MPO), NO, IL-6 and TNF-α in lung tissues and bronchoalveolar lavage fluid (BALF) in acute lung injury (ALI). Conclusion Taken together, our results demonstrate that sino is a promising drug to alleviate LPS-induced inflammatory reactions. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-021-03458-0.
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Affiliation(s)
- Yuancui Zhao
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.,Key Laboratory of External Drug Delivery System and Preparation Technology in University of Yunnan, Kunming, 650500, China
| | - Lili Cui
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, China
| | - Xing Xin Yang
- Key Laboratory of Southern Medicine Utilization, Kunming, 650500, China
| | - Xingqian Sun
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.,Yunnan Key Laboratory of Dai and Yi Medicine, School of Chinese Material Medicine Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Yunkuan Liu
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.,Key Laboratory of External Drug Delivery System and Preparation Technology in University of Yunnan, Kunming, 650500, China
| | - Zixian Yang
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Liyuan Zhu
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Chaorui Peng
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Danye Li
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Junfei Cai
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Yunshu Ma
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China. .,Yunnan Key Laboratory of Dai and Yi Medicine, School of Chinese Material Medicine Yunnan University of Chinese Medicine, Kunming, 650500, China.
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Mazzuferi G, Bacchetti T, Islam MO, Ferretti G. High density lipoproteins and oxidative stress in breast cancer. Lipids Health Dis 2021; 20:143. [PMID: 34696795 PMCID: PMC8543840 DOI: 10.1186/s12944-021-01562-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/20/2021] [Indexed: 12/29/2022] Open
Abstract
Breast cancer is one of the main leading causes of women death. In recent years, attention has been focused on the role of lipoproteins, alterations of cholesterol metabolism and oxidative stress in the molecular mechanism of breast cancer. A role for high density lipoproteins (HDL) has been proposed, in fact, in addition to the role of reverse cholesterol transport (RCT), HDL exert antioxidant and anti-inflammatory properties, modulate intracellular cholesterol homeostasis, signal transduction and proliferation. Low levels of HDL-Cholesterol (HDL-C) have been demonstrated in patients affected by breast cancer and it has been suggested that low levels of HDL-C could represent a risk factor of breast cancer. Contrasting results have been observed by other authors. Recent studies have demonstrated alterations of the activity of some enzymes associated to HDL surface such as Paraoxonase (PON1), Lecithin-Cholesterol Acyltransferase (LCAT) and Phospholipase A2 (PLA2). Higher levels of markers of lipid peroxidation in plasma or serum of patients have also been observed and suggest dysfunctional HDL in breast cancer patients. The review summarizes results on levels of markers of oxidative stress of plasma lipids and on alterations of enzymes associated to HDL in patients affected by breast cancer. The effects of normal and dysfunctional HDL on human breast cancer cells and molecular mechanisms potentially involved will be also reviewed.
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Affiliation(s)
- Gabriele Mazzuferi
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Polytechnic University of Marche, Ancona, Italy
| | - Tiziana Bacchetti
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy.
| | - Md Obaidul Islam
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Polytechnic University of Marche, Ancona, Italy
| | - Gianna Ferretti
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Polytechnic University of Marche, Ancona, Italy
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Martínez-Pérez C, Kay C, Meehan J, Gray M, Dixon JM, Turnbull AK. The IL6-like Cytokine Family: Role and Biomarker Potential in Breast Cancer. J Pers Med 2021; 11:1073. [PMID: 34834425 PMCID: PMC8624266 DOI: 10.3390/jpm11111073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 02/07/2023] Open
Abstract
IL6-like cytokines are a family of regulators with a complex, pleiotropic role in both the healthy organism, where they regulate immunity and homeostasis, and in different diseases, including cancer. Here we summarise how these cytokines exert their effect through the shared signal transducer IL6ST (gp130) and we review the extensive evidence on the role that different members of this family play in breast cancer. Additionally, we discuss how the different cytokines, their related receptors and downstream effectors, as well as specific polymorphisms in these molecules, can serve as predictive or prognostic biomarkers with the potential for clinical application in breast cancer. Lastly, we also discuss how our increasing understanding of this complex signalling axis presents promising opportunities for the development or repurposing of therapeutic strategies against cancer and, specifically, breast neoplasms.
