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Reitsam NG, Grosser B, Enke JS, Mueller W, Westwood A, West NP, Quirke P, Märkl B, Grabsch HI. Stroma AReactive Invasion Front Areas (SARIFA): a novel histopathologic biomarker in colorectal cancer patients and its association with the luminal tumour proportion. Transl Oncol 2024; 44:101913. [PMID: 38593584 PMCID: PMC11024380 DOI: 10.1016/j.tranon.2024.101913] [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: 09/19/2023] [Revised: 02/06/2024] [Accepted: 02/13/2024] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND Stroma AReactive Invasion Front Areas (SARIFA) is a novel prognostic histopathologic biomarker measured at the invasive front in haematoxylin & eosin (H&E) stained colon and gastric cancer resection specimens. The aim of the current study was to validate the prognostic relevance of SARIFA-status in colorectal cancer (CRC) patients and investigate its association with the luminal proportion of tumour (PoT). METHODS We established the SARIFA-status in 164 CRC resection specimens. The relationship between SARIFA-status, clinicopathological characteristics, recurrence-free survival (RFS), cancer-specific survival (CSS), and PoT was investigated. RESULTS SARIFA-status was positive in 22.6% of all CRCs. SARIFA-positivity was related to higher pT, pN, pTNM stage and high grade of differentiation. SARIFA-positivity was associated with shorter RFS independent of known prognostic factors analysing all CRCs (RFS: hazard ratio (HR) 2.6, p = 0.032, CSS: HR 2.4, p = 0.05) and shorter RFS and CSS analysing only rectal cancers. SARIFA-positivity, which was measured at the invasive front, was associated with PoT-low (p = 0.009), e.g., higher stroma content, and lower vessel density (p = 0.0059) measured at the luminal tumour surface. CONCLUSION Here, we validated the relationship between SARIFA-status and prognosis in CRC patients and provided first evidence for a potential prognostic relevance in the subgroup of rectal cancer patients. Interestingly, CRCs with different SARIFA-status also showed histological differences measurable at the luminal tumour surface. Further studies to better understand the relationship between high luminal intratumoural stroma content and absence of a stroma reaction at the invasive front (SARIFA-positivity) are warranted and may inform future treatment decisions in CRC patients.
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Affiliation(s)
- N G Reitsam
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - B Grosser
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - J S Enke
- Nuclear Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - W Mueller
- Gemeinschaftspraxis Pathologie, Starnberg, Germany
| | - A Westwood
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's University, University of Leeds, Leeds, UK
| | - N P West
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's University, University of Leeds, Leeds, UK
| | - P Quirke
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's University, University of Leeds, Leeds, UK
| | - B Märkl
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
| | - H I Grabsch
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's University, University of Leeds, Leeds, UK; Department of Pathology, GROW - Research Institute for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands.
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Angeli V, Lim HY. Biomechanical control of lymphatic vessel physiology and functions. Cell Mol Immunol 2023; 20:1051-1062. [PMID: 37264249 PMCID: PMC10469203 DOI: 10.1038/s41423-023-01042-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/26/2023] [Accepted: 04/29/2023] [Indexed: 06/03/2023] Open
Abstract
The ever-growing research on lymphatic biology has clearly identified lymphatic vessels as key players that maintain human health through their functional roles in tissue fluid homeostasis, immunosurveillance, lipid metabolism and inflammation. It is therefore not surprising that the list of human diseases associated with lymphatic malfunctions has grown larger, including issues beyond lymphedema, a pathology traditionally associated with lymphatic drainage insufficiency. Thus, the discovery of factors and pathways that can promote optimal lymphatic functions may offer new therapeutic options. Accumulating evidence indicates that aside from biochemical factors, biomechanical signals also regulate lymphatic vessel expansion and functions postnatally. Here, we review how mechanical forces induced by fluid shear stress affect the behavior and functions of lymphatic vessels and the mechanisms lymphatic vessels employ to sense and transduce these mechanical cues into biological signals.
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Affiliation(s)
- Veronique Angeli
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore.
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
| | - Hwee Ying Lim
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
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3
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Król W, Machelak W, Zielińska M. GDF11 as a friend or an enemy in the cancer biology? Biochim Biophys Acta Rev Cancer 2023; 1878:188944. [PMID: 37356738 DOI: 10.1016/j.bbcan.2023.188944] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/21/2023] [Accepted: 06/21/2023] [Indexed: 06/27/2023]
Abstract
The Growth and Differential Factor 11 (GDF11) is a recently discovered representative of Transforming Growth Factor β superfamily. The highest expression of GDF11 is detected in the nervous system, bladder, seminal vesicles and muscles whereas the lowest in the testis, liver or breast. GDF11 role in physiology is still not clear. GDF11 is a crucial factor in embryogenesis, cell cycle control and apoptosis, inasmuch it mainly targets cell retain stemness features, managing to the cell differentiation and the maturation. GDF11 is entangled in lipid metabolism, inflammatory processes and aging. GDF11 is strongly related to carcinogenesis and its expression in tumors is intruded. GDF11 can promote cancer growth in the colon or inhibit the cell proliferation in breast cancer. The aberrated expression is probably allied with the impaired maturation. In this article we summarized an impact of GDF11 on the tumor cells and review the all attitudes connecting GDF11 with carcinogenesis.
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Affiliation(s)
- Wojciech Król
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Weronika Machelak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Marta Zielińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
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4
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Delineating the dynamic evolution from preneoplasia to invasive lung adenocarcinoma by integrating single-cell RNA sequencing and spatial transcriptomics. Exp Mol Med 2022; 54:2060-2076. [PMID: 36434043 PMCID: PMC9722784 DOI: 10.1038/s12276-022-00896-9] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 09/18/2022] [Accepted: 10/05/2022] [Indexed: 11/27/2022] Open
Abstract
The cell ecology and spatial niche implicated in the dynamic and sequential process of lung adenocarcinoma (LUAD) from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and subsequent invasive adenocarcinoma (IAC) have not yet been elucidated. Here, we performed an integrative analysis of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to characterize the cell atlas of the invasion trajectory of LUAD. We found that the UBE2C + cancer cell subpopulation constantly increased during the invasive process of LUAD with remarkable elevation in IAC, and its spatial distribution was in the peripheral cancer region of the IAC, representing a more malignant phenotype. Furthermore, analysis of the TME cell type subpopulation showed a constant decrease in mast cells, monocytes, and lymphatic endothelial cells, which were implicated in the whole process of invasive LUAD, accompanied by an increase in NK cells and MALT B cells from AIS to MIA and an increase in Tregs and secretory B cells from MIA to IAC. Notably, for AIS, cancer cells, NK cells, and mast cells were colocalized in the cancer region; however, for IAC, Tregs colocalized with cancer cells. Finally, communication and interaction between cancer cells and TME cell-induced constitutive activation of TGF-β signaling were involved in the invasion of IAC. Therefore, our results reveal the specific cellular information and spatial architecture of cancer cells and TME subpopulations, as well as the cellular interaction between them, which will facilitate the identification and development of precision medicine in the invasive process of LUAD from AIS to IAC.
