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1
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Rhodes JD, Goldenring JR, Lee SH. Regulation of metaplasia and dysplasia in the stomach by the stromal microenvironment. Exp Mol Med 2024; 56:1322-1330. [PMID: 38825636 PMCID: PMC11263556 DOI: 10.1038/s12276-024-01240-z] [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: 11/30/2023] [Revised: 03/03/2024] [Accepted: 03/03/2024] [Indexed: 06/04/2024] Open
Abstract
Research on the microenvironment associated with gastric carcinogenesis has focused on cancers of the stomach and often underestimates premalignant stages such as metaplasia and dysplasia. Since epithelial interactions with T cells, macrophages, and type 2 innate lymphoid cells (ILC2s) are indispensable for the formation of precancerous lesions in the stomach, understanding the cellular interactions that promote gastric precancer warrants further investigation. Although various types of immune cells have been shown to play important roles in gastric carcinogenesis, it remains unclear how stromal cells such as fibroblasts influence epithelial transformation in the stomach, especially during precancerous stages. Fibroblasts exist as distinct populations across tissues and perform different functions depending on the expression patterns of cell surface markers and secreted factors. In this review, we provide an overview of known microenvironmental components in the stroma with an emphasis on fibroblast subpopulations and their roles during carcinogenesis in tissues including breast, pancreas, and stomach. Additionally, we offer insights into potential targets of tumor-promoting fibroblasts and identify open areas of research related to fibroblast plasticity and the modulation of gastric carcinogenesis.
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Affiliation(s)
- Jared D Rhodes
- Program in Cancer Biology, Nashville, TN, USA
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - James R Goldenring
- Program in Cancer Biology, Nashville, TN, USA.
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Section of Surgical Sciences, Nashville, TN, USA.
- Department of Cell and Developmental Biology, Nashville, TN, USA.
- Nashville VA Medical Center, Nashville, TN, USA.
| | - Su-Hyung Lee
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Section of Surgical Sciences, Nashville, TN, USA.
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2
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Cerulo L, Pezzella N, Caruso FP, Parente P, Remo A, Giordano G, Forte N, Busselez J, Boschi F, Galiè M, Franco B, Pancione M. Single-cell proteo-genomic reveals a comprehensive map of centrosome-associated spliceosome components. iScience 2023; 26:106602. [PMID: 37250316 PMCID: PMC10214398 DOI: 10.1016/j.isci.2023.106602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 01/16/2023] [Accepted: 03/29/2023] [Indexed: 05/31/2023] Open
Abstract
Ribonucleoprotein (RNP) condensates are crucial for controlling RNA metabolism and splicing events in animal cells. We used spatial proteomics and transcriptomic to elucidate RNP interaction networks at the centrosome, the main microtubule-organizing center in animal cells. We found a number of cell-type specific centrosome-associated spliceosome interactions localized in subcellular structures involved in nuclear division and ciliogenesis. A component of the nuclear spliceosome BUD31 was validated as an interactor of the centriolar satellite protein OFD1. Analysis of normal and disease cohorts identified the cholangiocarcinoma as target of centrosome-associated spliceosome alterations. Multiplexed single-cell fluorescent microscopy for the centriole linker CEP250 and spliceosome components including BCAS2, BUD31, SRSF2 and DHX35 recapitulated bioinformatic predictions on the centrosome-associated spliceosome components tissue-type specific composition. Collectively, centrosomes and cilia act as anchor for cell-type specific spliceosome components, and provide a helpful reference for explore cytoplasmic condensates functions in defining cell identity and in the origin of rare diseases.
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Affiliation(s)
- Luigi Cerulo
- Bioinformatics Laboratory, BIOGEM scrl, Ariano Irpino, Avellino, Italy
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Nunziana Pezzella
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei, 34, Pozzuoli, 80078 Naples, Italy
- School for Advanced Studies, Genomics and Experimental Medicine Program, Naples, Italy
| | - Francesca Pia Caruso
- Bioinformatics Laboratory, BIOGEM scrl, Ariano Irpino, Avellino, Italy
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
| | - Andrea Remo
- Pathology Unit, Mater Salutis Hospital AULSS9, “Scaligera”, 37122 Verona, Italy
| | - Guido Giordano
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy
| | - Nicola Forte
- Department of Clinical Pathology, Fatebenefratelli Hospital, 82100 Benevento, Italy
| | - Johan Busselez
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Federico Boschi
- Department of Computer Science, University of Verona, Strada Le Grazie 8, Verona, Italy
| | - Mirco Galiè
- Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy
| | - Brunella Franco
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei, 34, Pozzuoli, 80078 Naples, Italy
- School for Advanced Studies, Genomics and Experimental Medicine Program, Naples, Italy
- Medical Genetics, Department of Translational Medicine, University of Naples “Federico II”, Via Sergio Pansini, 80131 Naples, Italy
| | - Massimo Pancione
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University Madrid, 28040 Madrid, Spain
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3
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Khan A, Zhang X. Function of the Long Noncoding RNAs in Hepatocellular Carcinoma: Classification, Molecular Mechanisms, and Significant Therapeutic Potentials. Bioengineering (Basel) 2022; 9:406. [PMID: 36004931 PMCID: PMC9405066 DOI: 10.3390/bioengineering9080406] [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: 07/02/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common and serious type of primary liver cancer. HCC patients have a high death rate and poor prognosis due to the lack of clear signs and inadequate treatment interventions. However, the molecular pathways that underpin HCC pathogenesis remain unclear. Long non-coding RNAs (lncRNAs), a new type of RNAs, have been found to play important roles in HCC. LncRNAs have the ability to influence gene expression and protein activity. Dysregulation of lncRNAs has been linked to a growing number of liver disorders, including HCC. As a result, improved understanding of lncRNAs could lead to new insights into HCC etiology, as well as new approaches for the early detection and treatment of HCC. The latest results with respect to the role of lncRNAs in controlling multiple pathways of HCC were summarized in this study. The processes by which lncRNAs influence HCC advancement by interacting with chromatin, RNAs, and proteins at the epigenetic, transcriptional, and post-transcriptional levels were examined. This critical review also highlights recent breakthroughs in lncRNA signaling pathways in HCC progression, shedding light on the potential applications of lncRNAs for HCC diagnosis and therapy.
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Affiliation(s)
| | - Xiaobo Zhang
- College of Life Sciences, Zhejiang University, Hangzhou 310058, China
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4
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Galassi R, Luciani L, Gambini V, Vincenzetti S, Lupidi G, Amici A, Marchini C, Wang J, Pucciarelli S. Multi-Targeted Anticancer Activity of Imidazolate Phosphane Gold(I) Compounds by Inhibition of DHFR and TrxR in Breast Cancer Cells. Front Chem 2021; 8:602845. [PMID: 33490036 PMCID: PMC7821381 DOI: 10.3389/fchem.2020.602845] [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: 09/04/2020] [Accepted: 12/09/2020] [Indexed: 12/09/2022] Open
Abstract
A class of phosphane gold(I) compounds, made of azoles and phosphane ligands, was evaluated for a screening on the regards of Breast Cancer cell panels (BC). The compounds possess N-Au-P or Cl-Au-P bonds around the central metal, and they differ for the presence of aprotic or protic polar groups in the azoles and/or the phosphane moieties to tune their hydrophilicity. Among the six candidates, only the compounds having the P-Au-N environment and not displaying neither the hydroxyl nor carboxyl groups in the ligands were found active. The compounds were screened by MTT tests in SKBR3, A17, and MDA-MB231 cancer cells, and two compounds (namely the 4,5-dicyano-imidazolate-1yl-gold(I)-(triphenylphosphane, 5, and 4,5-dichloro-imidazolate-1yl-gold(I)-triphenylphosphane, 6) were found very cytotoxic, with the most active with an IC50 value of 3.46 μM in MDA-MB231 cells. By performing enzymatic assays in the treated cells lysates, the residual enzymatic activity of dihydrofolate reductase (DHFR) has been measured after cell treatment for 4 or 12 h in comparison with control cells. Upon 12 h of treatment, the activity of DHFR was significantly reduced in both SKBR3 and A17 cells by compounds 5 and 6, but not in human MDA-MB231 cells; interestingly, it was found remarkably high after 4 h of treatment, revealing a time dependence for the DHFR enzymatic assays. The DHFR inhibition data have been compared to those for the thioredoxin reductase (TrxR), the most recognized molecular target for gold compounds. For this latter, similar residual activities (i.e., 37 and 49% for the match of SKBR3 cells and compound 5 or 6, respectively) were found. Binding studies on the regards of ct-DNA (calf-thymus-DNA) and of plasma transporters proteins, such as BSA (bovine serum albumin) and ATF (apo transferrin), were performed. As expected for gold compounds, the data support strong binding to proteins (Ksv values range: 1.51 ÷ 2.46 × 104 M−1) and a weaker interaction with ct-DNA's minor groove (Ksv values range: 1.55 ÷ 6.12 × 103 M−1).
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Affiliation(s)
- Rossana Galassi
- School of Science and Technology, University of Camerino, Camerino, Italy
| | - Lorenzo Luciani
- School of Science and Technology, University of Camerino, Camerino, Italy
| | - Valentina Gambini
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
| | - Silvia Vincenzetti
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
| | - Giulio Lupidi
- School of Drugs and Health Products Sciences, University of Camerino, Camerino, Italy
| | - Augusto Amici
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
| | - Cristina Marchini
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
| | - Junbiao Wang
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
| | - Stefania Pucciarelli
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
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5
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Silvestri S, Cirilli I, Marcheggiani F, Dludla P, Lupidi G, Pettinari R, Marchetti F, Di Nicola C, Falcioni G, Marchini C, Orlando P, Tiano L, Amici A. Evaluation of anticancer role of a novel ruthenium(II)-based compound compared with NAMI-A and cisplatin in impairing mitochondrial functionality and promoting oxidative stress in triple negative breast cancer models. Mitochondrion 2020; 56:25-34. [PMID: 33220497 DOI: 10.1016/j.mito.2020.11.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/22/2020] [Accepted: 11/02/2020] [Indexed: 01/18/2023]
Abstract
Platinum-based compounds are the most widely used anticancer drugs but, their elevated toxicity and chemoresistance has stimulated the study of others, such as ruthenium-based compounds. NAMI-A and UNICAM-1 were tested in vitro, comparing the mechanisms of toxicity, in terms of mitochondrial functionality and cellular oxidative stress. UNICAM-1, showed a clear mitochondrial target and a cytotoxic dose-dependent response thanks to its ability to promote an imbalance of cellular redox status. It impaired directly mitochondrial respiratory chain, promoting mitochondrial superoxide anion production, leading to mitochondrial membrane depolarization. All these aspects, could make UNICAM-1 a valid alternative for chemotherapy treatment of breast cancer.