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Affiliation(s)
- Carlos Martínez-Pérez
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (C.K.); (J.M.D.); (A.K.T.)
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH8 9YL, UK; (J.M.); (M.G.)
| | - Charlene Kay
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (C.K.); (J.M.D.); (A.K.T.)
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH8 9YL, UK; (J.M.); (M.G.)
| | - James Meehan
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH8 9YL, UK; (J.M.); (M.G.)
| | - Mark Gray
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH8 9YL, UK; (J.M.); (M.G.)
| | - J. Michael Dixon
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (C.K.); (J.M.D.); (A.K.T.)
| | - Arran K. Turnbull
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (C.K.); (J.M.D.); (A.K.T.)
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH8 9YL, UK; (J.M.); (M.G.)
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Lee HS, Lee IH, Kang K, Park SI, Jung M, Yang SG, Kwon TW, Lee DY. Network Pharmacology-Based Dissection of the Comprehensive Molecular Mechanisms of the Herbal Prescription FDY003 Against Estrogen Receptor-Positive Breast Cancer. Nat Prod Commun 2021. [DOI: 10.1177/1934578x211044377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Estrogen receptor-positive breast cancer (ERPBC) is the commonest subtype of breast cancer, with a high prevalence, incidence, and mortality. Herbal drugs are increasingly being used to treat ERPBC, although their mechanisms of action are not fully understood. Therefore, in this study, we aimed to analyze the therapeutic properties of FDY003, a herbal anti-ERPBC prescription, using a network pharmacology approach. FDY003 decreased the viability of human ERPBC cells and sensitized them to tamoxifen, an endocrine drug that is widely used in the treatment of ERPBC. The network pharmacology analysis revealed 18 pharmacologically active components in FDY003 that may interact with and regulate 66 therapeutic targets. The enriched gene ontology terms for the FDY003 targets were associated with the modulation of cell survival and death, cell proliferation and growth arrest, and estrogen-associated cellular processes. Analysis of the pathway enrichment of the targets showed that FDY003 may target a variety of ERPBC-associated pathways, including the PIK3-Akt, focal adhesion, MAPK, and estrogen pathways. Overall, these data provide a comprehensive mechanistic insight into the anti-ERPBC activity of FDY003.
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Affiliation(s)
- Ho-Sung Lee
- The Fore, Seoul, Republic of Korea
- Forest Hospital, Seoul, Republic of Korea
| | | | | | | | - Minho Jung
- Forest Hospital, Seoul, Republic of Korea
| | | | | | - Dae-Yeon Lee
- The Fore, Seoul, Republic of Korea
- Forest Hospital, Seoul, Republic of Korea
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Zhu W, Cai E, Li H, Wang P, Shen A, Popp J, Hu J. Precise Encoding of Triple‐Bond Raman Scattering of Single Polymer Nanoparticles for Multiplexed Imaging Application. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202106136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Wei Zhu
- College of Chemistry and Molecular Sciences Wuhan University Wuhan 430072 P. R. China
| | - Er‐Li Cai
- Britton Chance Center for Biomedical Photonics Wuhan National Laboratory for Optoelectronics Huazhong University of Science and Technology Wuhan 430079 P. R. China
| | - Hao‐Zheng Li
- Britton Chance Center for Biomedical Photonics Wuhan National Laboratory for Optoelectronics Huazhong University of Science and Technology Wuhan 430079 P. R. China
| | - Ping Wang
- Britton Chance Center for Biomedical Photonics Wuhan National Laboratory for Optoelectronics Huazhong University of Science and Technology Wuhan 430079 P. R. China
| | - Ai‐Guo Shen