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5
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Devall MA, Eaton S, Ali MW, Powell SM, Li L, Casey G. Insights into Early Onset Colorectal Cancer through Analysis of Normal Colon Organoids of Familial Adenomatous Polyposis Patients. Cancers (Basel) 2022; 14:4138. [PMID: 36077675 PMCID: PMC9454756 DOI: 10.3390/cancers14174138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/22/2022] [Accepted: 08/25/2022] [Indexed: 01/07/2023] Open
Abstract
Early onset colorectal cancer (EOCRC) rates have increased in recent decades. While lowering the recommended age for routine colonoscopies to 45 may reduce this burden, such measures do not address those who develop CRC before that age. Additional measures are needed to identify individuals at-risk for CRC. To better define transcriptomic events that precede the development of CRC, we performed RNA-sequencing analysis in colon organoids derived from seven healthy and six familial adenomatous polyposis (FAP) patients. This led to the identification of 2635 significant differentially expressed genes (FDR < 0.05). Through secondary analysis of publicly available datasets, we found that these genes were enriched for significant genes also present in FAP CRC and non-hereditary CRC datasets, including a subset that were unique to EOCRC. By exposing FAP colon organoids to a three-day ethanol treatment, we found that two EOCRC-relevant genes were also targets of CRC related lifestyle factors. Our data provides unique insight into the potential, early mechanisms of CRC development in colon epithelial cells, which may provide biomarkers for patient monitoring. We also show how modifiable lifestyle factors may further alter genes relevant to EOCRC, adding weight to the hypothesis that such factors represent an important contributor to increased EOCRC incidence.
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Affiliation(s)
- Matthew A. Devall
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
- Department of Family Medicine, University of Virginia, Charlottesville, VA 22903, USA
| | - Stephen Eaton
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
- Department of Family Medicine, University of Virginia, Charlottesville, VA 22903, USA
| | - Mourad W. Ali
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
| | - Steven M. Powell
- Digestive Health Center, University of Virginia, Charlottesville, VA 22903, USA
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA 22903, USA
- Comprehensive Cancer Center, University of Virginia, Charlottesville, VA 22911, USA
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
- Comprehensive Cancer Center, University of Virginia, Charlottesville, VA 22911, USA
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA
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Stage I-IV Colorectal Cancer Prognosis Can Be Predicted by Type and Number of Intratumoral Macrophages and CLEVER-1 + Vessel Density. Cancers (Basel) 2021; 13:cancers13235988. [PMID: 34885098 PMCID: PMC8656733 DOI: 10.3390/cancers13235988] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Tumor-associated macrophages can either promote or prevent cancer growth depending on factors such as macrophage polarization status, tumor type, and disease stage. Macrophages and vessels interact with each other, and the number of lymphatic vessels also affects cancer survival. CLEVER-1 is a protein expressed both on immunosuppressive M2 macrophages and lymphatic vessels. The aim of this study was to validate our previous results regarding the prognostic role of CLEVER-1+ macrophages, CD68+ macrophages, and CLEVER-1+ lymphatic vessels in stage I–IV colorectal cancer. The results indicate that the prognostic role of tumor-associated macrophages and lymphatic vessels changes during disease progression. The findings resemble our earlier results, but are not completely equal, which may be due to the different types of tumor samples used in the two studies (whole section vs. tissue microarray). Abstract Macrophages, which are key players in the tumor microenvironment and affect the prognosis of many cancers, interact with lymphatic vessels in tumor tissue. However, the prognostic role of tumor-associated macrophages (TAM) and lymphatic vessels in human colorectal cancer (CRC) remains controversial. We investigated the prognostic role of CD68+ and CLEVER-1+ (common lymphatic endothelial and vascular endothelial receptor 1) TAMs in addition to CLEVER-1+ lymphatic vessels in 498 stage I–IV CRC patients. The molecular markers were detected by immunohistochemical (IHC) analysis. The results showed that, in early stage I CRC and in young patients (age below median, ≤67.4 years), a high number of CD68+ and CLEVER-1+ TAMs was associated with longer disease-specific survival (DSS). In early stage I CRC, high intratumoral CLEVER-1+ lymphatic vessel density (LVD) predicted a favorable prognosis, whereas the opposite pattern was observed in stage II CRC. The highest density of CLEVER-1+ lymphatic vessels was found in metastatic disease. The combination of intratumoral CLEVER-1+ lymphatic vesselhigh + CD68+ TAMlow was associated with poor DSS in stage I–IV rectal cancer. The present results indicate that the prognostic significance of intratumoral macrophages and CLEVER-1+ lymphatic vessels differs according to disease stage, reflecting the dynamic changes occurring in the tumor microenvironment during disease progression.
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Zhang Y, Liu Y, Shen D, Zhang H, Huang H, Li S, Ren J. Detection and prognostic value of intratumoral and peritumoral lymphangiogenesis in colorectal cancer. Transl Cancer Res 2020; 9:6189-6197. [PMID: 35117229 PMCID: PMC8798527 DOI: 10.21037/tcr-20-1038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 09/12/2020] [Indexed: 12/18/2022]
Abstract
Background Colorectal cancer (CRC) with lymphatic invasion is one of the critical prognostic factors in lymph node metastasis. Lymphangiogenesis has a significant effect on lymphatic metastasis and tumor progression. However, the significance of intratumoral and peritumoral lymphangiogenesis has been controversial in CRC. The aim of this study is to investigate the different role of introtumoral and peritumoral lymphangiogenesis in CRC progression and prognosis. Methods Lymphangiogenesis of 120 CRC specimens, as measured by lymphatic vessel density (LVD), was examined by immunostaining for podoplanin, a lymphatic vessel-specific marker. The mean number of lymphatic vessels of three hotspots was measured in intratumoral and peritumoral areas as intratumoral LVD (LVDit) and peritumoral LVD (LVDpt), respectively. The association of LVDit and LVDpt with the clinicopathological findings and prognosis was investigated. Results Compared to the peritumoral lymphatics, the intratumoral lymphatics were small, collapsed and irregular. The mean LVDpt was higher than the mean LVDit (P<0.001). LVDit was positively correlated with tumor size (P=0.009), tumor histologic grade (P=0.023), and overall survival (P=0.036). LVDpt was correlated with lymph node metastasis (P<0.001), tumor stage (P=0.004), and overall survival (P=0.016). Conclusions LVDpt plays a prominent role in lymph node metastasis, whereas LVDit is more closely correlated with tumor growth and histopathological differentiation. Both LVDpt and LVDit contribute to CRC progression and prognosis.