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Affiliation(s)
- Sonia Silvestri
- Department of Life and Environmental Sciences, DISVA-Biochemistry, Polytechnic University of Marche, 60131 Ancona, Italy; Biomedfood srl, Ex-Spinoff of Polytechnic University of Marche, 60125 Ancona, Italy
| | - Ilenia Cirilli
- Department of Life and Environmental Sciences, DISVA-Biochemistry, Polytechnic University of Marche, 60131 Ancona, Italy; School of Pharmacy, University of Camerino, Camerino, MC, Italy
| | - Fabio Marcheggiani
- Department of Life and Environmental Sciences, DISVA-Biochemistry, Polytechnic University of Marche, 60131 Ancona, Italy
| | - Phiwayinkosi Dludla
- Department of Life and Environmental Sciences, DISVA-Biochemistry, Polytechnic University of Marche, 60131 Ancona, Italy; Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa
| | - Giulio Lupidi
- School of Pharmacy, University of Camerino, Camerino, MC, Italy
| | | | - Fabio Marchetti
- School of Sciences and Technology, University of Camerino, Camerino, MC, Italy
| | - Corrado Di Nicola
- School of Sciences and Technology, University of Camerino, Camerino, MC, Italy
| | | | - Cristina Marchini
- University of Camerino, via Gentile III da Varano, 62032 Camerino, Italy
| | - Patrick Orlando
- Department of Life and Environmental Sciences, DISVA-Biochemistry, Polytechnic University of Marche, 60131 Ancona, Italy.
| | - Luca Tiano
- Department of Life and Environmental Sciences, DISVA-Biochemistry, Polytechnic University of Marche, 60131 Ancona, Italy
| | - Augusto Amici
- University of Camerino, via Gentile III da Varano, 62032 Camerino, Italy
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Wang J, Iannarelli R, Pucciarelli S, Laudadio E, Galeazzi R, Giangrossi M, Falconi M, Cui L, Navia AM, Buccioni M, Marucci G, Tomassoni D, Serini L, Sut S, Maggi F, Dall'Acqua S, Marchini C, Amici A. Acetylshikonin isolated from Lithospermum erythrorhizon roots inhibits dihydrofolate reductase and hampers autochthonous mammary carcinogenesis in Δ16HER2 transgenic mice. Pharmacol Res 2020; 161:105123. [PMID: 32822867 DOI: 10.1016/j.phrs.2020.105123] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 07/16/2020] [Accepted: 07/28/2020] [Indexed: 12/21/2022]
Abstract
Breast cancer (BC) is the most common cancer in women and, among different BC subtypes, triple negative (TN) and human epidermal growth factor receptor 2 (HER2)-positive BCs have the worst prognosis. In this study, we investigated the anticancer activity of the root ethanolic and hexane extracts from Lithospermum erythrorhizon, a traditional Chinese herbal medicine known also as tzu ts'ao or tzu-ken, against in vitro and in vivo models of TNBC and HER2-positive BC. Treatment with L. erythrorhizon root extracts resulted in a dose-dependent inhibition of BC cell viability and in a significant reduction of the growth of TNBC cells transplanted in syngeneic mice. Acetylshikonin, a naphthoquinone, was identified as the main bioactive component in extracts and was responsible for the observed antitumor activity, being able to decrease BC cell viability and to interfere with autochthonous mammary carcinogenesis in Δ16HER2 transgenic mice. Acetylshikonin anticancer effect depends on its ability to act as a potent inhibitor of dihydrofolate reductase (DHFR), to down-regulate key mediators governing cancer growth and progression, such as HER2, Src and STAT3, and to induce apoptosis by caspase-3 activation. The accumulation of acetylshikonin in blood samples as well as in brain, kidney, liver and tumor tissues was also investigated by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) highlighting that L. erythrorhizon treatment is effective in delivering the active compound into the target tissues. These results provide evidence that L. erythrorhizon extract and in particular its main component acetylshikonin are effective against aggressive BC subtypes and reveal new acetylshikonin mechanisms of action.
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Affiliation(s)
- Junbiao Wang
- School of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy
| | | | - Stefania Pucciarelli
- School of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy
| | - Emiliano Laudadio
- Dipartimento Scienze e Ingegneria della Materia, dell'Ambiente ed Urbanistica, Università Politecnica delle Marche, Ancona, 60128, Italy
| | - Roberta Galeazzi
- Dipartimento di Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Ancona, 60128, Italy
| | - Mara Giangrossi
- School of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy
| | - Maurizio Falconi
- School of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy
| | - Lishan Cui
- School of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy
| | | | - Michela Buccioni
- School of Pharmacy, University of Camerino, 62032, Camerino, Italy
| | | | - Daniele Tomassoni
- School of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy
| | - Laura Serini
- School of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy
| | - Stefania Sut
- DAFNAE Dipartimento di Agronomia, Animali, Alimenti, Risorse naturali e Ambiente, University of Padova, 35020, Legnaro, Italy
| | - Filippo Maggi
- School of Pharmacy, University of Camerino, 62032, Camerino, Italy
| | - Stefano Dall'Acqua
- DSF Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35121, Padova, Italy.
| | - Cristina Marchini
- School of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy.
| | - Augusto Amici
- School of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy
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7
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Wang Q, Li T, Wu W, Ding G. Interplay between mesenchymal stem cell and tumor and potential application. Hum Cell 2020; 33:444-458. [PMID: 32378164 DOI: 10.1007/s13577-020-00369-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 04/24/2020] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) possess the capabilities of self-renewal and multipotent differentiation. Firstly isolated from bone marrow, MSCs are subsequently identified from various post-natal tissue types. Based the differentiation into tissue-specific cells, MSCs were capable of replacing damaged and diseased tissues. In addition, MSCs have been demonstrated to possess important immunomodulatory properties. Increasing data showed that MSCs exhibited tropism for sites of the tumor microenvironment and interacted with tumor cells closely through paracrine signaling. Therefore, better understanding of crosstalk between MSCs and tumor cells will be able to develop potential strategies in the treatment of tumors in the future. Herein, we summarize the research progress of the influence of MSCs on tumor cells and the prospect of their application in tumor therapy in this review.
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Affiliation(s)
- Qing Wang
- Department of Dentistry, Weifang People's Hospital, Weifang, 261000, Shandong, People's Republic of China
| | - Ti Li
- Department of Dentistry, Weifang People's Hospital, Weifang, 261000, Shandong, People's Republic of China
| | - Wei Wu
- Department of Dentistry, Weifang People's Hospital, Weifang, 261000, Shandong, People's Republic of China
| | - Gang Ding
- Department of Stomatology, Yidu Central Hospital, Weifang Medical University, Linglongshan South Road No. 4138, Qingzhou, 262500, Shandong, People's Republic of China.
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8
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Cong X, Zhang Y, Zhu Z, Li S, Yin X, Zhai Z, Zhang Y, Xue Y. CD66b + neutrophils and α-SMA + fibroblasts predict clinical outcomes and benefits from postoperative chemotherapy in gastric adenocarcinoma. Cancer Med 2020; 9:2761-2773. [PMID: 32096331 PMCID: PMC7163111 DOI: 10.1002/cam4.2939] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/31/2020] [Accepted: 02/10/2020] [Indexed: 12/26/2022] Open
Abstract
Background Emerging evidence indicates that the tumor microenvironment (TME) influences tumor progression through the various cells it contains. Tumor‐associated neutrophils (TANs) and cancer‐associated fibroblasts (CAFs) are prominent constituents of diverse malignant solid tumors and are crucial in the TME and cancer evolution. However, the relationships and combined prognostic value of these two cell types are not known in gastric adenocarcinoma (GAC). Materials and Methods In total, 215 GAC patients who underwent curative surgery were enrolled. TANs were assessed by immunohistochemical staining for CD66b, and CAFs were evaluated by immunohistochemical staining for α‐smooth muscle actin (α‐SMA). Results The percentages of patients with high‐density TANs and CAFs in GAC tissue were 47.9% (103/215) and 43.3% (93/215), respectively. The densities of TANs and CAFs in GAC tissue samples were markedly elevated and independently correlated with GAC clinical outcomes. A strong correlation (R = .348, P < .001) was detected between TANs and CAFs in GAC. The combination of TANs and CAFs produced a more exact outcome than either factor alone. Patients with an α‐SMAlowCD66bhigh (hazard ratio [HR] = 1.791; 95% CI: 1.062‐3.021; P = .029), α‐SMAhighCD66blow (HR = 2.402; 95% CI: 1.379‐4.183; P = .002), or α‐SMAhighCD66bhigh (HR = 3.599; 95% CI: 2.330‐5.560; P < .001) phenotype were gradually correlated with poorer disease‐free survival than the subset of patients with an α‐SMAlowCD66blow phenotype. The same results were observed for disease‐specific survival in the subgroups. Noticeably, in stage II‐III patients with the α‐SMAlowCD66blow phenotype, an advantage was obtained with postoperative chemotherapeutics, and the risk of a poor prognosis was reduced compared with stage II‐III patients with the α‐SMAlowCD66bhigh, α‐SMAhighCD66blow or α‐SMAhighCD66bhigh phenotype (HR: 0.260, 95% CI: 0.124‐0.542, P < .001 for disease‐free survival; and HR: 0.258, 95% CI: 124‐0.538, P < .001 for disease‐specific survival). Conclusion Overall, we concluded that the combination of CD66b+ TANs and α‐SMA+ CAFs could be used as an independent factor for patient outcomes and to identify GAC patients who might benefit from the administration of postoperative chemotherapeutics.
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Affiliation(s)
- Xiliang Cong
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yongle Zhang
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ziyu Zhu
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Sen Li
- Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin Yin
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhao Zhai
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yu Zhang
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yingwei Xue
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
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9
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Yang Q, Chen J, Zhu Y, Xu Z. Mesenchymal Stem Cells Accelerate the Remodeling of Bladder VX2 Tumor Interstitial Microenvironment by TGFβ1-Smad Pathway. J Cancer 2019; 10:4532-4539. [PMID: 31528217 PMCID: PMC6746123 DOI: 10.7150/jca.30788] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 04/23/2019] [Indexed: 01/05/2023] Open
Abstract
Background: Mesenchymal stem cells (MSCs) have been proved to be able to differentiate into cells that are conducive to tumor growth and invasion. The mechanism is not clear. This present study was aimed to find out whether TGFβ1-Smad pathway was involved in this process. Methods: For the in vitro experiment, five groups of MSCs were cultured to test whether VX2 culture supernatant could induce the differentiation of MSCs into myofibroblasts. And then transforming growth factor β1(TGFβ1) receptor or Smad2 of MSCs were blocked by RNA interference technique to test whether TGFβ1-Smad pathway was involved in the differentiation. In the animal experiment, different kinds of MSCs were co-inoculated with VX2 cells in bladder to test whether the blockage of TGFβ1 receptor or Smad2 of MSCs could affect the expression of TGFβ1, epidermal growth factor (EGF), fibroblast activation protein alpha (FAPa), and matrix metalloprotein 9 (MMP9) in five animal groups. Results: VX2 culture supernatant could up-regulate the expression of α-SMA and Vimentin in MSCs, which indicated that VX2 culture supernatant could induce the differentiation of MSCs into myofibroblasts. Either the Blockage of TGFβ1 receptor or Smad2 of MSCs could lead to decreased expression of α-SMA and Vimentin in MSCs. In the animal experiment, MSCs could favor VX2 bladder tumor growth and up-regulate the expression of TGFβ1, EGF, FAPa, MMP9 in VX2 tumor tissue. However, when TGFβ1 receptor or Smad2 of MSCs was blocked, the above effects were attenuated. Conclusions: Under the induction of tumor microenvironment, MSCs can differentiate into myofibroblasts and then affect tumor interstitial microenvironment remodeling. This process is mediated by TGFβ1-Smad2 pathway.
