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Schlensog M, Ruehlmann AC, Haeberle L, Opitz F, Becher AK, Goering W, Buth J, Knoefel WT, Ladage D, Meyer A, Esposito I. Tenascin-C affects invasiveness of EGFR-mutated lung adenocarcinoma through a putative paracrine loop. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166684. [PMID: 36878305 DOI: 10.1016/j.bbadis.2023.166684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 01/26/2023] [Accepted: 02/28/2023] [Indexed: 03/07/2023]
Abstract
Tenascin C (TNC) is an extracellular matrix (ECM) protein and a potential biomarker affecting progression of different tumor types, such as pancreatic and lung cancer. Alternative splicing variants of TNC are known to have an impact on interaction partners like other ECM proteins or cell surface receptors, including epidermal growth factor receptor (EGFR), leading to numerous and sometimes opposite roles of TNC in tumor cell dissemination and proliferation. Only little is known about the impact of TNC on biologic characteristics of lung cancer, such as invasion and metastatic potential. In the present study, we could link an increased expression of TNC in lung adenocarcinoma (LUAD) tissues with an unfavorable clinical outcome of patients. Furthermore, we investigated the functional role of TNC in LUAD. Immunohistochemical staining of TNC revealed a significant increase of TNC levels in primary tumours and metastases compared to normal lung tissue. Additionally, a significant correlation between TNC mRNA expression and EGFR copy number and protein expression levels has been determined. Moreover, inhibition of TNC in lung fibroblasts led to reduced invasiveness of LUAD cells harboring EGFR-activating mutations and to a shorter lamellipodia perimeter and a reduced lamellipodia area on the surface of LUAD cells. This study provides the evidence that TNC expression might be a biological relevant factor in LUAD progression in an EGFR-dependent manner and that it regulates tumor cell invasion by rearrangement of the actin cytoskeleton, especially affecting lamellipodia formation.
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Affiliation(s)
- Martin Schlensog
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Ann-Cathrin Ruehlmann
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Lena Haeberle
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Friederike Opitz
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Ann-Kathrin Becher
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Wolfgang Goering
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Juliane Buth
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Wolfram Trudo Knoefel
- Department of General, Visceral and Pediatric Surgery, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Dennis Ladage
- Department of Pneumology, Kliniken Maria Hilf GmbH, Moenchengladbach, Germany
| | - Andreas Meyer
- Department of Pneumology, Kliniken Maria Hilf GmbH, Moenchengladbach, Germany
| | - Irene Esposito
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany.
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Urh K, Zidar N, Boštjančič E. Bioinformatics Analysis of RNA-seq Data Reveals Genes Related to Cancer Stem Cells in Colorectal Cancerogenesis. Int J Mol Sci 2022; 23:ijms232113252. [PMID: 36362041 PMCID: PMC9654446 DOI: 10.3390/ijms232113252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/26/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Cancer stem cells (CSC) play one of the crucial roles in the pathogenesis of various cancers, including colorectal cancer (CRC). Although great efforts have been made regarding our understanding of the cancerogenesis of CRC, CSC involvement in CRC development is still poorly understood. Using bioinformatics and RNA-seq data of normal mucosa, colorectal adenoma, and carcinoma (n = 106) from GEO and TCGA, we identified candidate CSC genes and analyzed pathway enrichment analysis (PEI) and protein–protein interaction analysis (PPI). Identified CSC-related genes were validated using qPCR and tissue samples from 47 patients with adenoma, adenoma with early carcinoma, and carcinoma without and with lymph node metastasis and were compared to normal mucosa. Six CSC-related genes were identified: ANLN, CDK1, ECT2, PDGFD, TNC, and TNXB. ANLN, CDK1, ECT2, and TNC were differentially expressed between adenoma and adenoma with early carcinoma. TNC was differentially expressed in CRC without lymph node metastases whereas ANLN, CDK1, and PDGFD were differentially expressed in CRC with lymph node metastases compared to normal mucosa. ANLN and PDGFD were differentially expressed between carcinoma without and with lymph node metastasis. Our study identified and validated CSC-related genes that might be involved in early stages of CRC development (ANLN, CDK1, ECT2, TNC) and in development of metastasis (ANLN, PDGFD).
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The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis. Cancers (Basel) 2021; 13:cancers13246206. [PMID: 34944826 PMCID: PMC8699466 DOI: 10.3390/cancers13246206] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is the third most common cancer worldwide. Metastasis to secondary organs, such as the liver and lungs, is a key driver of CRC-related mortality. The tumor microenvironment, which consists of the primary cancer cells, as well as associated support and immune cells, significantly affects the behavior of CRC cells at the primary tumor site, as well as in metastatic lesions. In this paper, we review the role of the individual components of the tumor microenvironment on tumor progression, immune evasion, and metastasis, and we discuss the implications of these components on antitumor therapies. Abstract Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastases, most frequently to the liver and lung. In the primary tumor, as well as at each metastatic site, the cellular components of the tumor microenvironment (TME) contribute to tumor engraftment and metastasis. These include immune cells (macrophages, neutrophils, T lymphocytes, and dendritic cells) and stromal cells (cancer-associated fibroblasts and endothelial cells). In this review, we highlight how the TME influences tumor progression and invasion at the primary site and its function in fostering metastatic niches in the liver and lungs. We also discuss emerging clinical strategies to target the CRC TME.
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Fujita M, Suzuki H, Fukai F. Involvement of integrin-activating peptides derived from tenascin-C in colon cancer progression. World J Gastrointest Oncol 2021; 13:980-994. [PMID: 34616507 PMCID: PMC8465449 DOI: 10.4251/wjgo.v13.i9.980] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 06/03/2021] [Accepted: 08/11/2021] [Indexed: 02/06/2023] Open
Abstract
Tenascin-C (TNC) is an adhesion modulatory protein present in the extracellular matrix that is highly expressed in several malignancies, including colon cancer. Although TNC is considered a negative prognostic factor for cancer patients, the substantial role of the TNC molecule in colorectal carcinogenesis and its malignant progression is poorly understood. We previously found that TNC has a cryptic functional site and that a TNC peptide containing this site, termed TNIIIA2, can potently and persistently activate beta1-integrins. In contrast, the peptide FNIII14, which contains a cryptic bioactive site within the fibronectin molecule, can inactivate beta1-integrins. This review presents the role of TNC in the development of colitis-associated colorectal cancer and in the malignant progression of colon cancer, particularly the major involvement of its cryptic functional site TNIIIA2. We propose new possible prophylactic and therapeutic strategies based on inhibition of the TNIIIA2-induced beta1-integrin activation by peptide FNIII14.