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Affiliation(s)
- Yanbin Zhang
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Department of Oncology, Capital Medical University Cancer Center, Beijing Shijitan Hospital, the Capital Medical University, Beijing, China
| | - Yue Liu
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Danhua Shen
- Department of Pathology, Peking University People's Hospital, Peking University, Beijing, China
| | - Hui Zhang
- Department of Pathology, Peking University People's Hospital, Peking University, Beijing, China
| | - Hongyan Huang
- Department of Oncology, Capital Medical University Cancer Center, Beijing Shijitan Hospital, the Capital Medical University, Beijing, China
| | - Sha Li
- Department of Oncology, Capital Medical University Cancer Center, Beijing Shijitan Hospital, the Capital Medical University, Beijing, China
| | - Jun Ren
- Department of Oncology, Capital Medical University Cancer Center, Beijing Shijitan Hospital, the Capital Medical University, Beijing, China
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8
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Simoni-Nieves A, Gerardo-Ramírez M, Pedraza-Vázquez G, Chávez-Rodríguez L, Bucio L, Souza V, Miranda-Labra RU, Gomez-Quiroz LE, Gutiérrez-Ruiz MC. GDF11 Implications in Cancer Biology and Metabolism. Facts and Controversies. Front Oncol 2019; 9:1039. [PMID: 31681577 PMCID: PMC6803553 DOI: 10.3389/fonc.2019.01039] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 09/24/2019] [Indexed: 01/06/2023] Open
Abstract
Growth Differentiation Factor 11 (GDF11), a member of the super family of the Transforming Growth Factor β, has gained more attention in the last few years due to numerous reports regarding its functions in other systems, which are different to those related to differentiation and embryonic development, such as age-related muscle dysfunction, skin biology, metabolism, and cancer. GDF11 is expressed in many tissues, including skeletal muscle, pancreas, kidney, nervous system, and retina, among others. GDF11 circulating levels and protein content in tissues are quite variable and are affected by pathological conditions or age. Although, GDF11 biology had a lot of controversies, must of them are only misunderstandings regarding the variability of its responses, which are independent of the tissue, grade of cellular differentiation or pathologies. A blunt fact regarding GDF11 biology is that its target cells have stemness feature, a property that could be found in certain adult cells in health and in disease, such as cancer cells. This review is focused to present and analyze the recent findings in the emerging research field of GDF11 function in cancer and metabolism, and discusses the controversies surrounding the biology of this atypical growth factor.
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Affiliation(s)
- Arturo Simoni-Nieves
- Posgrado en Biología Experimental, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.,Laboratorio de Fisiología Celular y Biología Molecular, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
| | - Monserrat Gerardo-Ramírez
- Posgrado en Biología Experimental, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.,Laboratorio de Fisiología Celular y Biología Molecular, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
| | - Gibrán Pedraza-Vázquez
- Posgrado en Biología Experimental, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.,Laboratorio de Fisiología Celular y Biología Molecular, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
| | - Lisette Chávez-Rodríguez
- Posgrado en Biología Experimental, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.,Laboratorio de Fisiología Celular y Biología Molecular, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
| | - Leticia Bucio
- Laboratorio de Fisiología Celular y Biología Molecular, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.,Laboratorio de Medicina Experimental, Unidad de Medicina Translacional, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cardiología Ignacio Chavez, Mexico City, Mexico
| | - Verónica Souza
- Laboratorio de Fisiología Celular y Biología Molecular, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.,Laboratorio de Medicina Experimental, Unidad de Medicina Translacional, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cardiología Ignacio Chavez, Mexico City, Mexico
| | - Roxana U Miranda-Labra
- Laboratorio de Fisiología Celular y Biología Molecular, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.,Laboratorio de Medicina Experimental, Unidad de Medicina Translacional, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cardiología Ignacio Chavez, Mexico City, Mexico
| | - Luis E Gomez-Quiroz
- Laboratorio de Fisiología Celular y Biología Molecular, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.,Laboratorio de Medicina Experimental, Unidad de Medicina Translacional, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cardiología Ignacio Chavez, Mexico City, Mexico
| | - María Concepción Gutiérrez-Ruiz
- Laboratorio de Fisiología Celular y Biología Molecular, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.,Laboratorio de Medicina Experimental, Unidad de Medicina Translacional, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cardiología Ignacio Chavez, Mexico City, Mexico
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Ungaro F, Colombo P, Massimino L, Ugolini GS, Correale C, Rasponi M, Garlatti V, Rubbino F, Tacconi C, Spaggiari P, Spinelli A, Carvello M, Sacchi M, Spanò S, Vetrano S, Malesci A, Peyrin-Biroulet L, Danese S, D'Alessio S. Lymphatic endothelium contributes to colorectal cancer growth via the soluble matrisome component GDF11. Int J Cancer 2019; 145:1913-1920. [PMID: 30889293 DOI: 10.1002/ijc.32286] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 01/25/2019] [Accepted: 02/28/2019] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) is one of the most malignant tumors worldwide. Stromal cells residing in the tumor microenvironment strongly contribute to cancer progression through their crosstalk with cancer cells and extracellular matrix. Here we provide the first evidence that CRC-associated lymphatic endothelium displays a distinct matrisome-associated transcriptomic signature, which distinguishes them from healthy intestinal lymphatics. We also demonstrate that CRC-associated human intestinal lymphatic endothelial cells regulate tumor cell growth via growth differentiation factor 11, a soluble matrisome component which in CRC patients was found to be associated with tumor progression. Our data provide new insights into lymphatic contribution to CRC growth, aside from their conventional role as conduits of metastasis.
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Affiliation(s)
- Federica Ungaro
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | | | - Luca Massimino
- Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
| | | | - Carmen Correale
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Milan, Italy
| | - Marco Rasponi
- Department of Electronics, Information and Bioengineering, Milan, Italy
| | | | - Federica Rubbino
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Carlotta Tacconi
- Institute of Pharmaceutical Sciences, Pharmacogenomics, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland
| | - Paola Spaggiari
- Department of Pathology, Humanitas Clinical and Research Center, Milan, Italy
| | - Antonino Spinelli
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Colon and Rectal Surgery Unit, Humanitas Clinical and Research Center, Milan, Italy
| | - Michele Carvello
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Colon and Rectal Surgery Unit, Humanitas Clinical and Research Center, Milan, Italy
| | - Matteo Sacchi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Colon and Rectal Surgery Unit, Humanitas Clinical and Research Center, Milan, Italy
| | - Salvatore Spanò
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Stefania Vetrano
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Alberto Malesci
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.,Department of Gastroenterology, Humanitas Clinical and Research Center, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Institut National de la Santé et de la Recherche Médicale U954 and Department of Gastroenterology, Nancy University Hospital, Lorraine University, Nancy, France
| | - Silvio Danese
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Silvia D'Alessio
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
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10
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Clinical Impact and Prognostic Role of KRAS/BRAF/PIK3CA Mutations in Stage I Colorectal Cancer. DISEASE MARKERS 2018; 2018:2959801. [PMID: 30018674 PMCID: PMC6029483 DOI: 10.1155/2018/2959801] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/04/2018] [Accepted: 05/20/2018] [Indexed: 02/07/2023]
Abstract
Stage I colorectal carcinoma has excellent prognosis, with 5-year survival rate up to 95%. The occurrence of lymphovascular invasion, tumor budding, high number of PDC, or lymph node micrometastases is associated with tumor progression. The aim of this study was to evaluate the mutational status of 62 stage I colorectal carcinomas (CRC) (taken from 37 patients surviving more than five years since the initial diagnosis and from 25 patients who died of disease) and to correlate it with histopathological features and the clinical outcome. Mutations of KRAS, NRAS, BRAF, and PIK3CA genes were analyzed through Myriapod Colon Status Kit, using the high-throughput genotyping platform Sequenom MassARRAY System. Mutations in those genes were found in 31 cases (50%) and mainly in those with poor prognosis. The most frequent mutations occurred at codons 12 and 13 of the KRAS gene (40% of cases). We found concomitant PIK3CA mutations in 5 cases (8%). The presence of PIK3CA mutations was mainly observed in tumors with poor prognosis and with unfavorable histopathological prognostic features. High PDC grade (P = 0.0112), the presence of tumor budding (P = 0.0334), LVI (P < 0.0001), KRAS mutations (P = 0.0228), PIK3CA mutations (P = 0.0214), multiple genetic mutations in KRAS and PIK3CA genes (P = 0.039), and nodal micrometastases (P < 0.0001) were significant prognostic variables for CSS. The presence of LVI was the only independent and statistically significant prognostic variable for CSS in our cohort of pTNM stage I CRCs. The analysis of KRAS/PIK3CA mutational status may be used to identify patients with stage I CRC at high risk of bad outcome and who may need additional treatments, including biological therapies.