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Affiliation(s)
- Qingya Yang
- Department of Urology, Qilu Hospital (Qingdao), Shandong University, Qingdao 266035, China
| | - Jun Chen
- Department of Urology, Qilu Hospital (Qingdao), Shandong University, Qingdao 266035, China.,Department of Urology, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Yaofeng Zhu
- Department of Urology, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Zhishun Xu
- Department of Urology, Qilu Hospital, Shandong University, Jinan 250012, China
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10
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Ogunwobi OO, Harricharran T, Huaman J, Galuza A, Odumuwagun O, Tan Y, Ma GX, Nguyen MT. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol 2019; 25:2279-2293. [PMID: 31148900 PMCID: PMC6529884 DOI: 10.3748/wjg.v25.i19.2279] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 03/27/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.
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Affiliation(s)
- Olorunseun O Ogunwobi
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Trisheena Harricharran
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Jeannette Huaman
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Anna Galuza
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Oluwatoyin Odumuwagun
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Yin Tan
- Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Grace X Ma
- Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Minhhuyen T Nguyen
- Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, United States
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11
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Chen J, Yang P, Xiao Y, Zhang Y, Liu J, Xie D, Cai M, Zhang X. Overexpression of α-sma-positive fibroblasts (CAFs) in Nasopharyngeal Carcinoma Predicts Poor Prognosis. J Cancer 2017; 8:3897-3902. [PMID: 29151978 PMCID: PMC5688944 DOI: 10.7150/jca.20324] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 08/03/2017] [Indexed: 01/18/2023] Open
Abstract
Purpose: The aim of this study is to investigate the differential expression of α-sma-positive fibroblasts (CAFs) in nasopharyngeal carcinomas (NPCs), nasopharyngitis, metastatic tissues of NPCs and its prognostic value in NPCs. Methods: The expression of α-sma-labeled CAFs in 85 NPCs, 32 nasopharyngitis and 12 metastatic tissues of NPCs was detected by immunohistochemical method. The relationship between CAFs and clinicopathological parameters of NPCs was analyzed. Results: The high density of CAFs in the NPCs, nasopharyngitis and metastatic tissues of NPCs group were 41.2% (35/85), 6.2% (2/32) and 83.3% (10/12), and a significant difference was showed among these three groups (P<0.05). Chi-square test showed that there was no significant correlation between the density of CAFs and gender, age, N stage, treatment (P>0.05), but closely correlated with T stage and relapse (P<0.05). Kaplan-Meier survival analysis showed that the mean overall survival of high-density and low-density CAFs was 86.8 months and 127.0 months, respectively. Correspondingly, the 5-year survival rates were 57.1% (20/35) and 90.0% (45/50), and there were inversely statistical differences between two groups (P<0.05). Cox multivariate analysis showed that the density of CAFs could be used as an independent prognostic factor for the survival of NPC patients (P<0.05). Conclusions: The density of CAFs could be closely related to the metastasis of NPCs, and also is an efficient prediction factor of poor survival in patients with NPCs.
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Affiliation(s)
- Jiewei Chen
- Department of pathology, Sun Yat-Sen University Cancer Center, 510060 Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
| | - Pengfei Yang
- Department of Pathology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, 519000, China
| | - Yongbo Xiao
- Department of pathology, Sun Yat-Sen University Cancer Center, 510060 Guangzhou, China
| | - Yijun Zhang
- Department of pathology, Sun Yat-Sen University Cancer Center, 510060 Guangzhou, China
| | - Jun Liu
- Department of pathology, Sun Yat-Sen University Cancer Center, 510060 Guangzhou, China
| | - Dan Xie
- Department of pathology, Sun Yat-Sen University Cancer Center, 510060 Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
| | - Muyan Cai
- Department of pathology, Sun Yat-Sen University Cancer Center, 510060 Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
| | - Xinke Zhang
- Department of pathology, Sun Yat-Sen University Cancer Center, 510060 Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
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12
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Tilio M, Gambini V, Wang J, Garulli C, Kalogris C, Andreani C, Bartolacci C, Elexpuru Zabaleta M, Pietrella L, Hysi A, Iezzi M, Belletti B, Orlando F, Provinciali M, Galeazzi R, Marchini C, Amici A. Irreversible inhibition of Δ16HER2 is necessary to suppress Δ16HER2-positive breast carcinomas resistant to Lapatinib. Cancer Lett 2016; 381:76-84. [DOI: 10.1016/j.canlet.2016.07.028] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 07/21/2016] [Accepted: 07/22/2016] [Indexed: 01/11/2023]
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13
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Piovesana S, Capriotti AL, Colapicchioni V, Ferraris F, La Barbera G, Ventura S. Membrane proteome functional characterization of breast cancer-initiating cells subjected to bone morphogenetic protein signaling inhibition by dorsomorphin. Med Chem Res 2016. [DOI: 10.1007/s00044-016-1657-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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14
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Polyphenol-rich strawberry extract (PRSE) shows in vitro and in vivo biological activity against invasive breast cancer cells. Sci Rep 2016; 6:30917. [PMID: 27498973 PMCID: PMC4976366 DOI: 10.1038/srep30917] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 07/11/2016] [Indexed: 12/20/2022] Open
Abstract
We describe the biological effects of a polyphenol-rich strawberry extract (PRSE), obtained from the “Alba” variety, on the highly aggressive and invasive basal-like breast cancer cell line A17. Dose-response and time-course experiments showed that PRSE is able to decrease the cellular viability of A17 cells in a time- and dose-dependent manner. PRSE effect on cell survival was investigated in other tumor and normal cell lines of both mouse and human origin, demonstrating that PRSE is more active against breast cancer cells. Cytofluorimetric analysis of A17 cells demonstrated that sub-lethal doses of PRSE reduce the number of cells in S phase, inducing the accumulation of cells in G1 phase of cell cycle. In addition, the migration of A17 cells was studied monitoring the ability of PRSE to inhibit cellular mobility. Gene expression analysis revealed the modulation of 12 genes playing different roles in the cellular migration, adhesion and invasion processes. Finally, in vivo experiments showed the growth inhibition of A17 cells orthotopically transplanted into FVB syngeneic mice fed with PRSE. Overall, we demonstrated that PRSE exerts important biological activities against a highly invasive breast cancer cell line both in vitro and in vivo suggesting the strawberry extracts as preventive/curative food strategy.
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15
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Montani M, Pazmay GVB, Hysi A, Lupidi G, Pettinari R, Gambini V, Tilio M, Marchetti F, Pettinari C, Ferraro S, Iezzi M, Marchini C, Amici A. The water soluble ruthenium(II) organometallic compound [Ru(p-cymene)(bis(3,5 dimethylpyrazol-1-yl)methane)Cl]Cl suppresses triple negative breast cancer growth by inhibiting tumor infiltration of regulatory T cells. Pharmacol Res 2016; 107:282-290. [PMID: 27038531 DOI: 10.1016/j.phrs.2016.03.032] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 02/11/2016] [Accepted: 03/01/2016] [Indexed: 12/21/2022]
Abstract
Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favorable toxicity and clearance properties. Here, we show that the ruthenium(II) complex [Ru(p-cymene)(bis(3,5-dimethylpyrazol-1-yl)methane)Cl]Cl (UNICAM-1) exhibits potent in vivo antitumor effects. When administered as four-dose course, by repeating a single dose (52.4mgkg-1) every three days, UNICAM-1 significantly reduces the growth of A17 triple negative breast cancer cells transplanted into FVB syngeneic mice. Pharmacokinetic studies indicate that UNICAM-1 is rapidly eliminated from kidney, liver and bloodstream thanks to its high hydrosolubility, exerting excellent therapeutic activity with minimal side effects. Immunohistological analysis revealed that the efficacy of UNICAM-1, mainly relies on its capacity to reverse tumor-associated immune suppression by significantly reducing the number of tumor-infiltrating regulatory T cells. Therefore, UNICAM-1 appears very promising for the treatment of TNBC.
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Affiliation(s)
- Maura Montani
- School of Bioscience and Veterinary Medicine, University of Camerino, Camerino, MC, 62032, Italy
| | - Gretta V Badillo Pazmay
- School of Bioscience and Veterinary Medicine, University of Camerino, Camerino, MC, 62032, Italy; School of Pharmacy, University of Camerino, Camerino, MC, 62032, Italy
| | - Albana Hysi
- Aging Research Centre, G. d⿿Annunzio University, Chieti, 66100, Italy
| | - Giulio Lupidi
- School of Pharmacy, University of Camerino, Camerino, MC, 62032, Italy.
| | | | - Valentina Gambini
- School of Bioscience and Veterinary Medicine, University of Camerino, Camerino, MC, 62032, Italy
| | - Martina Tilio
- School of Bioscience and Veterinary Medicine, University of Camerino, Camerino, MC, 62032, Italy
| | - Fabio Marchetti
- School of Science and Technology, University of Camerino, Camerino, MC, 62032, Italy
| | - Claudio Pettinari
- School of Pharmacy, University of Camerino, Camerino, MC, 62032, Italy
| | - Stefano Ferraro
- School of Science and Technology, University of Camerino, Camerino, MC, 62032, Italy
| | - Manuela Iezzi
- Aging Research Centre, G. d⿿Annunzio University, Chieti, 66100, Italy
| | - Cristina Marchini
- School of Bioscience and Veterinary Medicine, University of Camerino, Camerino, MC, 62032, Italy
| | - Augusto Amici
- School of Bioscience and Veterinary Medicine, University of Camerino, Camerino, MC, 62032, Italy.