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Affiliation(s)
- Motomichi Fujita
- Department of Molecular Patho-Physiology, Tokyo University of Science, Noda 278-8510, Chiba, Japan
| | - Hideo Suzuki
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Fumio Fukai
- Department of Molecular Patho-Physiology, Tokyo University of Science, Noda 278-8510, Chiba, Japan
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Antiproliferative and Antimetastatic Effects of Praeruptorin C on Human Non-Small Cell Lung Cancer Through Inactivating ERK/CTSD Signalling Pathways. Molecules 2020; 25:molecules25071625. [PMID: 32244796 PMCID: PMC7180937 DOI: 10.3390/molecules25071625] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 03/26/2020] [Accepted: 03/31/2020] [Indexed: 01/02/2023] Open
Abstract
Praeruptorin C (PC) reportedly has beneficial effects in terms of antiinflammation, antihypertension, and antiplatelet aggregation, and it potentially has anticancer activity. However, the effect of PC on human non-small cell lung cancer (NSCLC) is largely unknown. Compared with the effects of praeruptorin A and praeruptorin B, we observed that PC significantly suppressed cell proliferation, colony formation, wound closure, and migration and invasion of NSCLC cells. It induced cell cycle arrest in the G0/G1 phase, downregulated cyclin D1 protein, and upregulated p21 protein. PC also significantly reduced the expression of cathepsin D (CTSD). In addition, the phosphorylation/activation of the ERK1/2 signalling pathway was significantly suppressed in PC-treated NSCLC cells. Cotreatment with PC and U0126 synergistically inhibited CTSD expression, cell migration, and cell invasion, which suggests that the ERK1/2 signalling pathway is involved in the downregulation of CTSD expression and invasion activity of NSCLC cells by PC. These findings are the first to demonstrate the inhibitory effects of PC in NSCLC progression. Therefore, PC may represent a novel strategy for treating NSCLC.
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Thankam FG, Chandra I, Diaz C, Dilisio MF, Fleegel J, Gross RM, Agrawal DK. Matrix regeneration proteins in the hypoxia-triggered exosomes of shoulder tenocytes and adipose-derived mesenchymal stem cells. Mol Cell Biochem 2019; 465:75-87. [PMID: 31797254 DOI: 10.1007/s11010-019-03669-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/30/2019] [Indexed: 12/14/2022]
Abstract
Regenerative functions of exosomes rely on their contents which are influenced by pathological stimuli, including hypoxia, in rotator cuff tendon injuries (RCTI). The hypoxic environment triggers tenocytes and adjacent adipose-derived mesenchymal stem cells (ADMSCs) to release regenerative mediators to the ECM via the exosomes which elicit autocrine/paracrine responses to protect the tendon matrix from injury. We investigated the exosomal protein contents from tenocytes and subcutaneous ADMSCs from the shoulder of Yucatan microswine cultured under hypoxic conditions (2% O2). The exosomal proteins were detected using high-resolution mass spectrometry nano-LC-MS/MS Tribrid system and were compiled using 'Scaffold' software. Hypoxic exosomes from tenocytes and ADMSCs carried 199 and 65 proteins, respectively. The key proteins identified by mass spectrometry and associated with ECM homeostasis from hypoxic ADMSCs included MMP2, COL6A, CTSD and TN-C and those from hypoxic tenocytes were THSB1, NSEP1, ITIH4 and TN-C. These findings were confirmed at the mRNA and protein level in the hypoxic ADMSCs and tenocytes. These proteins are involved in multiple signaling pathways of ECM repair/regeneration. This warrants further investigations for their translational significance in the management of RCTI.
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Affiliation(s)
- Finosh G Thankam
- Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766-1854, USA
| | - Isaiah Chandra
- Departments of Clinical & Translational Science and Orthopedic Surgery, Creighton University School of Medicine, Omaha, NE, 68178, USA
| | - Connor Diaz
- Departments of Clinical & Translational Science and Orthopedic Surgery, Creighton University School of Medicine, Omaha, NE, 68178, USA
| | - Matthew F Dilisio
- Departments of Clinical & Translational Science and Orthopedic Surgery, Creighton University School of Medicine, Omaha, NE, 68178, USA
| | - Jonathan Fleegel
- Departments of Clinical & Translational Science and Orthopedic Surgery, Creighton University School of Medicine, Omaha, NE, 68178, USA
| | - R Michael Gross
- Departments of Clinical & Translational Science and Orthopedic Surgery, Creighton University School of Medicine, Omaha, NE, 68178, USA
| | - Devendra K Agrawal
- Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766-1854, USA.
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Tenascin C in colorectal cancer stroma is a predictive marker for liver metastasis and is a potent target of miR-198 as identified by microRNA analysis. Br J Cancer 2017; 117:1360-1370. [PMID: 29065427 PMCID: PMC5672932 DOI: 10.1038/bjc.2017.291] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 07/18/2017] [Accepted: 07/31/2017] [Indexed: 01/12/2023] Open
Abstract
Background: Tumour stroma has important roles in the development of colorectal cancer (CRC) metastasis. We aimed to clarify the roles of microRNAs (miRNAs) and their target genes in CRC stroma in the development of liver metastasis. Methods: Tumour stroma was isolated from formalin-fixed, paraffin-embedded tissues of primary CRCs with or without liver metastasis by laser capture microdissection, and miRNA expression was analysed using TaqMan miRNA arrays. Results: Hierarchical clustering classified 16 CRCs into two groups according to the existence of synchronous liver metastasis. Combinatory target prediction identified tenascin C as a predicted target of miR-198, one of the top 10 miRNAs downregulated in tumour stroma of CRCs with synchronous liver metastasis. Immunohistochemical analysis of tenascin C in 139 primary CRCs revealed that a high staining intensity was correlated with synchronous liver metastasis (P<0.001). Univariate and multivariate analyses revealed that the tenascin C staining intensity was an independent prognostic factor to predict postoperative overall survival (P=0.005; n=139) and liver metastasis-free survival (P=0.001; n=128). Conclusions: Alterations of miRNAs in CRC stroma appear to form a metastasis-permissive environment that can elevate tenascin C to promote liver metastasis. Tenascin C in primary CRC stroma has the potential to be a novel biomarker to predict postoperative prognosis.
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Biochemical and functional characterization of the human tissue kallikrein 9. Biochem J 2017; 474:2417-2433. [DOI: 10.1042/bcj20170174] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 05/25/2017] [Accepted: 05/30/2017] [Indexed: 12/23/2022]
Abstract
Human tissue kallikrein 9 (KLK9) is a member of the kallikrein-related family of proteases. Despite its known expression profile, much less is known about the functional roles of this protease and its implications in normal physiology and disease. We present here the first data on the biochemical characterization of KLK9, investigate parameters that affect its enzymatic activity (such as inhibitors) and provide preliminary insights into its putative substrates. We show that mature KLK9 is a glycosylated chymotrypsin-like enzyme with strong preference for tyrosine over phenylalanine at the P1 cleavage position. The enzyme activity is enhanced by Mg2+ and Ca2+, but is reversibly attenuated by Zn2+. KLK9 is inhibited in vitro by many naturally occurring or synthetic protease inhibitors. Using a combination of degradomic and substrate specificity assays, we identified candidate KLK9 substrates in two different epithelial cell lines [the non-tumorigenic human keratinocyte cells (HaCaT) and the tumorigenic tongue squamous carcinoma cells (SCC9)]. Two potential KLK9 substrates [KLK10 and midkine (MDK)] were subjected to further validation. Taken together, our data delineate some functional and biochemical properties of KLK9 for future elucidation of the role of this enzyme in health and disease.