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11
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Krediet JT, Kanitakis J, Bob A, Schmitter J, Krediet AC, Röwert J, Stockfleth E, Painsi C, Hügel R, Terhorst D, Lange-Asschenfeldt B. Prognostic value of the area and density of lymphatic vessels in cutaneous squamous cell carcinoma. J Dtsch Dermatol Ges 2018; 14:1114-1121. [PMID: 27879093 DOI: 10.1111/ddg.12880] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Accepted: 09/21/2015] [Indexed: 11/27/2022]
Abstract
BACKGROUND AND OBJECTIVES Cutaneous squamous cell carcinoma (SCC) is known for its capacity to metastasize via lymphatic vessels. In recent studies, the level of lymphangiogenesis has been reported as a potential prognostic factor for several skin tumors. The aim of this study was to quantify lymphangiogenesis in SCC using either computer-assisted image analysis or the Chalkley count technique. Vascular parameters were evaluated and compared with respect to their predictive power for tumor metastasis. PATIENT AND METHODS In this case-control study, clinical and histological data of 15 metastatic and 15 nonmetastatic SCC patients were retrospectively analyzed. SCC samples were immunostained for the lymphatic endothelial marker D2-40 and the panvascular marker CD31, and analyzed using computer-assisted morphometric image analyses within hot spots as well as the digitalized Chalkley counting method. RESULTS Lymphatic vessel density, relative lymphatic vessel area, and lymphatic Chalkley count were significantly elevated in metastatic SCC. Tumor thickness was significantly higher in metastatic SCC, and had the highest predictive power for metastatic disease. Tumor thickness was a significant predictor of lymphangiogenic parameters. CONCLUSIONS Lymphangiogenesis is elevated in metastatic SCC but its extent is influenced by tumor thickness. Tumor thickness remains the most reliable predictive factor for metastatic disease.
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Affiliation(s)
- Jorien Tannette Krediet
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité-Universitaetsmedizin Berlin, Berlin, Germany
| | - Jean Kanitakis
- Department of Dermatology, Ed. Herriot Hospital, Lyon, France
| | - Adrienne Bob
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité-Universitaetsmedizin Berlin, Berlin, Germany
| | - Julia Schmitter
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité-Universitaetsmedizin Berlin, Berlin, Germany
| | - Annelot Carine Krediet
- Department of Anesthesiology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Joachim Röwert
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité-Universitaetsmedizin Berlin, Berlin, Germany
| | - Eggert Stockfleth
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité-Universitaetsmedizin Berlin, Berlin, Germany
| | - Clemens Painsi
- Department of Dermatology and Venereology, State Hospital Klagenfurt, Klagenfurt am Wörthersee, Austria
| | - Rainer Hügel
- Department of Dermatology and Venereology, State Hospital Klagenfurt, Klagenfurt am Wörthersee, Austria
| | - Dorothea Terhorst
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité-Universitaetsmedizin Berlin, Berlin, Germany
| | - Bernhard Lange-Asschenfeldt
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité-Universitaetsmedizin Berlin, Berlin, Germany.,Department of Dermatology and Venereology, State Hospital Klagenfurt, Klagenfurt am Wörthersee, Austria
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12
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Bob A, Nielen F, Krediet J, Schmitter J, Freundt D, Terhorst D, Röwert-Huber J, Kanitakis J, Stockfleth E, Ulrich C, Weichenthal M, Egberts F, Lange-Asschenfeldt B. Tumor vascularization and clinicopathologic parameters as prognostic factors in merkel cell carcinoma. J Cancer Res Clin Oncol 2017; 143:1999-2010. [PMID: 28639083 DOI: 10.1007/s00432-017-2455-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Accepted: 06/06/2017] [Indexed: 12/22/2022]
Abstract
PURPOSE Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine tumor of the skin with an increasing incidence. The clinical course is variable and reliable prognostic factors are scarce. Tumor angiogenesis has been shown to have prognostic impact in different types of cancer. The aim of our study was to determine potential prognostic factors, including tumor vascularization, for clinical outcome of MCC. METHODS The medical records of 46 patients with MCC diagnosed between 1997 and 2010 were analyzed retrospectively. Tissue samples were immune-stained for the lymphatic endothelial vessel marker podoplanin/D2-40 and the panvascular marker CD31. These immunostained sections were analyzed using computer-assisted morphometric image analyses. Aside from the parameters of tumor vascularization, clinicopathologic features were investigated, and progression-free survival (PFS) and tumor-specific survival (TSS) were assessed. Univariate and multivariate analyses were performed to determine prognostic factors. RESULTS Male sex of the MCC patients and a high cross-sectional whole vessel area (WVA) in relation to the entire tumor area as determined on CD31-stained tumor sections were found to be negative prognostic factors for PFS in a univariate and multivariate regression analysis. Ulceration of the primary tumor was significantly associated with both impaired PFS and TSS. CONCLUSIONS Our results indicate a high prognostic impact of tumor vascularization on the clinical outcome of MCC patients. Male sex and ulceration of the primary MCC were identified as independent unfavorable prognostic markers for the clinical outcome. As an outlook, MCC patients with increased angiogenesis might be identified and subjected to a targeted anti-angiogenic treatment.