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16
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Chowdhury R, Webber JP, Gurney M, Mason MD, Tabi Z, Clayton A. Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts. Oncotarget 2015; 6:715-31. [PMID: 25596732 PMCID: PMC4359250 DOI: 10.18632/oncotarget.2711] [Citation(s) in RCA: 207] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 11/11/2014] [Indexed: 12/25/2022] Open
Abstract
Stromal fibroblasts become altered in response to solid cancers, to exhibit myofibroblastic characteristics, with disease promoting influence. Infiltrating mesenchymal stem cells (MSC) may contribute towards these changes, but the factors secreted by cancer cells that impact MSC differentiation are poorly understood. We investigated the role of nano-metre sized vesicles (exosomes), secreted by prostate cancer cells, on the differentiation of bone-marrow MSC (BM-MSC), and the subsequent functional consequences of such changes. Purified exosomes impaired classical adipogenic differentiation, skewing differentiation towards alpha-smooth muscle actin (αSMA) positive myofibroblastic cells. A single exosomes treatment generated myofibroblasts secreting high levels of VEGF-A, HGF and matrix regulating factors (MMP-1, −3 and −13). Differentiated MSC had pro-angiogenic functions and enhanced tumour proliferation and invasivity assessed in a 3D co-culture model. Differentiation was dependent on exosomal-TGFβ, but soluble TGFβ at matched dose could not generate the same phenotype. Exosomes present in the cancer cell secretome were the principal factors driving this phenotype. Prostate cancer exosomes dominantly dictate a programme of MSC differentiation generating myofibroblasts with functional properties consistent with disease promotion.
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Affiliation(s)
- Ridwana Chowdhury
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff, United Kingdom, CF14 2TL
| | - Jason P Webber
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff, United Kingdom, CF14 2TL.,Cardiff Institute for Tissue Engineering and Repair, Cardiff University
| | - Mark Gurney
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff, United Kingdom, CF14 2TL
| | - Malcolm D Mason
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff, United Kingdom, CF14 2TL
| | - Zsuzsanna Tabi
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff, United Kingdom, CF14 2TL
| | - Aled Clayton
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff, United Kingdom, CF14 2TL.Cardiff Institute for Tissue Engineering and Repair, Cardiff University.,Institute of Cancer and Genetics, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff, United Kingdom, CF14 2TL.Cardiff Institute for Tissue Engineering and Repair, Cardiff University
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17
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Luksic I, Suton P, Manojlovic S, Virag M, Petrovecki M, Macan D. Significance of myofibroblast appearance in squamous cell carcinoma of the oral cavity on the occurrence of occult regional metastases, distant metastases, and survival. Int J Oral Maxillofac Surg 2015; 44:1075-80. [DOI: 10.1016/j.ijom.2015.05.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 05/05/2015] [Accepted: 05/14/2015] [Indexed: 12/17/2022]
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18
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Lu Y, Lin N, Chen Z, Xu R. Hypoxia-induced secretion of platelet-derived growth factor-BB by hepatocellular carcinoma cells increases activated hepatic stellate cell proliferation, migration and expression of vascular endothelial growth factor-A. Mol Med Rep 2014; 11:691-7. [PMID: 25333351 DOI: 10.3892/mmr.2014.2689] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 07/17/2014] [Indexed: 12/14/2022] Open
Abstract
Angiogenesis has an important function in the proliferation and metastasis of hepatocellular carcinoma (HCC) under a hypoxic tumor microenvironment. Activated hepatic stellate cells (HSCs) infiltrate the stroma of liver tumors and potently increase angiogenesis through tumor-stromal interactions, however, the exact mechanism by which this occurs is unknown. The present study aimed to investigate the paracrine effects of HCC-derived platelet-derived growth factor-BB (PDGF-BB) on HSCs under hypoxic conditions. It was demonstrated that PDGF-BB expression was markedly increased in HepG2 cells exposed to hypoxia. Conditioned medium (CM) from HepG2 cells stimulated LX-2 cell proliferation, migration and vascular endothelial growth factor-A (VEGF-A) expression. It was then determined that blocking PDGF-BB expression in HepG2-CM abolished these effects on LX-2 cells. The ectopic expression of PDGF-BB in HepG2 cells strongly affected LX-2 cell proliferation, migration and VEGF-A expression. In conclusion, the present study suggests that hypoxia-induced PDGF-BB secretion by HCC cells stimulates HSCs to accumulate and proliferate in the tumor stroma and the enhanced VEGF-A expression in HSCs may promote HCC angiogenesis.
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Affiliation(s)
- Yi Lu
- Department of Hepatobiliary Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Nan Lin
- Department of Hepatobiliary Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhiju Chen
- Department of Hepatobiliary Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ruiyun Xu
- Department of Hepatobiliary Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
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19
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Kalogris C, Garulli C, Pietrella L, Gambini V, Pucciarelli S, Lucci C, Tilio M, Zabaleta ME, Bartolacci C, Andreani C, Giangrossi M, Iezzi M, Belletti B, Marchini C, Amici A. Sanguinarine suppresses basal-like breast cancer growth through dihydrofolate reductase inhibition. Biochem Pharmacol 2014; 90:226-34. [PMID: 24875448 DOI: 10.1016/j.bcp.2014.05.014] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 05/15/2014] [Accepted: 05/19/2014] [Indexed: 12/13/2022]
Abstract
Basal-like breast cancer (BLBC) remains a great challenge because of its clinically aggressive nature and lack of effective targeted therapy. We analyzed the potential anti-neoplastic effects of sanguinarine, a natural benzophenanthridine alkaloid, against BLBC cells. Sanguinarine treatment resulted in a reduction of cell migration, in a dose-dependent inhibition of cell viability and in the induction of cell death by apoptosis in both human (MDA-MB-231 cells) and mouse (A17 cells) in vitro models of BLBC. In vivo experiments demonstrated that oral administration of sanguinarine reduced the development and growth of A17 transplantable tumors in FVB syngeneic mice. Western blotting analysis revealed that suppression of BLBC growth by sanguinarine was correlated with a concurrent upregulation of p27 and downregulation of cyclin D1 and with the inhibition of STAT3 activation. In addition, we identified sanguinarine as a potent inhibitor of dihydrofolate reductase (DHFR), able to impair enzyme activity even in methotrexate resistant MDA-MB-231 cells. These results provide evidence that sanguinarine is a promising anticancer drug for the treatment of BLBC.
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Affiliation(s)
- Cristina Kalogris
- Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy
| | - Chiara Garulli
- Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy
| | - Lucia Pietrella
- Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy
| | - Valentina Gambini
- Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy
| | - Stefania Pucciarelli
- Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy
| | - Cristiano Lucci
- Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy
| | - Martina Tilio
- Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy
| | | | - Caterina Bartolacci
- Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy
| | - Cristina Andreani
- Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy
| | - Mara Giangrossi
- Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy
| | - Manuela Iezzi
- Aging Research Centre, G. d'Annunzio University, Chieti 66100, Italy
| | - Barbara Belletti
- Division of Experimental Oncology 2, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy
| | - Cristina Marchini
- Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
| | - Augusto Amici
- Department of Bioscience and Biotechnology, University of Camerino, Camerino 62032, Italy.
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20
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Dorsomorphin reverses the mesenchymal phenotype of breast cancer initiating cells by inhibition of bone morphogenetic protein signaling. Cell Signal 2013; 26:352-62. [PMID: 24280125 DOI: 10.1016/j.cellsig.2013.11.022] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Revised: 11/12/2013] [Accepted: 11/19/2013] [Indexed: 12/20/2022]
Abstract
Increasing evidence supports the theory that tumor growth, homeostasis, and recurrence are dependent on a small subset of cells with stem cell properties, redefined cancer initiating cells (CICs) or cancer stem cells. Bone morphogenetic proteins (BMPs) are involved in cell-fate specification during embryogenesis, in the maintenance of developmental potency in adult stem cells and may contribute to sustain CIC populations in breast carcinoma. Using the mouse A17 cell model previously related to mesenchymal cancer stem cells and displaying properties of CICs, we investigated the role of BMPs in the control of breast cancer cell plasticity. We showed that an autocrine activation of BMP signaling is crucial for the maintenance of mesenchymal stem cell phenotype and tumorigenic potential of A17 cells. Pharmacological inhibition of BMP signaling cascade by Dorsomorphin resulted in the acquisition of epithelial-like traits by A17 cells, including expression of Citokeratin-18 and E-cadherin, through downregulation of Snail and Slug transcriptional factors and Cyclooxygenase-2 (COX2) expression, and in the loss of their stem-features and self-renewal ability. This phenotypic switch compromised A17 cell motility, invasiveness and in vitro tumor growth. These results reveal that BMPs are key molecules at the crossroad between stemness and cancer.
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21
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Routray S, Sunkavali A, Bari KA. Carcinoma-associated fibroblasts, its implication in head and neck squamous cell carcinoma: a mini review. Oral Dis 2013; 20:246-53. [PMID: 23574536 DOI: 10.1111/odi.12107] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 03/08/2013] [Accepted: 03/11/2013] [Indexed: 12/21/2022]
Abstract
The communication between tumor stromal and parenchymal cells provides an insight to tumor progression. One of the main elements of the stroma, a major contributor to the extracellular environment of tumors, is carcinoma-associated fibroblasts. They can originate from either normal fibroblasts in the immediate vicinity of the tumor or from circulating bone marrow-derived mesenchymal stem cells. These myofibroblasts can arise locally from an endothelial-mesenchymal transformation at the invasive edge of the cancer and are physically associated with carcinoma cells, that is, in the development of high-grade malignancies and poor prognosis. These carcinoma-associated fibroblasts feed the epithelial tumor cells in a host-parasite relationship establishing its role in head and neck squamous cell carcinoma progression.
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Affiliation(s)
- S Routray
- Department of Oral Pathology & Microbiology, GITAM Dental College & Hospital, Vishakapatanam, India
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22
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Bravatà V, Cammarata FP, Forte GI, Minafra L. "Omics" of HER2-positive breast cancer. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2013; 17:119-29. [PMID: 23421906 DOI: 10.1089/omi.2012.0099] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
HER2/neu amplification/overexpression is the only somatic mutation widely considered to be a marker of disease outcome and response to treatment in breast cancer. Pathologists have made large efforts to achieve accuracy in characterizing HER2/neu status. The introduction of transtuzumab contributed to development of additional measures to identify sensitive and resistant subclasses of HER2/neu-positive tumors. In this article, we describe the latest advances in HER2/neu status diagnostic assessment and the most relevant research emerging from "Omics" (genomics, epigenetics, transcriptomics, and proteomics) studies on HER2/neu-positive breast cancer. A large quantity of biomarkers from different studies highlighted HER2/neu-positive specific proliferation, cell cycle arrest, and apoptosis mechanisms, as well as immunological and metabolic behavior. Major driver genes of tumor progression have had a candidate status (GRB7, MYC, CCND1, EGFR, etc.), even though the main role for HER2/neu is largely recognized. Nonetheless, existing omics data and HER2/neu-positive molecular profiles seem to suggest that few proteogenomic alterations in HER2, EGFR, and PI3K networks could significantly affect the effectiveness of transtuzumab. The systematic search of molecular alterations in and across these pathways can help to select the most appropriate drug for a given patient based on in-depth understanding of complexity in tumor biology.