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9
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Immunohistochemical Study of HER2/neu Expression in Colorectal Cancer and its Relation to other Clinicopathological Criteria and Prognostic Factors. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2017. [DOI: 10.5812/ijcm.5700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Tenascin-C and fibronectin expression divide early stage tongue cancer into low- and high-risk groups. Br J Cancer 2017; 116:640-648. [PMID: 28095396 PMCID: PMC5344290 DOI: 10.1038/bjc.2016.455] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 11/18/2016] [Accepted: 12/20/2016] [Indexed: 12/23/2022] Open
Abstract
Background: Oral tongue squamous cell carcinoma (OTSCC) metastasises early, especially to regional lymph nodes. There is an ongoing debate on which early stage (T1-T2N0) patients should be treated with elective neck dissection. We need prognosticators for early stage tongue cancer. Methods: Mice immunisation with human mesenchymal stromal cells resulted in production of antibodies against tenascin-C (TNC) and fibronectin (FN), which were used to stain 178 (98 early stage), oral tongue squamous cell carcinoma samples. Tenascin-C and FN expression in the stroma (negative, moderate or abundant) and tumour cells (negative or positive) were assessed. Similar staining was obtained using corresponding commercial antibodies. Results: Expression of TNC and FN in the stroma, but not in the tumour cells, proved to be excellent prognosticators both in all stages and in early stage cases. Among early stages, when stromal TNC was negative, the 5-year survival rate was 88%. Correspondingly, when FN was negative, no cancer deaths were observed. Five-year survival rates for abundant expression of TNC and FN were 43% and 25%, respectively. Conclusions: Stromal TNC and, especially, FN expressions differentiate patients into low- and high-risk groups. Surgery alone of early stage primary tumours might be adequate when stromal FN is negative. Aggressive treatments should be considered when both TNC and FN are abundant.
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11
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Čunderlíková B. Clinical significance of immunohistochemically detected extracellular matrix proteins and their spatial distribution in primary cancer. Crit Rev Oncol Hematol 2016; 105:127-44. [DOI: 10.1016/j.critrevonc.2016.04.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 04/03/2016] [Accepted: 04/27/2016] [Indexed: 02/07/2023] Open
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12
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Pulz LH, Strefezzi RF. Proteases as prognostic markers in human and canine cancers. Vet Comp Oncol 2016; 15:669-683. [PMID: 27136601 DOI: 10.1111/vco.12223] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 02/07/2016] [Indexed: 02/05/2023]
Abstract
The extracellular matrix (ECM) is composed of several types of proteins, which interact and form dynamic networks. These components can modulate cell behaviour and actively influence the growth and differentiation of tissues. ECM is also important in several pathological processes, such as cancer invasion and metastasis, by creating favourable microenvironments. Proteolysis in neoplastic tissues is mediated by proteinases, whose regulation involves complex interactions between neoplastic cells and non-neoplastic stromal cells. In this review, we discuss aspects of proteinase expression and tumor behaviour in humans and dogs. Different classes of proteases are summarized, with special emphasis being placed on molecules that have been shown to correlate with prognosis, reinforcing the need for a better understanding of the regulation of this microenvironment and its influences in tumor progression and metastasis, which should significantly aid the development of improved prognosis and treatment.
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Affiliation(s)
- L H Pulz
- Laboratório de Oncologia Comparada e Translacional (LOCT), Departamento de Medicina Veterinária, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, Brazil
| | - R F Strefezzi
- Laboratório de Oncologia Comparada e Translacional (LOCT), Departamento de Medicina Veterinária, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, Brazil
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Salem N, Kamal I, Al-Maghrabi J, Abuzenadah A, Peer-Zada AA, Qari Y, Al-Ahwal M, Al-Qahtani M, Buhmeida A. High expression of matrix metalloproteinases: MMP-2 and MMP-9 predicts poor survival outcome in colorectal carcinoma. Future Oncol 2016; 12:323-31. [PMID: 26814712 DOI: 10.2217/fon.15.325] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
AIM To evaluate the expression pattern of matrix metalloproteinases (MMPs); MMP-2, MMP-7 and MMP-9 in colorectal cancer (CRC) and determine its prognostic potential. PATIENTS & METHODS CRC samples of 127 patients were studied. Protein expressions of MMP-2, -7 and -9 were analyzed by immunohistochemistry and association with clinicopathological variables was statistically analyzed. RESULTS Overexpressions of MMP-2 and MMP-9 correlated with poor outcome as evaluated by univariate Kaplan-Meier for disease-free survival (p = 0.04, p = 0.0001) and disease-specific survival (p = 0.01, p = 0.01), respectively. Cox analysis of MMP-2 and -9 were significant independent predictors of disease-free survival (p = 0.006, p = 0.018) and disease-specific survival (p = 0.004, p = 0.049), respectively. CONCLUSION MMPs expression patterns provide useful prognostic information in CRC, while predicting the patients at high risk for recurrent disease.
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Affiliation(s)
- Nada Salem
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ibrahim Kamal
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Jaudah Al-Maghrabi
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Adel Abuzenadah
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Abdul Ali Peer-Zada
- Molecular Genetics, Pathology & Clinical Laboratory Medicine Administration, King Fahad Medical City, Riyadh 11525, Saudi Arabia
| | - Yousif Qari
- Department of Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mahmoud Al-Ahwal
- Department of Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mohammed Al-Qahtani
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Abdelbaset Buhmeida
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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Abstract
The extracellular matrix protein tenascin C (TNC) is a large glycoprotein expressed in connective tissues and stem cell niches. TNC over-expression is repeatedly observed in cancer, often at the invasive tumor front, and is associated with poor clinical outcome in several malignancies. The link between TNC expression and poor survival in cancer patients suggests a role for TNC in metastatic progression, which is responsible for the majority of cancer related deaths. Indeed, functional studies using mouse models are revealing new roles of TNC in cancer progression and underscore its important contribution to the development of metastasis. TNC has a pleiotropic role in advancing metastasis by promoting migratory and invasive cell behavior, angiogenesis and cancer cell viability under stress. TNC is an essential component of the metastatic niche and modulates stem cell signaling within the niche. This may be crucial for the fitness of disseminated cancer cells confronted with a foreign environment in secondary organs, that can exert a strong selective pressure on invading cells. TNC is a compelling example of how an extracellular matrix protein can provide a molecular context that is imperative to cancer cell fitness in metastasis.