- College of Chemistry and Molecular Sciences Wuhan University Wuhan 430072 P. R. China
- School of Printing and Packaging Wuhan University Wuhan 430072 P. R. China
| | - Jürgen Popp
- Institute of Physical Chemistry and Abbe Center of Photonics Friedrich Schiller University Jena Helmholtzweg 4 07743 Jena Germany
- Leibniz Institute for Photonic Technology Albert-Einstein-Strasse 9 07745 Jena Germany
| | - Ji‐Ming Hu
- College of Chemistry and Molecular Sciences Wuhan University Wuhan 430072 P. R. China
- Center of Analysis and Testing Wuhan University Wuhan 430074 P. R. China
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Notas G, Panagiotopoulos A, Vamvoukaki R, Kalyvianaki K, Kiagiadaki F, Deli A, Kampa M, Castanas E. ERα36-GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells. Int J Mol Sci 2021; 22:ijms22147603. [PMID: 34299224 PMCID: PMC8303269 DOI: 10.3390/ijms22147603] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/06/2021] [Accepted: 07/09/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammation is important for the initiation and progression of breast cancer. We have previously reported that in monocytes, estrogen regulates TLR4/NFκB-mediated inflammation via the interaction of the Erα isoform ERα36 with GPER1. We therefore investigated whether a similar mechanism is present in breast cancer epithelial cells, and the effect of ERα36 expression on the classic 66 kD ERα isoform (ERα66) functions. We report that estrogen inhibits LPS-induced NFκB activity and the expression of downstream molecules TNFα and IL-6. In the absence of ERα66, ERα36 and GPER1 are both indispensable for this effect. In the presence of ERα66, ERα36 or GPER1 knock-down partially inhibits NFκB-mediated inflammation. In both cases, ERα36 overexpression enhances the inhibitory effect of estrogen on inflammation. We also verify that ERα36 and GPER1 physically interact, especially after LPS treatment, and that GPER1 interacts directly with NFκB. When both ERα66 and ERα36 are expressed, the latter acts as an inhibitor of ERα66 via its binding to estrogen response elements. We also report that the activation of ERα36 leads to the inhibition of breast cancer cell proliferation. Our data support that ERα36 is an inhibitory estrogen receptor that, in collaboration with GPER1, inhibits NFκB-mediated inflammation and ERα66 actions in breast cancer cells.
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Affiliation(s)
- George Notas
- Correspondence: ; Tel.: +30-2810-3945-56; Fax: +30-2810-3945-81
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Zhu W, Cai EL, Li HZ, Wang P, Shen AG, Popp J, Hu JM. Precise Encoding of Triple-Bond Raman Scattering of Single Polymer Nanoparticles for Multiplexed Imaging Application. Angew Chem Int Ed Engl 2021; 60:21846-21852. [PMID: 34227191 DOI: 10.1002/anie.202106136] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/27/2021] [Indexed: 11/08/2022]
Abstract
Stimulated Raman scattering (SRS) microscopy in combination with innovative tagging strategies offers great potential as a universal high-throughput biomedical imaging tool. Here, we report rationally tailored small molecular monomers containing triple-bond units with large Raman scattering cross-sections, which can be polymerized at the nanoscale for enhancement of SRS contrast with smaller but brighter optical nanotags with artificial fingerprint output. From this, a class of triple-bond rich polymer nanoparticles (NPs) was engineered by regulating the relative dosages of three chemically different triple-bond monomers in co-polymerization. The bonding strategy allowed for 15 spectrally distinguishable triple-bond combinations. These accurately structured nano molecular aggregates, rather than long-chain macromolecules, could establish a universal method for generating small-sized biological SRS imaging tags with high sensitivity for high-throughput multi-color biomedical imaging.