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Affiliation(s)
- Valentina Bravatà
- Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Cefalù Unit, Cefalù, Italy
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23
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Bisaro B, Montani M, Konstantinidou G, Marchini C, Pietrella L, Iezzi M, Galiè M, Orso F, Camporeale A, Colombo SM, Di Stefano P, Tornillo G, Camacho-Leal MP, Turco E, Taverna D, Cabodi S, Amici A, Defilippi P. p130Cas/Cyclooxygenase-2 axis in the control of mesenchymal plasticity of breast cancer cells. Breast Cancer Res 2012; 14:R137. [PMID: 23098208 PMCID: PMC4053116 DOI: 10.1186/bcr3342] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 10/24/2012] [Indexed: 12/17/2022] Open
Abstract
Introduction Intrinsic plasticity of breast carcinoma cells allows them to undergo a transient and reversible conversion into mesenchymal cells to disseminate into distant organs, where they can re-differentiate to an epithelial-like status to form a cohesive secondary mass. The p130Cas scaffold protein is overexpressed in human ER+ and HER2+ breast cancer where it contributes to cancer progression, invasion and resistance to therapy. However, its role in regulating mesenchymal aggressive breast cancer cells remains to be determined. The aim of this study was to investigate the molecular and functional involvement of this adaptor protein in breast cancer cell plasticity. Methods We used silencing strategies and rescue experiments to evaluate phenotypic and biochemical changes from mesenchymal to epithelial traits in breast tumor cell lines. In the mouse A17 cell model previously related to mesenchymal cancer stem cells and basal-like breast cancer, we biochemically dissected the signaling pathways involved and performed functional in vivo tumor growth ability assays. The significance of the signaling platform was assessed in a human setting through the use of specific inhibitors in aggressive MDA-MB-231 subpopulation LM2-4175 cells. To evaluate the clinical relevance of the results, we analyzed publicly available microarray data from the Netherlands Cancer Institute and from the Koo Foundation Sun Yat-Sen Cancer Center. Results We show that p130Cas silencing induces loss of mesenchymal features, by downregulating Vimentin, Snail, Slug and Twist transcriptional factors, resulting in the acquirement of epithelial-like traits. Mechanistically, p130Cas controls Cyclooxygenase-2 transcriptional expression, which in turn contributes to p130Cas-dependent maintenance of mesenchymal phenotype. This cascade of events also compromises in vivo tumor growth through inhibition of cell signaling controlling cell cycle progression. c-Src and JNK kinases are sequential players in p130Cas/ Cyclooxygenase-2 axis and their pharmacological inhibition is sufficient to downregulate Cyclooxygenase-2 leading to an epithelial phenotype. Finally, in silico microarray data analysis indicates that p130Cas and Cyclooxygenase-2 concomitant overexpression predicts poor survival and high probability of breast tumor recurrence. Conclusions Overall, these data identify a new p130Cas/Cyclooxygenase-2 axis as a crucial element in the control of breast tumor plasticity, opening new therapeutic strategies leading to inhibition of these pathways in aggressive breast carcinoma.
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Conti G, Minicozzi A, Merigo F, Marzola P, Osculati F, Cordiano C, Sbarbati A. Morphogenetic events in the perinodal connective tissue in a metastatic cancer model. Biomed Pharmacother 2012; 67:1-6. [PMID: 23089477 DOI: 10.1016/j.biopha.2012.08.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Accepted: 08/15/2012] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The modifications of connective tissue surrounding metastatic lymph nodes in a murine model of rectal cancer are described. METHODS Athymic nude mice (n=36) were inoculated with 10×10(5) ht-29 cancer cells into the submucosal layer of the rectum. Control mice (n=5) were treated with a sterile buffer. Tumor and the involved lymph nodes were visualized in vivo by magnetic resonance imaging at 1 to 4 weeks after cell injection. After the sacrifice, the excised samples were processed for histology. RESULTS After one week from cell injection all treated animals developed rectal cancer. Since the first week, neoplastic cells were visible in the nodes. In the surrounding connective tissue, the diameter of the adipocytes was reduced and a mesenchymal-like pattern with stellate cells embedded in an oedematous environment was visible. Since the second week, in the perinodal connective an enlargement of the stroma was present. The tissue was organized in cords and areas with extracellular accumulation of lipids were found. At the fourth week, we observed an enlargement of multilocular areas and lobules of elongated elements almost devoid of lipid droplets. In control animals, in absence of neoplastic masses, pelvic nodes were surrounded by a typical connective tissue characterized by unilocular adipocytes with groups of multilocular adipocytes. CONCLUSIONS We have developed a model of rectal cancer with nodal metastases. Using this model, the work demonstrates that around secondary lesions, the morphogenetic events follow a standard evolution characterized by an early phase with lipolysis and mesenchymalization and later phases with a brown-like phenotype acquisition.
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Affiliation(s)
- G Conti
- Human Anatomy and Histology Section, University of Verona,Verona, Italy.
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Tumor angiogenesis: Role in locally aggressive biological behavior of ameloblastoma and keratocystic odontogenic tumor. Head Neck 2012; 35:329-34. [DOI: 10.1002/hed.22960] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2011] [Indexed: 12/16/2022] Open
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Kaur P, Ward B, Saha B, Young L, Groshen S, Techy G, Lu Y, Atkinson R, Taylor CR, Ingram M, Imam SA. Human breast cancer histoid: an in vitro 3-dimensional co-culture model that mimics breast cancer tissue. J Histochem Cytochem 2011; 59:1087-100. [PMID: 22034518 DOI: 10.1369/0022155411423680] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Progress in our understanding of heterotypic cellular interaction in the tumor microenvironment, which is recognized to play major roles in cancer progression, has been hampered due to unavailability of an appropriate in vitro co-culture model. The aim of this study was to generate an in vitro 3-dimensional human breast cancer model, which consists of cancer cells and fibroblasts. Breast cancer cells (UACC-893) and fibroblasts at various densities were co-cultured in a rotating suspension culture system to establish co-culture parameters. Subsequently, UACC-893, BT.20, or MDA.MB.453 were co-cultured with fibroblasts for 9 days. Co-cultures resulted in the generation of breast cancer histoid (BCH) with cancer cells showing the invasion of fibroblast spheroids, which were visualized by immunohistochemical (IHC) staining of sections (4 µm thick) of BCH. A reproducible quantitative expression of C-erbB.2 was detected in UACC-893 cancer cells in BCH sections by IHC staining and the Automated Cellular Imaging System. BCH sections also consistently exhibited qualitative expression of pancytokeratins, p53, Ki-67, or E-cadherin in cancer cells and that of vimentin or GSTPi in fibroblasts, fibronectin in the basement membrane and collagen IV in the extracellular matrix. The expression of the protein analytes and cellular architecture of BCH were markedly similar to those of breast cancer tissue.
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Affiliation(s)
- Pavinder Kaur
- Molecular Pathology Program, Huntington Medical Research Institutes, Pasadena, California 91101, USA
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Singer EM, Crocitto LE, Choi Y, Loera S, Weiss LM, Imam SA, Wilson TG, Smith SS. Biomarker identification with ligand-targeted nucleoprotein assemblies. Nanomedicine (Lond) 2011; 6:659-68. [PMID: 21718176 DOI: 10.2217/nnm.11.22] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIMS Since many biomarkers of both the tumor and its microenvironment are expected to involve differential expression of divalent proteins capable of protein or peptide ligand interaction, we are developing multivalent nanodevices for the identification of biomarkers in prostate cancer. PATIENTS & METHODS We compared a multivalent thioredoxin-targeted nanodevice with monovalent thioredoxin in binding to human prostate cell line(s) and freshly frozen tissue specimens obtained after resection from patients with biopsy-proven prostate cancer. CONCLUSION The nanodevice binds specifically with enhanced avidity to tumor microenvironment-associated stromal cells in prostate cancer tissue specimens. Cells that bind the nanodevice also reacted with antibodies to dimeric thioredoxin reductases 1 and 2, suggesting the utility of the nanodevice as a potentially specific and functional marker of tumor stromal cells.
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Affiliation(s)
- Elizabeth M Singer
- Beckman Research Institute & Division of Urology & Urological Oncology, Familian Science, Duarte, CA 91010, USA
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GSTPi-positive tumour microenvironment-associated fibroblasts are significantly associated with GSTPi-negative cancer cells in paired cases of primary invasive breast cancer and axillary lymph node metastases. Br J Cancer 2011; 105:1224-9. [PMID: 21897388 PMCID: PMC3208492 DOI: 10.1038/bjc.2011.352] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background: Glutathione S-transferase Pi (GSTPi) expression is one of the factors, which is known to be associated with development of resistance to chemotherapeutics in cancer patients, including those with breast cancer. Yet, its expression has been reported to be undetectable in cancer cells in high percent of patients with primary breast cancer. However, GSTPi expression in stromal cells in breast tumour microenvironment, namely cancer-associated fibroblast (CAF), which is recognised to have major roles in cancer progression, remains poorly reported. Methods: The aim of the study was to determine the expression of GSTPi; vimetin, a fibroblast-associated cytoskeleton protein; and α-smooth muscle actin (α-SMA), a known marker of CAF in breast cancer tissue, by immunohistochemical staining method in consecutive histologic sections of formalin-fixed and paraffin-embedded tissue biopsy specimens from a cohort of 39 paired cases of patients with invasive breast cancer and the corresponding axillary lymph nodes metastases. Results: Ductal and acinar luminal epithelial cells, myoepithelial cells and surrounding fibroblasts exhibited a homogeneous cytoplasmic reactivity with anti-GSTPi antibody in 11 of 11 cases of benign breast tissue biopsies. The vimentin-positive fibroblasts were unreactive with anti-α-SMA antibody. Loss of GSTPi expression was observed in breast cancer cells, at both the primary and metastatic sites, in 31 of 39 paired cases, as compared with benign breast epithelial cells (Fisher's exact test P<0.001). A significant association was observed between GSTPi-positive, vimentin-positive and α-SMA-positive fibroblast in tumour microenvironment at both sites. Conclusion: This is an original report of demonstration of a significance association between tumour microenvironment-associated GSTPi-positive CAF (vimentin/α-SMA-positive) and the GSTPi-negative cancer cells in paired cases of primary invasive breast cancer and the corresponding axillary lymph nodes metastases.