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Affiliation(s)
- Camille M Lowy
- a Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) ; Heidelberg , Germany
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Nicastri A, Gaspari M, Sacco R, Elia L, Gabriele C, Romano R, Rizzuto A, Cuda G. N-glycoprotein analysis discovers new up-regulated glycoproteins in colorectal cancer tissue. J Proteome Res 2014; 13:4932-41. [PMID: 25247386 DOI: 10.1021/pr500647y] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Colorectal cancer is one of the leading causes of death due to cancer worldwide. Therefore, the identification of high-specificity and -sensitivity biomarkers for the early detection of colorectal cancer is urgently needed. Post-translational modifications, such as glycosylation, are known to play an important role in cancer progression. In the present work, we used a quantitative proteomic technique based on (18)O stable isotope labeling to identify differentially expressed N-linked glycoproteins in colorectal cancer tissue samples compared with healthy colorectal tissue from 19 patients undergoing colorectal cancer surgery. We identified 54 up-regulated glycoproteins in colorectal cancer samples, therefore potentially involved in the biological processes of tumorigenesis. In particular, nine of these (PLOD2, DPEP1, SE1L1, CD82, PAR1, PLOD3, S12A2, LAMP3, OLFM4) were found to be up-regulated in the great majority of the cohort, and, interestingly, the association with colorectal cancer of four (PLOD2, S12A2, PLOD3, CD82) has not been hitherto described.
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Affiliation(s)
- Annalisa Nicastri
- Proteomics@UMG, Department of Experimental and Clinical Medicine and ‡Surgery Unit, Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro , viale Europa, 88100 Catanzaro, Italy
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Didem T, Faruk T, Senem K, Derya D, Murat S, Murat G, Oznur K. Clinical significance of serum tenascin-c levels in epithelial ovarian cancer. Tumour Biol 2014; 35:6777-82. [PMID: 24722824 DOI: 10.1007/s13277-014-1923-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 04/01/2014] [Indexed: 10/25/2022] Open
Abstract
Tenascin-C (TNC) is an extracellular matrix protein that is expressed at low levels in normal adult tissue but is highly expressed around many tumors including ovarian tumors. The objective of this study was to determine the clinical significance of the serum levels of TNC in epithelial ovarian cancer (EOC) patients. A total of 50 patients with a pathologically confirmed diagnosis of EOC were included in this study. Serum TNC levels were determined by the solid-phase sandwich enzyme-linked immunosorbent assay (ELISA) method. Age- and sex- matched 28 healthy controls were included in the analysis. Median age of the patients was 56.5 years old, range 22 to 83 years. Majority of the patients had advanced disease (FIGO stage III-IV) (90 %). The median serum TNC levels were found significantly higher in EOC patients (130.5 pg/mL) compared to healthy controls (90.1 pg/mL) (p = 0.03). We found no correlation between serum TNC levels and any prognostic parameters analyzed, including age of the patients, histology, tumor grade, stage of the disease, and response to chemotherapy. Survival analysis did not show statistically significant effect of serum TNC concentration on progression-free and overall survival (p = 0.36 and p = 0.19, respectively). However, patients with high serum TNC levels tend to have poor overall survival. In conclusion, although serum TNC levels are elevated, it has no predictive or prognostic roles on survival in EOC patients.
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Affiliation(s)
- Tastekin Didem
- Department of Medical Oncology, Oncology Institute, Istanbul University, Capa, 34390, Istanbul, Turkey,
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Pyatnitskiy M, Mazo I, Shkrob M, Schwartz E, Kotelnikova E. Clustering gene expression regulators: new approach to disease subtyping. PLoS One 2014; 9:e84955. [PMID: 24416320 PMCID: PMC3887006 DOI: 10.1371/journal.pone.0084955] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Accepted: 11/20/2013] [Indexed: 12/29/2022] Open
Abstract
One of the main challenges in modern medicine is to stratify different patient groups in terms of underlying disease molecular mechanisms as to develop more personalized approach to therapy. Here we propose novel method for disease subtyping based on analysis of activated expression regulators on a sample-by-sample basis. Our approach relies on Sub-Network Enrichment Analysis algorithm (SNEA) which identifies gene subnetworks with significant concordant changes in expression between two conditions. Subnetwork consists of central regulator and downstream genes connected by relations extracted from global literature-extracted regulation database. Regulators found in each patient separately are clustered together and assigned activity scores which are used for final patients grouping. We show that our approach performs well compared to other related methods and at the same time provides researchers with complementary level of understanding of pathway-level biology behind a disease by identification of significant expression regulators. We have observed the reasonable grouping of neuromuscular disorders (triggered by structural damage vs triggered by unknown mechanisms), that was not revealed using standard expression profile clustering. For another experiment we were able to suggest the clusters of regulators, responsible for colorectal carcinoma vs adenoma discrimination and identify frequently genetically changed regulators that could be of specific importance for the individual characteristics of cancer development. Proposed approach can be regarded as biologically meaningful feature selection, reducing tens of thousands of genes down to dozens of clusters of regulators. Obtained clusters of regulators make possible to generate valuable biological hypotheses about molecular mechanisms related to a clinical outcome for individual patient.
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Affiliation(s)
- Mikhail Pyatnitskiy
- Institute of Biomedical Chemistry, RAMS, Moscow, Russia
- Ariadne Diagnostics LLC, Rockville, Maryland, United States of America
- * E-mail:
| | - Ilya Mazo
- Ariadne Diagnostics LLC, Rockville, Maryland, United States of America
| | - Maria Shkrob
- Elsevier Inc, Rockville, Maryland, United States of America
| | - Elena Schwartz
- Ariadne Diagnostics LLC, Rockville, Maryland, United States of America
| | - Ekaterina Kotelnikova
- Ariadne Diagnostics LLC, Rockville, Maryland, United States of America
- Institute for Information Transmission Problems, RAS, Moscow, Russia
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Shin IY, Sung NY, Lee YS, Kwon TS, Si Y, Lee YS, Oh ST, Lee IK. The expression of multiple proteins as prognostic factors in colorectal cancer: cathepsin D, p53, COX-2, epidermal growth factor receptor, C-erbB-2, and Ki-67. Gut Liver 2013; 8:13-23. [PMID: 24516696 PMCID: PMC3916682 DOI: 10.5009/gnl.2014.8.1.13] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Revised: 12/23/2012] [Accepted: 03/13/2013] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND/AIMS A single gene mutation alone cannot explain the poor prognosis of colorectal cancer. This study aimed to establish a correlation between the expression of six proteins and the prognosis of colorectal cancer patients. METHODS Tissue samples were collected from 266 patients who underwent surgery for colorectal cancer at our institution from January 2006 to December 2007. The expression of six proteins were determined using immunohistochemical staining of specimens. RESULTS Cathepsin D, p53, COX-2, epidermal growth factor receptor, c-erbB-2, and Ki-67 expression were detected in 38.7%, 60.9%, 37.6%, 35.7%, 30.1%, and 74.4% of the samples, respectively. The expression of cathepsin D was significantly correlated with reduced cancer-free survival (p=0.036) and colorectal cancer-specific survival (p=0.003), but the other expression levels were not. In a multivariate analysis, cathepsin D expression was found to be an independent prognostic factor for poorer colorectal cancer-specific survival (hazard ratio, 8.55; 95% confidence interval, 1.07 to 68.49). Furthermore, patients with tumors expressing four or more of the proteins had a significantly decreased cancer-free survival rate (p=0.006) and colorectal cancer-specific survival rate (p=0.002). CONCLUSIONS Patients with cathepsin D positivity had a poorer outcome than patients who were cathepsin D-negative. Thus, cathepsin D may provide an indicator for appropriate intensive follow-up and adjuvant chemotherapy.