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Affiliation(s)
- A Bob
- Department of Dermatology, Venerology and Allergology, Charité University Medicine Berlin, Berlin, Germany
| | - F Nielen
- Department of Dermatology, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany
| | - J Krediet
- Department of Dermatology, Venerology and Allergology, Charité University Medicine Berlin, Berlin, Germany
| | - J Schmitter
- Department of Dermatology, Venerology and Allergology, Charité University Medicine Berlin, Berlin, Germany
- Department of Dermatology, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany
| | - D Freundt
- Department of Dermatology, Venerology and Allergology, Charité University Medicine Berlin, Berlin, Germany
| | - D Terhorst
- Department of Dermatology, Venerology and Allergology, Charité University Medicine Berlin, Berlin, Germany
| | - J Röwert-Huber
- Department of Dermatology, Venerology and Allergology, Charité University Medicine Berlin, Berlin, Germany
| | - J Kanitakis
- Department of Dermatology and Pathology, Edouard Herriot Hospital Group, Hospices Civils de Lyon, Lyon, France
| | - E Stockfleth
- Department of Dermatology, Venerology and Allergology, Charité University Medicine Berlin, Berlin, Germany
| | - Ch Ulrich
- Department of Dermatology, Venerology and Allergology, Charité University Medicine Berlin, Berlin, Germany
| | - M Weichenthal
- Department of Dermatology, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany
| | - F Egberts
- Department of Dermatology, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany.
| | - B Lange-Asschenfeldt
- Department of Dermatology, Venerology and Allergology, Charité University Medicine Berlin, Berlin, Germany.
- Department of Dermatology, State Hospital Klagenfurt, Klagenfurt Am Wörthersee, Austria.
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Abstract
Lymphatic metastasis is an important event in the progress of metastasis in colorectal cancer (CRC). The purpose of this article is to assess the role of lymphangiogenesis on CRC. In peritumoral areas of CRC, the lymphatic microvessel density (LMVD) is higher than those in normal colorectal tissues. Morever, the high LMVD is correlated with DFS and local recurrence in CRC. The VEGF-C/VEGF-D/VEGFR-3 pathway, sonic hedgehog (Shh) signaling pathway and extracellular matrix (ECM) are involved in the regulation of lymphangiogenesis in CRC. Inhibition of the VEGF-C/VEGF-D/VEGFR-3 pathway by specific antibodies has been reported to efficiently inhibit experimental tumor lymphangiogenesis and metastasis in animal experiments. Although lymphangiogenesis has been reported to play an important role in the occurrence of colon cancer and to be associated with prognosis, it remains unclear whether it is a valid therapeutic target molecule. Further study of the potential of targeting this process for anti-lymphatic therapies is worthwhile.
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Affiliation(s)
- Ciyou Huang
- Department of Endocrinology, Wuxi Second Hospital, Nanjing Medical University, Jiangsu, China. E-mail.
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14
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Krediet JT, Kanitakis J, Bob A, Schmitter J, Carine Krediet A, Röwert J, Stockfleth E, Painsi C, Hügel R, Terhorst D, Lange‐Asschenfeldt B. Prognostischer Wert der Fläche und Dichte von Lymphgefäßen bei kutanem Plattenepithelkarzinom. J Dtsch Dermatol Ges 2016; 14:1116-1124. [DOI: 10.1111/ddg.12880_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Accepted: 09/21/2015] [Indexed: 11/30/2022]
Affiliation(s)
- Jorien Tannette Krediet
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité‐Universitaetsmedizin Berlin, Berlin, Germany (Hauttumorcentrum Charité, Klinik für Dermatologie, Venerologie und Allergologie, Charité‐Universitätsmedizin Berlin, Berlin, Deutschland)
| | - Jean Kanitakis
- Department of Dermatology, Ed. Herriot Hospital, Lyon, Frankreich
| | - Adrienne Bob
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité‐Universitaetsmedizin Berlin, Berlin, Germany (Hauttumorcentrum Charité, Klinik für Dermatologie, Venerologie und Allergologie, Charité‐Universitätsmedizin Berlin, Berlin, Deutschland)
| | - Julia Schmitter
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité‐Universitaetsmedizin Berlin, Berlin, Germany (Hauttumorcentrum Charité, Klinik für Dermatologie, Venerologie und Allergologie, Charité‐Universitätsmedizin Berlin, Berlin, Deutschland)
| | | | - Joachim Röwert
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité‐Universitaetsmedizin Berlin, Berlin, Germany (Hauttumorcentrum Charité, Klinik für Dermatologie, Venerologie und Allergologie, Charité‐Universitätsmedizin Berlin, Berlin, Deutschland)
| | - Eggert Stockfleth
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité‐Universitaetsmedizin Berlin, Berlin, Germany (Hauttumorcentrum Charité, Klinik für Dermatologie, Venerologie und Allergologie, Charité‐Universitätsmedizin Berlin, Berlin, Deutschland)
| | - Clemens Painsi
- Department of Dermatology and Venereology, State Hospital Klagenfurt, Klagenfurt am Wörthersee, Austria (Abteilung für Dermatologie und Venerologie, Klinikum Klagenfurt, Klagenfurt am Wörthersee, Österreich)
| | - Rainer Hügel
- Department of Dermatology and Venereology, State Hospital Klagenfurt, Klagenfurt am Wörthersee, Austria (Abteilung für Dermatologie und Venerologie, Klinikum Klagenfurt, Klagenfurt am Wörthersee, Österreich)
| | - Dorothea Terhorst
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité‐Universitaetsmedizin Berlin, Berlin, Germany (Hauttumorcentrum Charité, Klinik für Dermatologie, Venerologie und Allergologie, Charité‐Universitätsmedizin Berlin, Berlin, Deutschland)
| | - Bernhard Lange‐Asschenfeldt
- Skin Cancer Center Charité, Department of Dermatology and Allergy, Charité‐Universitaetsmedizin Berlin, Berlin, Germany (Hauttumorcentrum Charité, Klinik für Dermatologie, Venerologie und Allergologie, Charité‐Universitätsmedizin Berlin, Berlin, Deutschland)
- Department of Dermatology and Venereology, State Hospital Klagenfurt, Klagenfurt am Wörthersee, Austria (Abteilung für Dermatologie und Venerologie, Klinikum Klagenfurt, Klagenfurt am Wörthersee, Österreich)
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15
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Dieterich LC, Detmar M. Tumor lymphangiogenesis and new drug development. Adv Drug Deliv Rev 2016; 99:148-160. [PMID: 26705849 DOI: 10.1016/j.addr.2015.12.011] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Revised: 10/12/2015] [Accepted: 12/09/2015] [Indexed: 02/07/2023]
Abstract
Traditionally, tumor-associated lymphatic vessels have been regarded as passive by-standers, serving simply as a drainage system for interstitial fluid generated within the tumor. However, with growing evidence that tumors actively induce lymphangiogenesis, and that the number of lymphatic vessels closely correlates with metastasis and clinical outcome in various types of cancer, this picture has changed dramatically in recent years. Tumor-associated lymphatic vessels have now emerged as a valid therapeutic target to control metastatic disease, and the first specific anti-lymphangiogenic drugs have recently entered clinical testing. Furthermore, we are just beginning to understand the whole functional spectrum of tumor-associated lymphatic vessels, which not only concerns transport of fluid and metastatic cells, but also includes the regulation of cancer stemness and specific inhibition of immune responses, opening new venues for therapeutic applications. Therefore, we predict that specific targeting of lymphatic vessels and their function will become an important tool for future cancer treatment.