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Su Y, Shankar K, Rahal O, Simmen RCM. Bidirectional signaling of mammary epithelium and stroma: implications for breast cancer--preventive actions of dietary factors. J Nutr Biochem 2011; 22:605-11. [PMID: 21292471 DOI: 10.1016/j.jnutbio.2010.09.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2010] [Accepted: 09/18/2010] [Indexed: 12/28/2022]
Abstract
The mammary gland is composed of two major cellular compartments: a highly dynamic epithelium that undergoes cycles of proliferation, differentiation and apoptosis in response to local and endocrine signals and the underlying stroma comprised of fibroblasts, endothelial cells and adipocytes, which collectively form the mammary fat pad. Breast cancer originates from subversions of normal growth regulatory pathways in mammary epithelial cells due to genetic mutations and epigenetic modifications in tumor suppressors, oncogenes and DNA repair genes. Diet is considered a highly modifiable determinant of breast cancer risk; thus, considerable efforts are focused on understanding how certain dietary factors may promote resistance of mammary epithelial cells to growth dysregulation. The recent indications that stromal cells contribute to the maintenance of the mammary epithelial 'niche' and the increasing appreciation for adipose tissue as an endocrine organ with a complex secretome have led to the novel paradigm that the mammary stromal compartment is itself a relevant target of bioactive dietary factors. In this review, we address the potential influence of dietary factors on mammary epithelial-stromal bidirectional signaling to provide mechanistic insights into how dietary factors may promote early mammary epithelial differentiation to decrease adult breast cancer risk.
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Affiliation(s)
- Ying Su
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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Marchini C, Montani M, Konstantinidou G, Orrù R, Mannucci S, Ramadori G, Gabrielli F, Baruzzi A, Berton G, Merigo F, Fin S, Iezzi M, Bisaro B, Sbarbati A, Zerani M, Galiè M, Amici A. Mesenchymal/stromal gene expression signature relates to basal-like breast cancers, identifies bone metastasis and predicts resistance to therapies. PLoS One 2010; 5:e14131. [PMID: 21152434 PMCID: PMC2994727 DOI: 10.1371/journal.pone.0014131] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2010] [Accepted: 10/07/2010] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Mounting clinical and experimental evidence suggests that the shift of carcinomas towards a mesenchymal phenotype is a common paradigm for both resistance to therapy and tumor recurrence. However, the mesenchymalization of carcinomas has not yet entered clinical practice as a crucial diagnostic paradigm. METHODOLOGY/PRINCIPAL FINDINGS By integrating in silico and in vitro studies with our epithelial and mesenchymal tumor models, we compare herein crucial molecular pathways of previously described carcinoma-derived mesenchymal tumor cells (A17) with that of both carcinomas and other mesenchymal phenotypes, such as mesenchymal stem cells (MSCs), breast stroma, and various types of sarcomas. We identified three mesenchymal/stromal-signatures which A17 cells shares with MSCs and breast stroma. By using a recently developed computational approach with publicly available microarray data, we show that these signatures: 1) significantly relates to basal-like breast cancer subtypes; 2) significantly relates to bone metastasis; 3) are up-regulated after hormonal treatment; 4) predict resistance to neoadjuvant therapies. CONCLUSIONS/SIGNIFICANCE Our results demonstrate that mesenchymalization is an intrinsic property of the most aggressive tumors and it relates to therapy resistance as well as bone metastasis.
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Affiliation(s)
- Cristina Marchini
- Genetic Immunization Laboratory, Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino, Italy
| | - Maura Montani
- Genetic Immunization Laboratory, Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino, Italy
| | - Georgia Konstantinidou
- Genetic Immunization Laboratory, Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino, Italy
| | - Rita Orrù
- Genetic Immunization Laboratory, Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino, Italy
| | - Silvia Mannucci
- Genetic Immunization Laboratory, Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino, Italy
| | - Giorgio Ramadori
- Genetic Immunization Laboratory, Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino, Italy
| | - Federico Gabrielli
- Genetic Immunization Laboratory, Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino, Italy
| | - Anna Baruzzi
- Anatomy and Histology Section, Department of Morphological and Biomedical Sciences, University of Verona, Verona, Italy
| | - Giorgio Berton
- Anatomy and Histology Section, Department of Morphological and Biomedical Sciences, University of Verona, Verona, Italy
| | - Flavia Merigo
- Anatomy and Histology Section, Department of Morphological and Biomedical Sciences, University of Verona, Verona, Italy
| | - Stefania Fin
- Anatomy and Histology Section, Department of Morphological and Biomedical Sciences, University of Verona, Verona, Italy
| | - Manuela Iezzi
- Surgical Pathology Section, Department of Oncology and Neuroscience, University of Chieti, Chieti, Italy
| | - Brigitte Bisaro
- Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Andrea Sbarbati
- Anatomy and Histology Section, Department of Morphological and Biomedical Sciences, University of Verona, Verona, Italy
| | - Massimo Zerani
- Genetic Immunization Laboratory, Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino, Italy
| | - Mirco Galiè
- Anatomy and Histology Section, Department of Morphological and Biomedical Sciences, University of Verona, Verona, Italy
- * E-mail: (AA); (MG)
| | - Augusto Amici
- Genetic Immunization Laboratory, Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino, Italy
- * E-mail: (AA); (MG)
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Boschi F, Calderan L, D'Ambrosio D, Marengo M, Fenzi A, Calandrino R, Sbarbati A, Spinelli AE. In vivo ¹⁸F-FDG tumour uptake measurements in small animals using Cerenkov radiation. Eur J Nucl Med Mol Imaging 2010; 38:120-7. [PMID: 20882278 DOI: 10.1007/s00259-010-1630-y] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2010] [Accepted: 09/13/2010] [Indexed: 12/17/2022]
Abstract
PURPOSE 2-[(18)F]Fluoro-2-deoxy-D-glucose ((18)F-FDG) is a widely used PET radiotracer for the in vivo diagnosis of several diseases such as tumours. The positrons emitted by (18)F-FDG, travelling into tissues faster than the speed of light in the same medium, are responsible for Cerenkov radiation (CR) emission which is prevalently in the visible range. The purpose of this study is to show that CR escaping from tumour tissues of small living animals injected with (18)F-FDG can be detected with optical imaging (OI) techniques using a commercial optical instrument equipped with charge-coupled detectors (CCD). METHODS The theory behind the Cerenkov light emission and the source depth measurements using CR is first presented. Mice injected with (18)F-FDG or saline solution underwent dynamic OI acquisition and a comparison between images was performed. Multispectral analysis of the radiation was used to estimate the depth of the source of Cerenkov light. Small animal PET images were also acquired in order to compare the (18)F-FDG bio-distribution measured using OI and PET scanner. RESULTS Cerenkov in vivo whole-body images of tumour-bearing mice and the measurements of the emission spectrum (560-660 nm range) are presented. Brain, kidneys and tumour were identified as a source of visible light in the animal body: the tissue time-activity curves reflected the physiological accumulation of (18)F-FDG in these organs. The identification is confirmed by the comparison between CR and (18)F-FDG images. CONCLUSION These results will allow the use of conventional OI devices for the in vivo study of glucose metabolism in cancer and the assessment, for example, of anti-cancer drugs. Moreover, this demonstrates that (18)F-FDG can be employed as it is a bimodal tracer for PET and OI techniques.
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Affiliation(s)
- Federico Boschi
- Department of Morphological-Biomedical Sciences, Section of Anatomy and Histology, University of Verona, Strada Le Grazie N. 8, Verona, Italy.
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Sancho-Bru P, Juez E, Moreno M, Khurdayan V, Morales-Ruiz M, Colmenero J, Arroyo V, Brenner DA, Ginès P, Bataller R. Hepatocarcinoma cells stimulate the growth, migration and expression of pro-angiogenic genes in human hepatic stellate cells. Liver Int 2010; 30:31-41. [PMID: 19929904 DOI: 10.1111/j.1478-3231.2009.02161.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Activated hepatic stellate cells (HSC) and other fibrogenic cell types are frequently found around hepatocellular carcinoma. It is unknown whether hepatocarcinoma cells regulate the biological functions of HSC. AIMS This study aimed to investigate the paracrine effects of hepatocarcinoma cells on human HSC using a co-culture system. METHODS Huh7 or HepG2 cells, human hepatocarcinoma cell lines, were co-cultured with primary human HSC. Intracellular calcium mobilization, proliferation, migration, expression of pro-angiogenic and fibrogenic genes, smooth muscle alpha-actin (alpha-SMA) protein expression, inflammatory properties (nuclear factor kappa B activation and interleukin 8 secretion) and intracellular signalling pathways (AKT and ERK) were analysed in HSC. RESULTS Culture of HSC with Huh7 cells for 24 h stimulated HSC proliferation, migration and expression of pro-angiogenic genes. The migration effect was corroborated with HepG2 cells. The effects of Huh7 cells on cell proliferation and migration were mediated mainly by PI3K/AKT activation. Moreover, Huh7 cells reduced the expression of genes involved in fibrogenesis, while they did not modify the inflammatory properties of HSC. The expression of alpha-SMA was induced by Huh7 cells. Because hepatitis C virus (HCV) infection is a major cause of hepatocarcinoma, we next investigated whether these effects are regulated by the expression of HCV in hepatocarcinoma cells. Expression of a subgenomic replicon expressing HCV nonstructural proteins (NS3-NS5) in Huh7 cells did not affect paracrine actions in HSC (cell proliferation and migration). CONCLUSIONS These results suggested that there is a cross-talk between hepatocarcinoma cells and HSC. Activated HSC may be stimulated by cancer cells to accumulate and express angiogenic genes.
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Affiliation(s)
- Pau Sancho-Bru
- Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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Galiè M, Farace P, Merigo F, Fiorini S, Tambalo S, Nicolato E, Sbarbati A, Marzola P. Washout of small molecular contrast agent in carcinoma-derived experimental tumors. Microvasc Res 2009; 78:370-8. [PMID: 19804787 DOI: 10.1016/j.mvr.2009.09.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Revised: 09/10/2009] [Accepted: 09/26/2009] [Indexed: 10/20/2022]
Abstract
The use of contrast-enhanced magnetic resonance imaging (MRI) for the assessment of breast carcinomas reveals satisfactory sensitivity, but due to low specificity, it does not obviate the need for subsequent tissue sampling. Its capability to differentiate benign from malignant lesion is under continuous investigation. Dynamic contrast-enhanced MRI (DCE-MRI) could improve specificity of MRI through the analysis of the kinetic of contrast enhancement. In particular, the study of the washout pattern is considered a promising tool to improve in vivo diagnosis and even to evaluate the response under chemotherapy. To provide a comprehensive characterization of this parameter in malignant tumor models, in vivo mapping of the washout of small molecular contrast agent (Gd-DTPA, molecular weight 0.57 kDa) was carried out in three transplanted/spontaneous mammary tumors, which differed in their histopathological and microvascular features. It resulted that in all models around 40% of tumor volume lacks efficient washout; washout areas are frequently, but not always, restricted to the tumor periphery and that non-washout areas are not restricted to necrotic regions. Difference in the distribution of lymphatic vessels characterized spontaneous vs. transplanted tumors but did not produce a corresponding different washout pattern, confirming that Gd-DTPA drainage does not mainly depend on lymphatic architecture. Finally, the efficiency of washout is correlated with parameters obtainable during the earlier phases of the enhancement curve and in malignant tumors it could be indirectly estimated from them.