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Affiliation(s)
- Il Yong Shin
- Department of Surgery, Yeouido St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Na Young Sung
- Department of Biostatistics and Computing, Yonsei University College of Medicine, Seoul, Korea
| | - Youn Soo Lee
- Department of Hospital Pathology, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Taek Soo Kwon
- Department of Surgery, Yeouido St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Yoon Si
- Department of Surgery, Yeouido St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Yoon Suk Lee
- Department of Surgery, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Seong Taek Oh
- Department of Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - In Kyu Lee
- Department of Surgery, Yeouido St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
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Abstract
Metastasis is an inefficient process and most cancer cells fail to colonize secondary sites. There are several possible reasons for this. First, the nature of the infiltrating cells is important as a small population of cancer stem cells has been shown to have exclusive metastasis-initiating potential. Secondly, supportive niches are required to promote the outgrowth of disseminated tumour cells. Such niches are either produced prior to the arrival of cancer cells in the target organ or are induced ad hoc upon cell infiltration. Components of the extracellular matrix (ECM) have been found to play a role in establishing these niches. This has highlighted the importance of the ECM for metastatic progression, and suggests that such components may provide alternative targets for treatment of metastatic disease.
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Affiliation(s)
- A Santamaria-Martínez
- École Polytechnique Fédérale de Lausanne (EPFL), ISREC (Swiss Institute for Experimental Cancer Research), National Center of Competence in Research (NCCR) 'Molecular Oncology', Lausanne, Switzerland
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Derijks-Engwegen JY, Cats A, Smits ME, Schellens JH, Beijnen JH. Improving colorectal cancer management: the potential of proteomics. Biomark Med 2012; 2:253-89. [PMID: 20477414 DOI: 10.2217/17520363.2.3.253] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. Successful treatment is heavily dependent on tumor stage at the time of detection, but unfortunately CRC is often only detected in advanced stages. New biomarkers in the form of genes or proteins that can be used for diagnosis, prognostication, follow-up, and treatment selection and monitoring could be of great benefit for the management of CRC. Furthermore, proteins could prove valuable new targets for therapy. Therefore, clinical proteomics has gained a lot of scientific interest in this regard. To get an overall insight into the extent to which this research has contributed to a better management of CRC, we give a comprehensive overview of the results of proteomics research on CRC, focusing on expression proteomics, in other words, protein profiling studies. Furthermore, we evaluate the potential of the discriminating proteins identified in this research for clinical use as biomarkers for (early) diagnosis, prognosis and follow-up of CRC or as targets for new therapeutic regimens.
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Overexpression of matrix metalloproteinase-21 is associated with poor overall survival of patients with colorectal cancer. J Gastrointest Surg 2011; 15:1188-94. [PMID: 21590459 DOI: 10.1007/s11605-011-1519-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Accepted: 03/24/2011] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Matrix metalloproteinase-21 (MMP-21) is a member of the MMP family, which is overexpressed in some solid tumors and is thought to enhance the tumor invasion and metastasis ability. The aim of the present study is to examine the MMP-21 expression in human colorectal cancer and normal colorectal tissue using tissue microarray technique and to determine its association with clinicopathological characteristics and prognostic value. MATERIALS AND METHODS Four array blocks including 256 cases of colorectal cancer and adjacent normal tissues were investigated by immunohistochemistry assay. Staining evaluation results were analyzed statistically in relation to various clinicopathological characters and overall survival. RESULTS High level of MMP-21 expression was detected in colorectal cancer, significantly more than in normal colorectal epithelial cells. In colorectal cancer, MMP-21 was significantly positively correlated with depth of invasion, lymph node metastasis, and distant metastasis. The overall survival rate was significantly lower for patients with MMP-21 positive than those with MMP-21 negative tumors. However, no correlations between MMP-21 expression and patients' age, sex tumor location, or differentiation status were detected. CONCLUSION Our findings emphasize the important role of MMP-21 in the invasion and metastasis process in human colorectal cancer. It might also serve as a novel prognostic marker that is independent of, and additive to, the TNM staging system.
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Wu T, Li Y, Liu X, Lu J, He X, Wang Q, Li J, Du X. Identification of high-risk stage II and stage III colorectal cancer by analysis of MMP-21 expression. J Surg Oncol 2011; 104:787-91. [PMID: 21656525 DOI: 10.1002/jso.21970] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Accepted: 04/12/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND The expression of matrix metalloproteinase-21 (MMP-21) has been shown to be elevated in some solid tumor and thought to enhance tumor invasion and metastasis ability. In the present study, we investigated the expression of MMP-21 and its association with prognosis in stage II and III colorectal cancer. METHODS MMP-21 expression was investigated in 286 cases of colorectal cancer by immunohistochemistry assay. Statistical analysis was utilized to evaluate the association of MMP-21 expression with clinicopathological characters and overall survival of patients with stage II and III colorectal cancer. RESULTS MMP-21 expression was significantly higher in colorectal cancer, compared with that in normal epithelial tissue. And it also correlated with tumor invasion, lymph node metastasis, and distant metastasis of colorectal cancer. MMP-21 was also proved to be an independent prognostic factor in patients with stage II as well as stage III colorectal cancer. However, no correlations between MMP-21 expression and patients' age, sex, tumor location, or differentiation status were detected. CONCLUSION These results suggested the potential role of MMP-21 in the invasion and metastasis process of human colorectal cancer. It could also be a novel molecular marker to predict prognosis of patients with stage II and stage III colorectal cancer.