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Affiliation(s)
- Wei Zhu
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P. R. China
| | - Er-Li Cai
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, 430079, P. R. China
| | - Hao-Zheng Li
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, 430079, P. R. China
| | - Ping Wang
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, 430079, P. R. China
| | - Ai-Guo Shen
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P. R. China.,School of Printing and Packaging, Wuhan University, Wuhan, 430072, P. R. China
| | - Jürgen Popp
- Institute of Physical Chemistry and Abbe Center of Photonics, Friedrich Schiller University Jena, Helmholtzweg 4, 07743, Jena, Germany.,Leibniz Institute for Photonic Technology, Albert-Einstein-Strasse 9, 07745, Jena, Germany
| | - Ji-Ming Hu
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P. R. China.,Center of Analysis and Testing, Wuhan University, Wuhan, 430074, P. R. China
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Salamt N, Idrus RBH, Kashim MIAM, Mokhtar MH. Anticancer, antiplatelet, gastroprotective and hepatoprotective effects of camel urine: A scoping review. Saudi Pharm J 2021; 29:740-750. [PMID: 34400869 PMCID: PMC8347850 DOI: 10.1016/j.jsps.2021.05.006] [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: 02/26/2021] [Accepted: 05/29/2021] [Indexed: 01/18/2023] Open
Abstract
Camel urine has traditionally been used to treat multiple human diseases and possesses the most beneficial effects amongst the urine of other animals. However, scientific review evaluating the anticancer, antiplatelet, gastroprotective and hepatoprotective effects of camel urine is still scarce. Thus, this scoping review aimed to provide scientific evidence on the therapeutic potentials of camel urine. Three databases were searched to identify relevant articles (Web of Science, PubMed and Scopus) up to September 2020. Original articles published in English that investigated the effects of camel urine in various diseases were included. The literature search identified six potential articles that met all the inclusion criteria. Three articles showed that camel urine possesses cytotoxic activities against different types of cancer cells. Two studies revealed camel urine's protective effects against liver toxicity and gastric ulcers, whilst another study showed the role of camel urine as an antiplatelet agent. All studies demonstrated significant positive effects with different effective dosages. Thus, camel urine shows promising therapeutic potential in treating human diseases, especially cancer. However, the standardised dosage and potential side effects should be determined before camel urine could be offered as an alternative treatment.
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Affiliation(s)
- Norizam Salamt
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Ruszymah Binti Haji Idrus
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Mohd Izhar Ariff Mohd Kashim
- Centre of Shariah, Faculty of Islamic Studies, Universiti Kebangsaan Malaysia, Bangi 43600, Malaysia
- Institute of Islam Hadhari, Universiti Kebangsaan Malaysia, Bangi 43600, Malaysia
| | - Mohd Helmy Mokhtar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
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Martínez-Pérez C, Leung J, Kay C, Meehan J, Gray M, Dixon JM, Turnbull AK. The Signal Transducer IL6ST (gp130) as a Predictive and Prognostic Biomarker in Breast Cancer. J Pers Med 2021; 11:618. [PMID: 34210062 PMCID: PMC8304290 DOI: 10.3390/jpm11070618] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/23/2021] [Accepted: 06/27/2021] [Indexed: 02/07/2023] Open
Abstract
Novel biomarkers are needed to continue to improve breast cancer clinical management and outcome. IL6-like cytokines, whose pleiotropic functions include roles in many hallmarks of malignancy, rely on the signal transducer IL6ST (gp130) for all their signalling. To date, 10 separate independent studies based on the analysis of clinical breast cancer samples have identified IL6ST as a predictor. Consistent findings suggest that IL6ST is a positive prognostic factor and is associated with ER status. Interestingly, these studies include 4 multigene signatures (EndoPredict, EER4, IRSN-23 and 42GC) that incorporate IL6ST to predict risk of recurrence or outcome from endocrine or chemotherapy. Here we review the existing evidence on the promising predictive and prognostic value of IL6ST. We also discuss how this potential could be further translated into clinical practice beyond the EndoPredict tool, which is already available in the clinic. The most promising route to further exploit IL6ST's promising predicting power will likely be through additional hybrid multifactor signatures that allow for more robust stratification of ER+ breast tumours into discrete groups with distinct outcomes, thus enabling greater refinement of the treatment-selection process.