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16
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Barresi V, Branca G, Vitarelli E, Tuccari G. Micropapillary pattern and poorly differentiated clusters represent the same biological phenomenon in colorectal cancer: a proposal for a change in terminology. Am J Clin Pathol 2014; 142:375-83. [PMID: 25125629 DOI: 10.1309/ajcpfea7ka0sbbna] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Colorectal carcinomas (CRCs) with a micropapillary pattern and those showing high counts of poorly differentiated clusters (PDCs) are characterized by a higher probability to develop nodal metastases and have a worse prognosis. In light of the morphologic similarity to the micropapillary component, we aimed to verify whether PDCs also display an inverted secretory pattern. METHODS The immunohistochemical expression of MUC1 and E-cadherin was assessed in a cohort of CRCs with PDCs and compared with that observed in CRCs without PDCs. RESULTS PDCs in our cases always displayed an inverted MUC1 pattern. In addition, we found abnormal (lost or cytoplasmic) expression of E-cadherin in PDCs. CONCLUSIONS The altered expression of MUC1 and E-cadherin may account for the aggressive behavior and higher metastatic potential of CRCs with high PDC counts and indicate an epithelial-mesenchymal transition. Our findings suggest that regardless of the morphologic aspect, PDCs and the micropapillary component may reflect the same biological phenomenon in CRCs. Thus, we wonder whether the micropapillary areas should be considered a variant of CRCs or more objectively counted as PDCs to predict prognosis. We also believe that the term PDC better describes the biological phenomena underlying this peculiar morphologic aspect in comparison with the misnomer micropapillary.
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Affiliation(s)
- Valeria Barresi
- From the Department of Human Pathology "Gaetano Barresi," University of Messina, Messina, Italy.
| | - Giovanni Branca
- From the Department of Human Pathology "Gaetano Barresi," University of Messina, Messina, Italy
| | - Enrica Vitarelli
- From the Department of Human Pathology "Gaetano Barresi," University of Messina, Messina, Italy
| | - Giovanni Tuccari
- From the Department of Human Pathology "Gaetano Barresi," University of Messina, Messina, Italy
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17
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Caie PD, Turnbull AK, Farrington SM, Oniscu A, Harrison DJ. Quantification of tumour budding, lymphatic vessel density and invasion through image analysis in colorectal cancer. J Transl Med 2014; 12:156. [PMID: 24885583 PMCID: PMC4098951 DOI: 10.1186/1479-5876-12-156] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 05/26/2014] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Tumour budding (TB), lymphatic vessel density (LVD) and lymphatic vessel invasion (LVI) have shown promise as prognostic factors in colorectal cancer (CRC) but reproducibility using conventional histopathology is challenging. We demonstrate image analysis methodology to quantify the histopathological features which could permit standardisation across institutes and aid risk stratification of Dukes B patients. METHODS Multiplexed immunofluorescence of pan-cytokeratin, D2-40 and DAPI identified epithelium, lymphatic vessels and all nuclei respectively in tissue sections from 50 patients diagnosed with Dukes A (n = 13), Dukes B (n = 29) and Dukes C (n = 8) CRC. An image analysis algorithm was developed and performed, on digitised images of the CRC tissue sections, to quantify TB, LVD, and LVI at the invasive front. RESULTS TB (HR =5.7; 95% CI, 2.38-13.8), LVD (HR =5.1; 95% CI, 2.04-12.99) and LVI (HR =9.9; 95% CI, 3.57-27.98) were successfully quantified through image analysis and all were shown to be significantly associated with poor survival, in univariate analyses. LVI (HR =6.08; 95% CI, 1.17-31.41) is an independent prognostic factor within the study and was correlated to both TB (Pearson r =0.71, p <0.0003) and LVD (Pearson r =0.69, p <0.0003). CONCLUSION We demonstrate methodology through image analysis which can standardise the quantification of TB, LVD and LVI from a single tissue section while decreasing observer variability. We suggest this technology is capable of stratifying a high risk Dukes B CRC subpopulation and we show the three histopathological features to be of prognostic significance.
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Affiliation(s)
- Peter D Caie
- Digital Pathology Unit, Laboratory medicine, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK.
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18
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Barresi V, Branca G, Ieni A, Reggiani Bonetti L, Baron L, Mondello S, Tuccari G. Poorly differentiated clusters (PDCs) as a novel histological predictor of nodal metastases in pT1 colorectal cancer. Virchows Arch 2014; 464:655-62. [PMID: 24771119 DOI: 10.1007/s00428-014-1580-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 03/24/2014] [Accepted: 04/09/2014] [Indexed: 12/15/2022]
Abstract
The practical use of histological factors such as submucosal (SM) invasion depth, poor differentiation, presence of lymphovascular invasion (LVI) and tumour budding to establish the risk of nodal dissemination in pT1 colorectal cancer (CRC) is limited by their low standardization and high inter-observer variability. It was recently suggested that the presence in CRC histological sections of poorly differentiated clusters (PDCs), defined as ≥5 cancer cells with no gland formation, may predict the metastatic potential of CRC. In addition, PDC assessment was shown to be more reproducible than the evaluation of the other aforementioned histological predictors. Hence, in this study, we investigated and compared the predictive value of PDC and other histological parameters on the risk of nodal involvement in pT1 CRC. The presence of PDC, SM invasion depth ≥1,000 μm and LVI was significantly associated with N+ status in pT1 CRC (P < 0.0001). Among these parameters, SM invasion depth had the highest sensitivity to identify N+ pT1 CRC but with the lowest specificity. When the analysis was restricted to CRCs with SM invasion depth ≥1,000 μm, the presence of PDC was the only independent risk factor for nodal metastases and allowed the identification of 87.5 % of N+ cancers. In conclusion, in this study, we demonstrate that the presence of PDC is associated with the metastatic potential of pT1 CRC. The combination of this parameter with SM invasion depth may allow identifying most of the pT1 CRC with nodal metastases.
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Affiliation(s)
- Valeria Barresi
- Department of Human Pathology "Gaetano Barresi", University of Messina, 98125, Messina, Italy,
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19
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Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer 2014; 14:159-72. [PMID: 24561443 DOI: 10.1038/nrc3677] [Citation(s) in RCA: 597] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The generation of new lymphatic vessels through lymphangiogenesis and the remodelling of existing lymphatics are thought to be important steps in cancer metastasis. The past decade has been exciting in terms of research into the molecular and cellular biology of lymphatic vessels in cancer, and it has been shown that the molecular control of tumour lymphangiogenesis has similarities to that of tumour angiogenesis. Nevertheless, there are significant mechanistic differences between these biological processes. We are now developing a greater understanding of the specific roles of distinct lymphatic vessel subtypes in cancer, and this provides opportunities to improve diagnostic and therapeutic approaches that aim to restrict the progression of cancer.