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Affiliation(s)
- Tao Wu
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
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23
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Cavdar Z, Canda AE, Terzi C, Sarioglu S, Fuzun M, Oktay G. Role of gelatinases (matrix metalloproteinases 2 and 9), vascular endothelial growth factor and endostatin on clinicopathological behaviour of rectal cancer. Colorectal Dis 2011; 13:154-60. [PMID: 19888958 DOI: 10.1111/j.1463-1318.2009.02105.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM The aim of this study was to evaluate the role of matrix metalloproteinases (MMPs), their tissue inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] and activators [membrane-type MMPs (MT1-MMPs)], vascular endothelial growth factor (VEGF) and endostatin on clinicopathological variables and prognosis in patients with rectal cancer. METHOD Paired samples of tumour tissue and normal tissue were obtained from patients with rectal cancer who underwent curative surgery (n = 34). Gelatin zymography for MMP-2 and MMP-9, an activity assay for MT1-MMP and enzyme-linked immunoassays for TIMP-2, VEGF and endostatin were performed using extracts from the paired tissue samples. RESULTS Active MMP-9 showed statistically significant relationships with metastatic disease and perineural invasion (P = 0.002 and P = 0.042). A significant relationship was observed between the levels of tumoral pro-MMP-2 and pro-MMP-9 and the presence of lymph node metastasis (P = 0.012 and P = 0.021, respectively). Tumoral TIMP-2 levels showed a significant relationship with tumour recurrence (P = 0.011). A significant relationship was also observed between tumour VEGF levels and the presence of perineural invasion (P = 0.044), and VEGF levels were correlated with the size of the tumour (P = 0.009, r = 0.454). CONCLUSION These results might contribute to further investigation of a possible prognostic significance in rectal cancer.
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Affiliation(s)
- Z Cavdar
- Research Laboratory, Dokuz Eylül University School of Medicine, Inciralti, Izmir, Turkey
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24
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Sundov Z, Tomić S, Vilović K, Kunac N, Kalebić M, Bezić J. Immunohistochemically detected high expression of matrix metalloproteinase-2 as predictor of poor prognosis in Duke's B colon cancer. Croat Med J 2009; 49:636-42. [PMID: 18925697 DOI: 10.3325/cmj.2008.5.636] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
AIM To demonstrate immunohistochemical expression of matrix metalloproteinase-2 (MMP-2) protein in Duke's B colon cancer and determine its correlation with age, sex, grade, presence of vascular invasion, and patients' overall survival. METHOD The study took place from January 1995 to December 1997. We determined the expression of MMP-2 in 152 formalin-fixed, paraffin embedded specimens of Duke's B colon carcinomas by immunohistochemical analysis using MMP-2 monoclonal antibody. Immunohistochemical expression was scored semiquantitatively. Carcinomas were graded as low or high grade. Survival time was analyzed with Kaplan-Meier method, and the log-rank test was used to assess the differences between groups. Cox proportional hazard regression model was used for multivariate survival analysis. RESULT Univariate analysis showed that positive staining for MMP-2, high histological grade, vascular invasion, male sex, and age>60 years were associated with shorter survival in patients with Duke's B colon cancer (P range from 0.023 to <0.001). Multivariate analysis showed that only MMP-2 overexpression (P<0.001; hazard ratio [HR]=3.64) and vascular invasion (P<0.001; HR=4.27) were associated with shorter overall survival. CONCLUSION Expression of MMP-2 is an important independent indicator of shorter survival in patients with Duke's B colon cancer and should be taken into consideration in decision-making on the use of adjuvant systemic therapy in patients with Duke's B colon cancer.
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Affiliation(s)
- Zeljko Sundov
- Department of Internal Medicine, Split University School of Medicine, Split, Croatia
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25
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Chang CL. Genome-wide oligonucleotide microarray analysis of gene-expression profiles of Taiwanese patients with anaplastic astrocytoma and glioblastoma multiforme. ACTA ACUST UNITED AC 2008; 13:912-21. [PMID: 18812569 DOI: 10.1177/1087057108323908] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
This study investigated the relationship between gene expression and disease based on the expression profiles of tissue-specific genes, with the aim of discovering the candidate genes associated with disease risk as diagnostic markers. The gene-expression profiles of approximately 20,000 genes from 4 anaplastic astrocytomas (AAs), 7 glioblastoma multiformes (GBMs), and 1 nontumor brain (NB) were analyzed by in situ-synthesized 60-mer oligonucleotide microarray. The signal intensity of each feature was measured by laser scanner, and gene expression was quantified as the tumor/NB intensity ratio. Gene expression was defined as having increased or decreased when the ratio was >or=1.5 or <or= 0.67, respectively. In comparison with NB, 20 genes showed increased expression, and 32 showed decreased expression in AA, while 20 genes showed increased expression, and 164 showed decreased expression in GBM. This research indicates that changes in expression levels of 4 genes in AA and 6 genes in GBM may be useful diagnostic markers. Quantitative reverse transcription-polymerase chain reaction also supported the microarray results for the 6 selected genes. In conclusion, microarray images of excellent quality are of high data reproducibility using entirely standard procedures, and these genes may be associated with the molecular events leading to AA or GBM.
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Affiliation(s)
- Chia-Lin Chang
- Research Institute of Biotechnology, HungKuang University, Taichung Hsien, Taiwan (R.O.C.).
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26
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Abstract
Cathepsins are a class of globular proteases, initially described as intracellular peptide hydrolases, although several cathepsins also have extracellular functions. Cathepsins B, C, F, H, L, K, O, S, V, W, and X are cysteine proteases of the papain family, and represent the largest and best-known class of the cathepsins. Cathepsin G is a serine carboxypeptidases, and cathepsins D and E are aspartic proteases. Cathepsins are synthesized as inactive proenzymes and processed to become mature and active enzymes. Endogenous protein inhibitors, such as cystatins and some serpins, inhibit active enzymes. As primarily lysosomal proteases, cathepsins play important roles in proteolysis during physiological processes, as well as in several diseases. On the basis of their ability to degrade extracellular matrix proteins, cathepsins have been implicated to play a role in invasion and metastasis of colorectal cancer. In the present review, the role of cathepsins in the disease process of colorectal cancers and the correlation of cathepsin expression and activity with clinicopathological features is discussed. Furthermore, we give an overview of the recent developments of cathepsins in animal models and in in vitro experiments of colorectal disease, and provide information on inhibitors of cathepsins as possible therapeutics.
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Lundin M, Nordling S, Lundin J, Haglund C. Tenascin-C expression and its prognostic significance in colorectal cancer. Oncology 2008; 72:403-9. [PMID: 18196927 DOI: 10.1159/000113490] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2007] [Accepted: 07/18/2007] [Indexed: 11/19/2022]
Abstract
OBJECTIVE The extracellular matrix glycoprotein tenascin-C has been proposed as a tumor marker with prognostic significance in many cancer forms, but in colorectal cancer, reported results have been controversial. The aim of this study was to evaluate the prognostic value of immunohistochemical tenascin-C expression in a series of 231 patients with colorectal cancer. METHODS Paraffin-embedded formalin-fixed specimens were stained with a tenascin-C-specific monoclonal antibody, and the stromal staining intensity and pattern were analyzed. RESULTS Tenascin-C immunoreactivity was observed in all 231 specimens, with a pattern of staining that was diffuse and interstitial. The staining was occasional in 39 (17%), moderate in 106 (46%) and strong in 86 specimens (37%). There was no statistically significant association between tenascin-C immunoreactivity and any of the other clinicopathological variables. The cumulative 5-year survival rates of patients with occasional and weak staining were similar (56.8 and 54.9%, respectively), while the patients with strong tenascin-C staining had a lower survival rate (46.1%). This difference in survival was not significant (p = 0.23). The staining pattern and distribution can be viewed from digitized representative microscope slides (virtual slides) at http://www.webmicroscope.net/supplements/tenascin. CONCLUSIONS Our results indicate that immunohistochemical expression of tenascin-C is not of prognostic significance in colorectal cancer.