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Affiliation(s)
- Carlos Martínez-Pérez
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (J.L.); (C.K.); (J.M.D.); (A.K.T.)
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (J.M.); (M.G.)
| | - Jess Leung
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (J.L.); (C.K.); (J.M.D.); (A.K.T.)
| | - Charlene Kay
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (J.L.); (C.K.); (J.M.D.); (A.K.T.)
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (J.M.); (M.G.)
| | - James Meehan
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (J.M.); (M.G.)
| | - Mark Gray
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (J.M.); (M.G.)
| | - J Michael Dixon
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (J.L.); (C.K.); (J.M.D.); (A.K.T.)
| | - Arran K Turnbull
- Breast Cancer Now Edinburgh Research Team, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (J.L.); (C.K.); (J.M.D.); (A.K.T.)
- Translational Oncology Research Group, MRC Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK; (J.M.); (M.G.)
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46
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ZARE MOAIEDI M, AHMADPOOR F, RASHIDI M, AHMADZADEH A, SALMASI AA, MOHAMMADZADEH G. The association between mRNA expression of resistin, TNF- α, IL-6, IL-8, and ER-α in peripheral blood mononuclear cells and breast cancer. Turk J Med Sci 2021; 51:1345-1353. [PMID: 33517609 PMCID: PMC8283432 DOI: 10.3906/sag-2008-292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 01/30/2021] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Adipocytokines, adipose tissue-derived proteins, were demonstrated to be involved in the pathogenesis of breast cancer. We assessed the mRNA expression of resistin, tumor necrosis factor-alpha (TNF-α), interleukins 6 and 8 (IL-6, and IL-8), and estrogen receptor alpha (ER-α) in peripheral blood mononuclear cells (PBMCs) of women with and without breast cancer. METHODS The PBMCs were isolated from the whole blood of 32 women with breast cancer and 18 women without breast cancer using density gradient centrifugation. The mRNA expression of the target genes was measured by reverse-transcription polymerase chain reaction (RT-PCR). Body mass index was calculated, additionally, clinicopathological characteristics of the breast cancer patients were determined by histopathological examination. RESULTS The mRNA expression of resistin (3.5-fold) and IL-6 (15-fold) in PBMCs of breast cancer patients significantly increased in comparison to healthy controls. Resistin expression was significantly associated with inflammatory markers including TNF-α, IL-6, IL-8, but not with anthropometric indices. Logistic regression analysis revealed the studied adipokines were not associated with breast cancer. Based on the ROC curve analysis the diagnostic performance of IL-6 was significant (0.825, 95% CI: 0.549-0.94, p = 0.030), thus, it might be considered as a breast cancer biomarker that reflecting an early and inflammatory stage of the disease. DISCUSSION Breast cancer is not associated with increased expression of inflammatory cytokines in PBMCs. Our results suggested that a PBMC-based gene expression test may be developed to detect breast cancer early.