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Affiliation(s)
- Steven A Stacker
- 1] Tumour Angiogenesis Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. [2] Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3010, Australia. [3] Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia
| | - Steven P Williams
- Tumour Angiogenesis Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia
| | - Tara Karnezis
- 1] Tumour Angiogenesis Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. [2] Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3010, Australia
| | - Ramin Shayan
- 1] Tumour Angiogenesis Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. [2] Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia. [3] Department of Surgery, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria 3065, Australia. [4] O'Brien Institute, Australian Catholic University, Fitzroy, Victoria 3065, Australia
| | - Stephen B Fox
- 1] Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3010, Australia. [2] Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia
| | - Marc G Achen
- 1] Tumour Angiogenesis Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. [2] Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3010, Australia. [3] Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia
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van Wyk HC, Roxburgh CS, Horgan PG, Foulis AF, McMillan DC. The detection and role of lymphatic and blood vessel invasion in predicting survival in patients with node negative operable primary colorectal cancer. Crit Rev Oncol Hematol 2013; 90:77-90. [PMID: 24332522 DOI: 10.1016/j.critrevonc.2013.11.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 10/09/2013] [Accepted: 11/14/2013] [Indexed: 12/15/2022] Open
Abstract
Although vascular invasion in colorectal cancer has been recognised since 1938, detection methods and results remain inconsistent. Vascular invasion is currently an independent prognostic factor in colorectal cancer influencing disease progression and survival. The vascular system consists of three components, arterial, venous and lymphatic vessels, all of which can be invaded but accurate distinction between the components remains difficult with routine staining techniques. Even though higher detection rates with elastica staining, for large vessel invasion, and recent techniques for immunohistochemistry for small vessel invasion, have been reported, a standardised method of detection has not been agreed upon which is reflected in the variability of published results. As a result of the Bowel Cancer Screening Programme in the UK it will be necessary to attempt to identify and stratify patients better, to be able to handle the stage migration to early node negative colorectal cancer. At present up to a third of patients, with node-negative colorectal cancer on conventional histopathological analysis, ultimately die of recurrent disease. It is therefore important to develop and standardised methods to identify lymphatic and blood vessel invasion which will influence ultimate survival. The present review summarises the current status of detection methods for these components of vascular invasion.
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Affiliation(s)
- Hester C van Wyk
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK.
| | - Campbell S Roxburgh
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK
| | - Paul G Horgan
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK
| | - Alan F Foulis
- University Department of Pathology, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Southern General Hospital, Glasgow, UK
| | - Donald C McMillan
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK
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21
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Li ZJ, Ying XJ, Chen HL, Ye PJ, Chen ZL, Li G, Jiang HF, Liu J, Zhou SZ. Insulin-like growth factor-1 induces lymphangiogenesis and facilitates lymphatic metastasis in colorectal cancer. World J Gastroenterol 2013; 19:7788-7794. [PMID: 24282367 PMCID: PMC3837280 DOI: 10.3748/wjg.v19.i43.7788] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of insulin-like growth factor-1 (IGF-1)/insulin-like growth factor-1 receptor (IGF-1R) in colorectal cancer (CRC) tissues and to analyze their correlation with lymphangiogenesis and lymphatic metastasis.
METHODS: Immunohistochemistry was used to evaluate IGF-1 and IGF-1R expression and lymphatic vessel density (LVD) in 40 CRC specimens. The correlation between IGF-1/IGF-1R and LVD was investigated. Effects of IGF-1 on migration and invasion of CRC cells were examined using transwell chamber assays. A LoVo cell xenograft model was established to further detect the role of IGF-1 in CRC lymphangiogenesis in vivo.
RESULTS: Elevated IGF-1 and IGF-1R expression in CRC tissues was correlated with lymph node metastasis (r = 0.715 and 0.569, respectively, P < 0.05) and tumor TNM stage (r = 0.731 and 0.609, P < 0.05). A higher LVD was also found in CRC tissues and was correlated with lymphatic metastasis (r = 0.405, P < 0.05). A positive correlation was found between LVD and IGF-1R expression (r = 0.437, P < 0.05). Transwell assays revealed that IGF-1 increased the migration and invasion of CRC cells. In vivo mouse studies showed that IGF-1 also increased LVD in LoVo cell xenografts.
CONCLUSION: IGF-1/IGF-1R signaling induces tumor-associated lymphangiogenesis and contributes to lymphatic metastasis of CRC.
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Colorectal carcinoma grading by quantifying poorly differentiated cell clusters is more reproducible and provides more robust prognostic information than conventional grading. Virchows Arch 2012; 461:621-8. [PMID: 23093109 DOI: 10.1007/s00428-012-1326-8] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Revised: 09/05/2012] [Accepted: 09/27/2012] [Indexed: 12/20/2022]
Abstract
The most widely used system to define the histological grade of colorectal carcinoma (CRC) is based on the degree of gland formation. This system suffers from significant interobserver variability which may limit its prognostic value and consequently better standardized criteria for the assessment of histological grading of CRC are needed. The present study aims to evaluate and to compare, in a cohort of postsurgical pTNM stage I CRC, conventional histological grading, and a novel grading system based on the number of poorly differentiated clusters of neoplastic cells, in terms of interobserver reproducibility, prognostic significance on progression-free survival, and association with other clinicopathological characteristics. Grading with both systems was performed by two pathologists independently and blinded to the clinicopathological data. Interobserver agreement was higher when grade was assessed by counting poorly differentiated clusters than by assessing the relative proportion of the glandular component. Contrary to conventional grading, the novel system provided significant prognostic information in terms of progression-free survival and was significantly associated with budding, invasive growth, lymphatic invasion, and occult nodal metastases of CRC. In conclusion, our findings suggest that a tumor grading system based on the number of poorly differentiated clusters is more reproducible and provides better prognostic stratification of pTNM stage I CRC patients than conventional grading.