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Affiliation(s)
- M Lundin
- Department of Surgery, University of Helsinki, Helsinki, Finland
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Li M, Li JY, Zhao AL, He JS, Zhou LX, Li YA, Gu J. Survival stratification panel of colorectal carcinoma with combined expression of carcinoembryonic antigen, matrix metalloproteinases-2, and p27 kip1. Dis Colon Rectum 2007; 50:1887-98. [PMID: 17882488 DOI: 10.1007/s10350-007-9053-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2006] [Revised: 03/24/2007] [Accepted: 05/23/2007] [Indexed: 02/08/2023]
Abstract
PURPOSE The prognosis varies greatly in colorectal carcinoma patients, even in the same stage. We examined the association between the expression of matrix metalloproteinases-2, carcinoembryonic antigen, p27 kip1, and clinicopathologic features in patients with colorectal carcinoma to identify a possible panel of tumor markers in predicting prognosis of colorectal carcinoma. METHODS The expressions of three individual markers in 127 colorectal carcinoma cases were analyzed by immunohistochemistry method. Univariate and multivariate analysis were performed to analyze the expression with the disease-free survival time in colorectal carcinoma. RESULTS High expression of matrix metalloproteinases-2, carcinoembryonic antigen, and low expression of p27 kip1 were related to poor prognosis in univariate analysis (P = 0.0002; P < 0.0001; P = 0.0008). The expression of matrix metalloproteinases-2, carcinoembryonic antigen, p27 kip1, and tumor differentiation were independent prognostic factors for disease-free survival by Cox regression analysis. The coexpression panel of matrix metalloproteinases-2, carcinoembryonic antigen, and p27 kip had significant prognostic value in all patients (P AB = 0.0103; P(BC) = 0.0068; P CD = 0.0117). Multivariate analysis with Cox regression reveals that coexpression of matrix metalloproteinases-2, carcinoembryonic antigen, and p27 kip1 were independent prognostic factors as tumor differentiation in colorectal carcinoma. In different stages, coexpression tumor markers functioned in Stages II and III but not in the 19 cases of Stage I. The reason might be the number of patients was too small. CONCLUSIONS The results of this study provided further evidence that the combination of tumor markers of matrix metalloproteinases-2, carcinoembryonic antigen, and p27 kip1 was more informative than any single tumor marker alone for the disease-free survival stratification of colorectal carcinoma. Coexpression of matrix metalloproteinases-2, carcinoembryonic antigen, and p27 kip1 might be a useful survival stratification panel for clinical management.
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Affiliation(s)
- Ming Li
- Gastrointestinal Surgery Unit, Peking University School of Oncology, Beijing Cancer Hospital, Beijing Institute for Cancer Research, Beijing, People's Republic of China
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Schwandner O, Schlamp A, Broll R, Bruch HP. Clinicopathologic and prognostic significance of matrix metalloproteinases in rectal cancer. Int J Colorectal Dis 2007; 22:127-36. [PMID: 16896992 DOI: 10.1007/s00384-006-0173-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/01/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS The aim of this study was to determine the prognostic role of matrix metalloproteinases in rectal cancer. MATERIALS AND METHODS Formalin-fixed and paraffin-embedded tissue sections of 94 rectal carcinomas were used for the immunohistochemical analysis of matrix metalloproteinases (MMP)-2, MMP-7, MT1-MMP, and tissue inhibitor of metalloproteinases (TIMP)-2. Inclusion criteria were sporadic rectal adenocarcinoma resected curatively (including total mesorectal excision), adjuvant radiochemotherapy in UICC stages II and III, and complete intra-institutional follow-up. Results of immunohistochemistry were correlated with clinical and histopathologic data from the prospective rectal cancer registry and prognosis. End points of the prognostic analysis were tumor progression caused by local and/or distant recurrence and 5-year survival (disease-free and overall). To assess prognostic significance, statistics included univariate and multivariate analysis (p<0.05 statistically significant). RESULTS Of the 94 rectal carcinomas, 35% (33/94) showed an epithelial MMP-2 expression, 77% (72/94) were MMP-2 positive in the stroma. Fifty-four percent (51/94) were MMP-7 positive, and 47% (46/94) were positive for both MT1-MMP and TIMP-2. The stromal MMP-2 staining pattern was correlated with the depth of invasion (pT status, p=0.006) with MMP-7 (p=0.016) and TIMP-2 expression (p=0.036). Positive expression of MMP-2 in tumor epithelium was correlated with MMP-7 (p=0.027), MT1-MMP (p=0.036), and TIMP-2 expression (p<0.0001). A positive staining pattern of MMP-7 was significantly correlated with depth of invasion and TIMP-2 (p<0.01). The positive staining pattern of MT1-MMP was correlated with epithelial MMP-2 (p=0.036), MMP-7 (p=0.004), and TIMP-2 expression (p=0.002). TIMP-2 immunoreactivity correlated with depth of invasion (p=0.013), epithelial MMP-2 (p<0.001), stromal MMP-2 (p=0.036), MMP-7 (p<0.001), and MT1-MMP (p=0.002). Neither pattern correlated with age, gender, tumor stage (UICC), grading, preoperative serum carcinoembryonic antigen (CEA) level, or nodal status (p>0.05). Within a mean follow-up of 46 months, tumor progression, caused by either local recurrence or distant metastasis, occurred in 14 patients (15.4%). There was no significant association between the MMP expression and the incidence of local and/or distant recurrence. In terms of survival, preoperative CEA level (disease-free 5-year survival 46% with increased CEA vs 70% with normal CEA, p=0.01; overall 5-year survival 43 vs 74%, p<0.01) and UICC stage were the only factors to be significantly related to 5-year survival by univariate analysis, whereas the metalloproteinases failed to show a significant association. In multivariate analysis, CEA and UICC stage were not identified as independent factors predictive of survival. CONCLUSION MMP-2, MMP-7, MT1-MMP, and TIMP-2 do not appear to be significant predictors of prognosis in a homogenous collective of curatively resected rectal adenocarcinomas.
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Affiliation(s)
- O Schwandner
- Department of Surgery, Caritas-Krankenhaus St. Josef, Landshuter Strasse 65, 93053 Regensburg, Germany.