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Affiliation(s)
- Mirco Galiè
- Dip. Scienze Morfologico-Biomediche, sez. Anatomia ed Istologia, Università di Verona, Verona, Italy.
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Mozzicafreddo M, Cuccioloni M, Bonfili L, Eleuteri AM, Fioretti E, Angeletti M. Antiplasmin activity of natural occurring polyphenols. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2008; 1784:995-1001. [PMID: 18456009 DOI: 10.1016/j.bbapap.2008.03.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2007] [Revised: 03/31/2008] [Accepted: 03/31/2008] [Indexed: 01/01/2023]
Abstract
The equilibrium between proteolytic enzymes and their cognate inhibitors is crucial in a number of physiological as well as pathological processes, including cancer, inflammatory processes and thrombosis. Therefore, both synthetic and natural small molecule inhibitors are object of extensive studies as drugs in the treatment of these pathologies. Two natural occurring polyphenolic compounds, representative of glycosylated and unglycosylated flavonoid structures, namely quercetin and rutin, were thereby tested as potential ligands of plasmin(ogen), a serine (pro)protease, whose role in tumor cell invasion and migration has been reported. Quercetin showed a ten folds higher affinity with plasmin with respect to rutin in terms of equilibrium dissociation constant, both compounds acting as in vitro moderate reversible inhibitors; additionally, quercetin and rutin prevented plasmin-incubated BB1 cells from releasing E-cadherin fragment to a different extent, respectively. Furthermore, a feasible mechanism of interaction was analyzed and discussed using a molecular modeling approach.
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Kellermann MG, Sobral LM, da Silva SD, Zecchin KG, Graner E, Lopes MA, Nishimoto I, Kowalski LP, Coletta RD. Myofibroblasts in the stroma of oral squamous cell carcinoma are associated with poor prognosis. Histopathology 2008; 51:849-53. [PMID: 18042073 DOI: 10.1111/j.1365-2559.2007.02873.x] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Epithelial and mesenchymal tumor compartments exhibit in vivo complementary patterns of vascular perfusion and glucose metabolism. Neoplasia 2007; 9:900-8. [PMID: 18030358 DOI: 10.1593/neo.07541] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2007] [Revised: 09/05/2007] [Accepted: 09/07/2007] [Indexed: 01/15/2023] Open
Abstract
Glucose transport and consumption are increased in tumors, and this is considered a diagnostic index of malignancy. However, there is recent evidence that carcinoma-associated stromal cells are capable of aerobic metabolism with low glucose consumption, at least partly because of their efficient vascular supply. In the present study, using dynamic contrast-enhanced magnetic resonance imaging and [F-18]fluorodeoxyglucose (FDG) positron emission tomography (PET), we mapped in vivo the vascular supply and glucose metabolism in syngeneic experimental models of carcinoma and mesenchymal tumor. We found that in both tumor histotypes, regions with high vascular perfusion exhibited a significantly lower FDG uptake. This reciprocity was more conspicuous in carcinomas than in mesenchymal tumors, and regions with a high-vascular/low-FDG uptake pattern roughly overlapped with a stromal capsule and intratumoral large connectival septa. Accordingly, mesenchymal tumors exhibited a higher vascular perfusion and a lower FDG uptake than carcinomas. Thus, we provide in vivo evidence of vascular/metabolic reciprocity between epithelial and mesenchymal histotypes in tumors, suggesting a new intriguing aspect of epithelial-stromal interaction. Our results suggests that FDG-PET-based clinical analysis can underestimate the malignity or tumor extension of carcinomas exhibiting any trait of "mesenchymalization" such as desmoplasia or epithelial-mesenchymal transition.
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Blechschmidt K, Kremmer E, Hollweck R, Mylonas I, Höfler H, Kremer M, Becker KF. The E-cadherin Repressor Snail Plays a Role in Tumor Progression of Endometrioid Adenocarcinomas. ACTA ACUST UNITED AC 2007; 16:222-8. [DOI: 10.1097/pdm.0b013e31806219ae] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Galiè M, Konstantinidou G, Peroni D, Scambi I, Marchini C, Lisi V, Krampera M, Magnani P, Merigo F, Montani M, Boschi F, Marzola P, Orrù R, Farace P, Sbarbati A, Amici A. Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice. Oncogene 2007; 27:2542-51. [PMID: 17998939 DOI: 10.1038/sj.onc.1210920] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Tumor microenvironment in carcinomas recruits mesenchymal cells with an abnormal proangiogenic and invasive phenotype. It is not clear whether mesenchymal tumor cells (MTCs) derive from the activation of mature fibroblasts or from their stem cell precursors. However, stromal cell activation in tumors resembles in several aspects the mesenchymal rearrangement which normally occurs during reparative processes such as wound healing. Mesenchymal stem cells (MSCs) play a crucial role in developmental and reparative processes and have extraordinary proangiogenic potential, on the basis of which they are thought to show great promise for the treatment of ischemic disorders. Here, we show that MTCs have proangiogenic potential and that they share the transcriptional expression of the best-known proangiogenic factors with MSCs. We also found that MTCs and MSCs have the same molecular signature for stemness-related genes, and that when co-implanted with cancer cells in syngeneic animals MSCs determine early tumor appearance, probably by favoring the angiogenic switch. Our data (1) reveal crucial aspects of the proangiogenic phenotype of MTCs, (2) strongly suggest their stem origin and (3) signal the risk of therapeutic use of MSCs in tumor-promoting conditions.
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Affiliation(s)
- M Galiè
- Department of Morphological and Biomedical Sciences, Anatomy and Histology Section, University of Verona, Verona, Italy.
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Kellermann MG, Sobral LM, da Silva SD, Zecchin KG, Graner E, Lopes MA, Kowalski LP, Coletta RD. Mutual paracrine effects of oral squamous cell carcinoma cells and normal oral fibroblasts: induction of fibroblast to myofibroblast transdifferentiation and modulation of tumor cell proliferation. Oral Oncol 2007; 44:509-17. [PMID: 17826300 DOI: 10.1016/j.oraloncology.2007.07.001] [Citation(s) in RCA: 113] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2007] [Revised: 06/27/2007] [Accepted: 07/02/2007] [Indexed: 12/30/2022]
Abstract
Several lines of evidence demonstrated that the stroma surrounding the tumors plays an important role in the growth and progression of several neoplasms, including oral squamous cell carcinomas (OSCC). We evaluated the presence of myofibroblasts in OSCC and determined whether their presence is associated with clinicopathological features of the tumors. We also investigated the mutual paracrine effects of tumor cells and myofibroblasts on fibroblast-myofibroblast transdifferentiation and tumor cell proliferation. Immunohistochemical analysis showed the approximately 60% of the OSCCs contained myofibroblasts in the stroma of the tumor. Abundant presence of myofibroblasts significantly correlated with N stage, disease stage, regional recurrence, and proliferative potential of the tumor cells. Using OSCC cell lines and primary oral normal fibroblasts (ONF), we demonstrated that tumor cells induced transdifferentiation of ONFs to myofibroblasts via secretion of transforming growth factor-beta 1 (TGF-beta 1). In turn, myofibroblasts secreted factors that stimulated OSCC cell proliferation, as revealed by measuring BrdU incorporation and Ki67 expression. The results of the study suggest that during tumor invasion OSCC-derived TGF-beta 1 promote fibroblast-myofibroblast transdifferentiation, and that tumor cellular proliferation can be induced by factors released from myofibroblasts, which may favor tumor growth.
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Affiliation(s)
- Michele G Kellermann
- Department of Oral Diagnosis, School of Dentistry, State University of Campinas, Piracicaba, São Paulo, Brazil
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Caracciolo G, Pozzi D, Caminiti R, Marchini C, Montani M, Amici A, Amenitsch H. Transfection efficiency boost by designer multicomponent lipoplexes. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2007; 1768:2280-92. [PMID: 17662958 DOI: 10.1016/j.bbamem.2007.06.027] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2007] [Revised: 06/25/2007] [Accepted: 06/27/2007] [Indexed: 11/23/2022]
Abstract
Cationic liposome-DNA complexes (lipoplexes) have emerged as leading nonviral gene carriers in worldwide gene therapy clinical trials. Arriving at therapeutic dosages requires the full understanding of the mechanism of transfection. We investigated the correlation between structural evolution of multicomponent lipoplexes when interacting with cellular lipids, the extent of DNA release and the efficiency in transfecting mouse fibroblast (NIH 3T3), ovarian (CHO) and tumoral myofibroblast-like (A17) cell lines. We show, for the first time, that the transfection pattern increases monotonically with the number of lipid components and further demonstrate by means of synchrotron small angle X- ray scattering (SAXS) that structural changes of lipoplexes induced by cellular lipids correlate with the transfection efficiency. Specifically, inefficient lipoplexes either fused too rapidly upon interaction with anionic lipids or, alternatively, are found to be extremely resistant to solubilization. The most efficient lipoplex formulations exhibited an intermediate behaviour. The extent of DNA unbinding (measured by electrophoresis on agarose gel) correlates with structural evolution of the lipoplexes but DNA-release does not scale with the extent of transfection. The general meaning of our results is of broad interest in the field of non-viral gene delivery: rational adjusting of lipoplex composition to generate the proper interaction between lipoplexes and cellular lipids may be the most appropriate strategy in optimizing synthetic lipid transfection agents.
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Affiliation(s)
- Giulio Caracciolo
- Department of Chemistry, University of Rome La Sapienza, P.le A. Moro 5, 00185 Rome, Italy
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Yamate J, Sakamori M, Kuwamura M, Kotani T. Neoplastic and non-neoplastic cell lines from a malignant peripheral nerve sheath tumour of the cervix of a rat. J Comp Pathol 2007; 137:9-21. [PMID: 17537454 DOI: 10.1016/j.jcpa.2007.03.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2006] [Accepted: 03/07/2007] [Indexed: 01/13/2023]
Abstract
A homotransplantable tumour (LY) and cell lines (LY-PPB6 and LY-H12) were established from a spontaneous malignant peripheral nerve sheath tumour (PNST) of the uterine cervix of an F344 rat. Primary and LY tumours consisted of oval or spindle-shaped cells arranged in a flatfield or streaming fashion, and indistinct nuclear palisades were seen. Immunohistochemically, neoplastic cells reacted to vimentin, S-100 protein, neuron-specific enolase (NSE), myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP) in varying degrees, indicating neurogenic derivation. LY-PPB6-induced tumours in syngeneic rats developed cellular whorling patterns reacting particularly strongly to S-100 protein, NSE, MBP and GFAP. Nerve growth factor (NGF) mRNA expression was shown in LY-PPB6 cells by the reverse transcription-polymerase chain reaction (RT-PCR). By contrast, LY-H12 had a normal chromosomal number of 42, and did not produce tumours when injected into syngeneic rats. LY-H12 cells reacted to vimentin and alpha-smooth muscle actin (alpha-SMA), and the alpha-SMA-positive cell number was increased dose-dependently by the addition of transforming growth factor (TGF)-beta1, indicating a myofibroblastic nature. LY-PPB6 cells were neoplastic with properties of PNS cells, whereas LY-H12 cells were non-neoplastic stromal cells showing myofibroblastic differentiation. As TGF-beta1 mRNA expression was shown in both LY-PPB6 and LY-H12 cells by the RT-PCR, the myofibroblastic phenotype of LY-H12 cells may be mediated by paracrine or autocrine signalling in tumour tissues. LY-PPB6 and LY-H12 may prove useful for studies on the pathobiological nature of neoplastic cells and interactions between neoplastic and stromal cells in PNSTs.