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Affiliation(s)
- Maasoumeh ZARE MOAIEDI
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, AhvazIran
| | - Fatemeh AHMADPOOR
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, AhvazIran
| | - Mojtaba RASHIDI
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, AhvazIran
| | - Ahmad AHMADZADEH
- Department of Hematology-Oncology, Faculty of Medicine, Firoozgar Clinical Research Development Center, Iran University of Medical Sciences, TehranIran
| | - Amir Ahmad SALMASI
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, AhvazIran
- Department of Surgery, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, AhvazIran
| | - Ghorban MOHAMMADZADEH
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Science, Hyperlipidemia Research center, AhvazIran
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47
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Dettorre GM, Patel M, Gennari A, Pentheroudakis G, Romano E, Cortellini A, Pinato DJ. The systemic pro-inflammatory response: targeting the dangerous liaison between COVID-19 and cancer. ESMO Open 2021; 6:100123. [PMID: 33932622 PMCID: PMC8026271 DOI: 10.1016/j.esmoop.2021.100123] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 03/30/2021] [Accepted: 04/01/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammation is an established driver of severe SARS-CoV-2 infection and a mechanism linked to the increased susceptibility to fatal COVID-19 demonstrated by patients with cancer. As patients with cancer exhibit a higher level of inflammation compared with the general patient population, patients with cancer and COVID-19 may uniquely benefit from strategies targeted at overcoming the unrestrained pro-inflammatory response. Targeted and non-targeted anti-inflammatory therapies may prevent end-organ damage in SARS-CoV-2-infected patients with cancer and decrease mortality. Here, we review the clinical role of selective inhibition of pro-inflammatory interleukins, tyrosine kinase modulation, anti-tumor necrosis factor agents, and other non-targeted approaches including corticosteroids in their roles as disease-modulating agents in patients with COVID-19 and cancer. Investigation of these therapeutics in this highly vulnerable patient group is posited to facilitate the development of tailored therapeutics for this patient population, aiding the transition of systemic inflammation from a prognostic domain to a source of therapeutic targets.
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Affiliation(s)
- G M Dettorre
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - M Patel
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - A Gennari
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale and Maggiore della Carità Hospital, Novara, Italy
| | - G Pentheroudakis
- Department of Medical Oncology, University of Ioannina, Ioannina, Greece; Chief Medical Officer, European Society for Medical Oncology, Lugano, Switzerland
| | - E Romano
- Department of Medical Oncology, Center for Cancer Immunotherapy, Institut Curie, Paris, France
| | - A Cortellini
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK; Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
| | - D J Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale and Maggiore della Carità Hospital, Novara, Italy.
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Wright G, Sonavane M, Gassman NR. Activated STAT3 Is a Novel Regulator of the XRCC1 Promoter and Selectively Increases XRCC1 Protein Levels in Triple Negative Breast Cancer. Int J Mol Sci 2021; 22:ijms22115475. [PMID: 34067421 PMCID: PMC8196947 DOI: 10.3390/ijms22115475] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/18/2021] [Accepted: 05/20/2021] [Indexed: 02/07/2023] Open
Abstract
Base Excision Repair (BER) addresses base lesions and abasic sites induced by exogenous and endogenous stressors. X-ray cross complementing group 1 (XRCC1) functions as a scaffold protein in BER and single-strand break repair (SSBR), facilitating and coordinating repair through its interaction with a host of critical repair proteins. Alterations of XRCC1 protein and gene expression levels are observed in many cancers, including colorectal, ovarian, and breast cancer. While increases in the expression level of XRCC1 are reported, the transcription factors responsible for this up-regulation are not known. In this study, we identify the signal transducer and activator of transcription 3 (STAT3) as a novel regulator of XRCC1 through chromatin immunoprecipitation. Activation of STAT3 through phosphorylation at Y705 by cytokine (IL-6) signaling increases the expression of XRCC1 and the occupancy of STAT3 within the XRCC1 promoter. In triple negative breast cancer, the constitutive activation of STAT3 upregulates XRCC1 gene and protein expression levels. Increased expression of XRCC1 is associated with aggressiveness and resistance to DNA damaging chemotherapeutics. Thus, we propose that activated STAT3 regulates XRCC1 under stress and growth conditions, but constitutive activation in cancers results in dysregulation of XRCC1 and subsequently BER and SSBR.
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Affiliation(s)
- Griffin Wright
- Department of Physiology and Cell Biology, University of South Alabama College of Medicine, 307 N University Blvd, Mobile, AL 36688, USA; (G.W.); (M.S.)
- Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL 36604-1405, USA
| | - Manoj Sonavane
- Department of Physiology and Cell Biology, University of South Alabama College of Medicine, 307 N University Blvd, Mobile, AL 36688, USA; (G.W.); (M.S.)
- Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL 36604-1405, USA
| | - Natalie R. Gassman
- Department of Physiology and Cell Biology, University of South Alabama College of Medicine, 307 N University Blvd, Mobile, AL 36688, USA; (G.W.); (M.S.)
- Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL 36604-1405, USA
- Correspondence:
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Local Anesthetics and Recurrence after Cancer Surgery-What's New? A Narrative Review. J Clin Med 2021; 10:jcm10040719. [PMID: 33670434 PMCID: PMC7918400 DOI: 10.3390/jcm10040719] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/27/2021] [Accepted: 02/08/2021] [Indexed: 12/16/2022] Open
Abstract
The perioperative use of regional anesthesia and local anesthetics is part of almost every anesthesiologist’s daily clinical practice. Retrospective analyses and results from experimental studies pointed towards a potential beneficial effect of the local anesthetics regarding outcome—i.e., overall and/or recurrence-free survival—in patients undergoing cancer surgery. The perioperative period, where the anesthesiologist is responsible for the patients, might be crucial for the further course of the disease, as circulating tumor cells (shed from the primary tumor into the patient’s bloodstream) might form new micro-metastases independent of complete tumor removal. Due to their strong anti-inflammatory properties, local anesthetics might have a certain impact on these circulating tumor cells, either via direct or indirect measures, for example via blunting the inflammatory stress response as induced by the surgical stimulus. This narrative review highlights the foundation of these principles, features recent experimental and clinical data and provides an outlook regarding current and potential future research activities.
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50
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Zhang X, Liu G, Shi X, Shi X, Li J, Mo L, Gao J, Long Z, Tan W. Sequential administration of anti-PD-1 and anti-Tim-3 combined with an SA-GM-CSF-anchored vaccine overcomes adaptive immune resistance to reject established bladder cancer. J Cancer 2021; 12:2000-2009. [PMID: 33753998 PMCID: PMC7974521 DOI: 10.7150/jca.44769] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 12/15/2020] [Indexed: 01/23/2023] Open
Abstract
Program death receptor-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein-3 (Tim-3) play an important role in tumor immune evasion. PD-1 blockade could produce an effective anti-tumor effect but the response rate was low due to lacking of tumor infiltrating lymphocytes (TILs) and existing of other negative regulatory pathways. Streptavidin(SA)-GM-CSF surface-anchored tumor cells vaccine could induce specific anti-tumor immune response. However, this vaccine failed to induce regression of established tumor because it also up-regulated PD-1 expression on tumor cells dependent on IFNγ and up-regulated PD-1/Tim-3 expression on CD8+ TILs. Subsets of CD8+ TILs assay showed that PD-1 expression was closely associated with CD8+ TILs exhaustion, and Tim-3 expression was closely correlated with secretion function but not proliferation of CD8+ TILs. Sequential administration of anti-PD-1 and anti-Tim-3 could further improve the efficacy of SA-GM-CSF-anchored vaccine therapy, and tumor regression was noted in over 50%. This triple therapy improves the specific cytotoxic activity and decreased the apoptosis of CD8+ TILs. These findings indicated that this triple therapy could induce a more robust anti-tumor immune response.
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Affiliation(s)
- Xinji Zhang
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.,Department of Urology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde District, Foshan), Foshan, 528300, China
| | - Guang Liu
- Department of Urology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde District, Foshan), Foshan, 528300, China
| | - Xianghua Shi
- Department of Urology, The First People's Hospital of Foshan, Guangdong,528000, China
| | - Xiaojun Shi
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jinlong Li
- Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Lijun Mo
- Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Jimin Gao
- Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Zhaolin Long
- Department of Urology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde District, Foshan), Foshan, 528300, China
| | - Wanlong Tan
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
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