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Hatakeyama H, Kondo T, Fujii K, Nakanishi Y, Kato H, Fukuda S, Hirohashi S. Protein clusters associated with carcinogenesis, histological differentiation and nodal metastasis in esophageal cancer. Proteomics 2006; 6:6300-16. [PMID: 17133371 DOI: 10.1002/pmic.200600488] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We examined the proteomic background of esophageal cancer. We used laser microdissection to obtain tumor tissues from 72 esophageal squamous cell carcinoma cases and adjacent normal tissues in 57 of these cases. The 2D-DIGE generated quantitative expression profiles with 1730 protein spots. Based on the intensity of the protein spots, unsupervised classification distinguished the tumor tissues from their normal counterparts, and subdivided the tumor tissues according to their histological differentiation. We identified 498 protein spots with altered intensity in the tumor tissues, which protein identification by LC-MS/MS showed to correspond to 217 gene products. We also found 41 protein spots that were associated with nodal metastasis, and identified 33 proteins corresponding to the spots, including cancer-associated proteins such as alpha-actinin 4, hnRNP K, periplakin, squamous cell carcinoma antigen 1 and NudC. The identified cancer-associated proteins have been previously reported to be individually involved in a range of cancer types, and our study observed them collectively in a single type of malignancy, esophageal cancer. As the identified proteins are involved in important biological processes such as cytoskeletal/structural organization, transportation, chaperon, oxidoreduction, transcription and signal transduction, they may function in a coordinate manner in carcinogenesis and tumor progression of esophageal cancer.
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Affiliation(s)
- Hiromitsu Hatakeyama
- Proteome Bioinformatics Project, National Cancer Center Research Institute, Tokyo, Japan
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Giatromanolaki A, Sivridis E, Koukourakis MI. Angiogenesis in colorectal cancer: prognostic and therapeutic implications. Am J Clin Oncol 2006; 29:408-17. [PMID: 16891872 DOI: 10.1097/01.coc.0000221317.56731.4e] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Angiogenesis is important for tumor growth and metastasis. This account reviews the clinicopathological studies conducted in the field of angiogenesis in colorectal cancer, the methods of assessing vascular-related characteristics in tissue sections and provides a background for the usefulness of antiangiogenic policies along with chemotherapy and radiotherapy. Highly angiogenic colorectal tumors are associated with aggressive histopathological features and poor patients' survival. Similarly, factors stimulating angiogenesis, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase (TP), and others, are commonly related to increased vascular density (VD) and, therefore, to an unfavorable clinical course. Anti-VEGF agents have improved prognosis in patients with metastatic colorectal cancer, when added to standard chemotherapy. It is expected that, in addition to adjuvant chemotherapy and radiotherapy, agents blocking the stimulatory effect of VEGF on endothelial cells would prove beneficial to the patient.
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Affiliation(s)
- Alexandra Giatromanolaki
- Department of Pathology, Democritus University of Thrace Medical School, Alexandroupolis, Greece
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Tsukamoto T, Iida J, Dobashi Y, Furukawa T, Konishi F. Overexpression in colorectal carcinoma of two lysosomal enzymes, CLN2 and CLN1, involved in neuronal ceroid lipofuscinosis. Cancer 2006; 106:1489-97. [PMID: 16518810 DOI: 10.1002/cncr.21764] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Lysosomal proteases are implicated in cancer progression and metastasis. In the current study, using subtraction cloning for genes that are differentially expressed in metastasis, the authors isolated a clone encoding ceroid lipofuscinosis, neuronal 2 (CLN2), which is a lysosomal serine protease defective in neuronal ceroid lipofuscinosis (NCL). Increased CLN2 activity has been reported in breast carcinoma and the antiapoptotic effect of another causative gene of NCL, ceroid lipofuscinosis, neuronal 1 (CLN1), is known. METHODS The mRNA levels of CLN2, CLN1, and cathepsins B, D, H, and L were investigated in colorectal carcinoma patients with different clinical stages using real-time quantitative reverse transcriptase polymerase chain reaction. A polyclonal antibody was raised against a recombinant CLN2 protein for immunoblotting and immunohistochemistry. RESULTS The mRNA levels of CLN1 and cathepsins B, D, and L were significantly higher in metastatic lesions than in primary tumors. In the primary tumors, mRNA expressions of CLN2 and cathepsin D were associated with advanced clinical stages (P < .015 and P < .031, respectively). Among the lysosomal enzymes examined, only the mRNA expression of CLN2 in both the primary tumors of all patients and the pT3 tumors was correlated with the presence of liver metastases (P < .0049 and P < .029, respectively). The polyclonal antibody prepared in the current study demonstrated CLN2 overexpression by immunoblotting and immunohistochemistry. CONCLUSIONS The results indicate that there is a close correlation between CLN2 and CLN1 expression and colorectal carcinoma progression and metastasis and suggest that they may be potential molecular targets.
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Affiliation(s)
- Toshihiko Tsukamoto
- Department of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
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Skrzydlewska E, Sulkowska M, Wincewicz A, Koda M, Sulkowski S. Evaluation of serum cathepsin B and D in relation to clinicopathological staging of colorectal cancer. World J Gastroenterol 2005; 11:4225-9. [PMID: 16015694 PMCID: PMC4615447 DOI: 10.3748/wjg.v11.i27.4225] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Proteolytic degradation of the extracellular matrix facilitates cancer invasion and promotes metastasis. The study aims at evaluation of preoperative and postoperative serum cathepsins B and D levels in correlation with selected anatomoclinical features of colorectal cancer.
METHODS: Blood samples were collected from 63 colorectal cancer patients before curative operation of the tumor 10 d later. Blood that was obtained from 20 healthy volunteers, served as a control. The activity of cathepsin B was measured with Bz-DL-arginine-pNA as a substrate at pH 6.0, while cathepsin D activity was determined with urea-denatured hemoglobin (pH 4.0).
RESULTS: The preoperative and postoperative activities of cathepsin B were significantly (P < 0.00001) lower in serum of colorectal cancer patients than in control group. However, postoperative values of this protease were significantly increased in comparison with preoperative ones (P = 0.031). Activity of cathepsin D appeared to be significantly higher in colorectal cancer sera (P < 0.00001) compared with controls. No statistically significant differences between preoperative and postoperative activity of cathepsin D were noted (P = 0.09). We revealed a strong linkage of cathepsins’ levels with lymph node status and pT stage of colorectal cancer.
CONCLUSION: Blood serum activities of cathepsin B and D depend on the time of sampling, tumor size and lymph node involvement. Significantly, increased activity of cathepsin D could indicate a malignant condition of the large intestine. In our work, the serum postoperative decrease of cathepsin B activity appears as an obvious concomitant of local lymph node metastasis-the well-known clinicopathological feature of poor prognosis.
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Affiliation(s)
- Elzbieta Skrzydlewska
- Department of Analytical Chemistry, Medical University of Bialystok, Mickiewicza 2, 15-230 Bialystok, Poland.
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