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Affiliation(s)
- J Yamate
- Laboratory of Veterinary Pathology, Life and Environmental Sciences, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan.
| | - M Sakamori
- Laboratory of Veterinary Pathology, Life and Environmental Sciences, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan
| | - M Kuwamura
- Laboratory of Veterinary Pathology, Life and Environmental Sciences, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan
| | - T Kotani
- Laboratory of Veterinary Pathology, Life and Environmental Sciences, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan
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Caracciolo G, Marchini C, Pozzi D, Caminiti R, Amenitsch H, Montani M, Amici A. Structural stability against disintegration by anionic lipids rationalizes the efficiency of cationic liposome/DNA complexes. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2007; 23:4498-508. [PMID: 17341104 DOI: 10.1021/la063456o] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Reported here is the correlation between the transfection efficiency of cationic liposome/DNA complexes (lipoplexes) and the structural evolution that they undergo when interacting with anionic membrane lipids. Multicomponent lipoplexes, incorporating from three to six lipid species simultaneously, presented a much higher transfection efficiency than binary lipoplexes, which are more commonly used for gene-delivery purposes. The discovery that a high transfection efficiency can be achieved by employing multicomponent complexes at a lower-than-ever-before membrane charge density of lipoplexes was of primary significance. Synchrotron small-angle X-ray diffraction (SAXD) experiments showed that anionic liposomes made of dioleoylphosphatidylglycerol (DOPG) disintegrated the lamellar phase of lipoplexes. DNA unbinding was measured by electrophoresis on agarose gels. Most importantly, structural changes induced by anionic lipids strictly depended on the lipid composition of lipoplexes. We found evidence of the existence of three different regimes of stability related to the interaction between complexes and anionic membranes. Both unstable (with low membrane charge density, sigmaM) and highly stable lipoplexes (with high sigmaM) exhibited low transfection efficiency whereas highly efficient multicomponent lipoplexes exhibited an "optimal stability". This intermediate regime reflects a compromise between two opposing constraints: protection of DNA in the cytosol and endosomal escape. Here we advance the concept that structural stability, upon interaction with cellular anionic lipids, is a key factor governing the transfection efficiency of lipoplexes. Possible molecular mechanisms underlying experimental observations are also discussed.
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Affiliation(s)
- Giulio Caracciolo
- Department of Chemistry, University of Rome "La Sapienza", P.le A. Moro 5, 00185 Rome, Italy.
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Sauer LA, Blask DE, Dauchy RT. Dietary factors and growth and metabolism in experimental tumors. J Nutr Biochem 2007; 18:637-49. [PMID: 17418560 DOI: 10.1016/j.jnutbio.2006.12.009] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2006] [Revised: 12/06/2006] [Accepted: 12/28/2006] [Indexed: 11/17/2022]
Abstract
Development of a diet that provides adequate nutrition and effective cancer prevention is an important goal in nutrition and cancer research. A confounding aspect of dietary control of tumor growth is the fact that some nutrients may up-regulate tumor growth, whereas other nutrients and nonnutrients down-regulate growth. Both up- and down-regulators may be present in the same foodstuff. Identification of these substances, determination of their mechanisms of action and potencies, as well as the interactions among the different mechanisms are topics of ongoing research. In this review, we describe results obtained in vivo or during perfusion in situ using solid tissue-isolated rodent tumors and human cancer xenografts in nude rats. Linoleic acid (LA), an essential n-6 polyunsaturated fatty acid (PUFA), was identified as an agent in dietary fat that is responsible for an up-regulation of tumor growth in vivo. Tumor LA uptake, mediated by high intratumor cAMP, stimulated formation of the mitogen, 13-hydroxyoctadecadienoic acid (13-HODE) and also increased ERK1/2 phosphorylation, [(3)H]thymidine incorporation and growth. A mechanism for control of this growth-promoting pathway was revealed during studies of the effects of dietary nutrients and nonnutrients known to inhibit tumor growth. These included four groups of lipophilic agents: n-3 fatty acids, melatonin, conjugated LA isomers and trans fatty acids. Each of these agents activated an inhibitory G protein-coupled receptor-mediated pathway that specifically suppressed tumor uptake of saturated, monounsaturated and n-6 PUFAs, thereby inhibiting an early step in the LA-dependent growth-promoting pathway.
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Francí C, Takkunen M, Dave N, Alameda F, Gómez S, Rodríguez R, Escrivà M, Montserrat-Sentís B, Baró T, Garrido M, Bonilla F, Virtanen I, García de Herreros A. Expression of Snail protein in tumor-stroma interface. Oncogene 2006; 25:5134-44. [PMID: 16568079 DOI: 10.1038/sj.onc.1209519] [Citation(s) in RCA: 178] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The product of Snail gene is a repressor of E-cadherin transcription and an inductor of the epithelial-to-mesenchymal transition in several epithelial tumor cell lines. In order to examine Snail expression in animal and human tissues, we have raised a monoclonal antibody (MAb) that reacts with the regulatory domain of this protein. Analysis of murine embryos shows that Snail is expressed in extraembryonic tissues and embryonic mesoderm, in mesenchymal cells of lungs and dermis as well as in cartilage. Little reactivity was detected in adult tissues as Snail was not constitutively expressed in most mesenchymal cells. However, Snail expression was observed in activated fibroblasts involved in wound healing in mice skin. Moreover, Snail was detected in pathological conditions causing hyperstimulation of fibroblasts, such as fibromatosis. Analysis of Snail expression in tumors revealed that it was highly expressed in sarcomas and fibrosarcomas. In epithelial tumors, it presented a more limited distribution, restricted to stromal cells placed in the vicinity of the tumor and to tumoral cells in the same areas. These results demonstrate that Snail is present in activated mesenchymal cells, indicate its relevance in the communication between tumor and stroma and suggest that it can promote the conversion of carcinoma cells to stromal cells.
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Affiliation(s)
- C Francí
- Unitat de Biologia Cellular i Molecular, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, Barcelona, Spain
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Gherghiceanu M, Popescu LM. Interstitial Cajal-like cells (ICLC) in human resting mammary gland stroma. Transmission electron microscope (TEM) identification. J Cell Mol Med 2006; 9:893-910. [PMID: 16364198 PMCID: PMC6740089 DOI: 10.1111/j.1582-4934.2005.tb00387.x] [Citation(s) in RCA: 92] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
We have previously shown the existence of ICLC in human resting mammary gland stroma by means of methylene blue (vital) staining and c-kit immunopositivity (immunofluorescence and immunohistochemistry). In addition, we reported the phenotype characteristics of these ICLC in vitro (primary cell cultures). Since the identification of ICLC outside the gut requires, at this moment, the obligatory use of TEM, we used this technique and provide unequivocal evidence for the presence of ICLC in the intralobular stroma of human resting mammary gland. According to the 'platinum standard' (10 TEM criteria for the certitude diagnosis of ICLC), we found interstitial cells with the following characteristics: 1. location: among the tubulo-alveolar structures, in the non-epithelial space; 2. caveolae: approximately 2.5% of cell volume; 3. mitochondria: approximately 10% of cell volume; 4. endoplasmic reticulum: either smooth or rough, approximately 2-3% of cell volume; 5. cytoskeleton: intermediate and thin filaments, as well as microtubules are present; 6. myosin thick filaments: undetectable; 7. basal lamina: occasionally found; 8. gap junctions: occasionally found; 9. close contacts with targets: nerve fibers, capillaries, immunoreactive cells by 'stromal synapses'; 10. characteristic cytoplasmic processes: i) number: frequently 2-3; ii) length: several tens of mum; iii) thickness: uneven caliber, 0.1-0.5 microm, with dilations, but very thin from the emerging point; iv) aspect: moniliform, usually with mitochondria located in dilations; v) branching: dichotomous pattern; vi) Ca(2+) release units: are present; vii) network labyrinthic system: overlapping cytoplasmic processes. It remains to be established which of the possible roles that we previously suggested for ICLC (e.g. juxta- and/or paracrine secretion, uncommited progenitor cells, immunological surveillance, intercellular signaling, etc.) are essential for the epithelium/stroma equilibrium in the mammary gland under normal or pathological conditions.
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Fiegl H, Millinger S, Goebel G, Müller-Holzner E, Marth C, Laird PW, Widschwendter M. Breast cancer DNA methylation profiles in cancer cells and tumor stroma: association with HER-2/neu status in primary breast cancer. Cancer Res 2006; 66:29-33. [PMID: 16397211 DOI: 10.1158/0008-5472.can-05-2508] [Citation(s) in RCA: 140] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The HER-2/neu gene is amplified and overexpressed in 20% to 30% of invasive breast carcinomas and is associated with increased metastatic potential and less tamoxifen sensitivity. We generated the DNA methylation profiles of 143 human breast tumors and found significant differences in HER-2/neu expression and DNA methylation of five genes. For three of these five genes [PGR (coding for the progesterone receptor), HSD17B4 (coding for type 4 17-beta-hydroxysteroid dehydrogenase, an enzyme that mainly degrades active 17-beta-estradiol into inactive metabolites), and CDH13 (coding for H-cadherin)] a higher prevalence of DNA methylation in HER-2/neu-positive cancers was confirmed in an independent set of microdissected primary breast cancers. DNA methylation was not only present in cancer cells but also in the tumor stroma fraction. Of the isolated fractions in HER-2/neu-positive versus -negative cancers, 27.1% versus 10.5%, respectively, showed DNA methylation of the five genes (P = 0.011, Fisher's exact test). In Her-2++/+++ breast cancers, HSD17B4 mRNA expression was inversely associated with HSD17B4 methylation (P = 0.04). These data support the view that in addition to HER-2/neu-associated signaling, epigenetic changes in cancer as well as in tumor stroma cells might attribute to the specific biological features of HER-2/neu-positive cancers.
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Affiliation(s)
- Heidi Fiegl
- Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria
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