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23
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Cacchi C, Arnholdt HM, Jähnig H, Anthuber M, Probst A, Oruzio DV, Märkl B. Clinical significance of lymph vessel density in T3 colorectal carcinoma. Int J Colorectal Dis 2012; 27:721-6. [PMID: 22228115 DOI: 10.1007/s00384-011-1373-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/15/2011] [Indexed: 02/04/2023]
Abstract
PURPOSE The purpose of the present study is to characterise the lymphatic vessel density (LVD) in the T3 colorectal carcinoma and to correlate it with N status, grading and presence of tumour budding. METHODS A total of 56 cases of T3 colorectal carcinoma were retrieved from the pathology's archive of Klinikum Augsburg. All slides were stained immunohistochemically with D2-40 (lymphatic endothelium) and with pancytokeratin to assess the tumour budding. Tumour budding and lymph vessel density were investigated independently by BM and CC. The highest density of lymphatic vessels was counted both in tumour centre (ILVD) and at the periphery of the tumour (PLVD) within an area of 0.24 mm(2). RESULTS Due to the strong intra-observer (BM and CC) difference in ILVD and PLVD, all cases were re-evaluated establishing a consensus that has been used for the further analyses. There was a significant difference between PLVD and ILVD (12 ± 4 versus 6 ± 3; P < 0.001). Moreover, we found a non-significant trend towards high PLVD in the cases with nodal metastasis versus the negative one, 13 ± 5/hpf versus 11 ± 4 (P = 0.072). There was no association between tumour budding and ILVD and PLVD (P = 0.249 and 0.38). CONCLUSION Colorectal carcinoma induces lymphangiogenesis. A higher PLVD could increase the capability of cancer cell to invade the lymphatic system. However, the obvious difficulties in immunohistochemical evaluation and the rather small differences between nodal positive and negative cases in T3 colorectal cancer seem to limit the clinical value of LVD evaluation.
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Affiliation(s)
- Claudio Cacchi
- Institute of Pathology, Klinikum Augsburg, Augsburg, Germany.
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Xiang L, Xie G, Ou J, Wei X, Pan F, Liang H. The extra domain A of fibronectin increases VEGF-C expression in colorectal carcinoma involving the PI3K/AKT signaling pathway. PLoS One 2012; 7:e35378. [PMID: 22496919 PMCID: PMC3322170 DOI: 10.1371/journal.pone.0035378] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Accepted: 03/16/2012] [Indexed: 12/29/2022] Open
Abstract
The extra domain A (EDA)-containing fibronectin (EDA-FN), an alternatively spliced form of the extracellular matrix protein fibronectin, is predominantly expressed in various malignancies but not in normal tissues. In the present study, we investigated the potential pro-lymphangiogenesis effects of extra domain A (EDA)-mediated vascular endothelial growth factor-C (VEGF-C) secretion in colorectal carcinoma (CRC). We detected the expressions of EDA and VEGF-C in 52 human colorectal tumor tissues and their surrounding mucosae by immunohistochemical analysis, and further tested the correlation between the expressions of these two proteins in aforementioned CRC tissues. Both EDA and VEGF-C were abundantly expressed in the specimens of human CRC tissues. And VEGF-C was associated with increased expression of EDA in human CRC according to linear regression analysis. Besides, EDA expression was significantly correlated with lymph node metastasis, tumor differentiation and clinical stage by clinicopathological analysis of tissue microarrays containing tumor tissues of 115 CRC patients. Then, human CRC cell SW480 was transfected with lentivectors to elicit expression of shRNA against EDA (shRNA-EDA), and SW620 was transfected with a lentiviral vector to overexpress EDA (pGC-FU-EDA), respectively. We confirmed that VEGF-C was upregulated in EDA-overexpressed cells, and downregulated in shRNA-EDA cells. Moreover, a PI3K-dependent signaling pathway was found to be involved in EDA-mediated VEGF-C secretion. The in vivo result demonstrated that EDA could promote tumor growth and tumor-induced lymphangiogenesis in mouse xenograft models. Our findings provide evidence that EDA could play a role in tumor-induced lymphangiogenesis via upregulating autocrine secretion of VEGF-C in colorectal cancer, which is associated with the PI3K/Akt-dependent pathway.
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Affiliation(s)
- Lisha Xiang
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ganfeng Xie
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Juanjuan Ou
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xing Wei
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Feng Pan
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Houjie Liang
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
- * E-mail:
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Barresi V, Reggiani Bonetti L, Vitarelli E, Di Gregorio C, Ponz de Leon M, Barresi G. Immunohistochemical assessment of lymphovascular invasion in stage I colorectal carcinoma: prognostic relevance and correlation with nodal micrometastases. Am J Surg Pathol 2012; 36:66-72. [PMID: 21989343 DOI: 10.1097/pas.0b013e31822d3008] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Several studies have suggested that the presence of occult nodal metastases (micrometastases) is related to adverse clinical course in stage I colorectal carcinoma. Herein we analyzed the correlation between nodal micrometastases and lymphovascular invasion (LVI) or lymphatic vessel density (LVD) in a series of stage I colorectal carcinomas; the cohort included cases characterized or not characterized by disease progression during the follow-up. In these cases, LVI and LVD were evidenced through the immunohistochemical detection of the specific marker for lymphatic vessels, D2-40. LVI was significantly more frequent in colorectal carcinomas characterized by the presence of micrometastases (P<0.0001), high peritumoral LVD (P<0.0001), and disease progression (P<0.0001). The analysis for progression risk indicated that nodal micrometastases and LVI were significant, negative, independent prognostic parameters associated with shorter disease-free survival of stage I colorectal cancer (P=0.0001; P=0.0242). In conclusion, in this study we demonstrated for the first time that LVI is significantly associated with nodal occult metastases in stage I colorectal carcinoma. In the light of its significant, independent, prognostic value in this neoplasia, the detection of LVI may represent a faster and cheaper tool compared with the time-consuming evaluation of micrometastases to select high-risk patients who may benefit from adjuvant systemic treatment. Furthermore, the assessment of LVI may be applied to establish the likelihood of nodal involvement from carcinomas treated with conservative local excision techniques, which provide no regional nodes for histologic examination.
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Affiliation(s)
- Valeria Barresi
- Department of Human Pathology, University of Messina, Messina, Italy.
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Du B, Yang ZY, Zhong XY, Fang M, Yan YR, Qi GL, Pan YL, Zhou XL. Metastasis-associated protein 1 induces VEGF-C and facilitates lymphangiogenesis in colorectal cancer. World J Gastroenterol 2011; 17:1219-26. [PMID: 21448429 PMCID: PMC3063917 DOI: 10.3748/wjg.v17.i9.1219] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Revised: 12/09/2010] [Accepted: 12/16/2010] [Indexed: 02/06/2023] Open
Abstract
AIM To study the correlation between high metastasis-associated protein 1 (MTA1) expression and lymphangiogenesis in colorectal cancer (CRC) and its role in production of vascular endothelial growth factor-C(VEGF-C). METHODS Impact of high MTA1 and VEGF-C expression levels on disease progression and lymphovascular density (LVD, D2-40-immunolabeled) in 81 cases of human CRC was evaluated by immunohistochemistry. VEGF-C mRNA and protein expressions in human LoVo and HCT116 cell lines were detected by real-time polymerase chain reaction and Western blotting, respectively, with a stable expression vector or siRNA. RESULTS The elevated MTA1 and VEGF-C expression levels were correlated with lymph node metastasis and Dukes stages (P < 0.05). Additionally, high MTA1 expression level was correlated with a large tumor size (P < 0.05). A significant correlation was found between MTA1 and VEGF-C protein expressions in tumor cells (r = 0.371, P < 0.05). Similar to the VEGF-C expression level, high MTA1 expression level was correlated with high LVD in CRC (P < 0.05). Furthermore, over-expression of MTA1 significantly enhanced the VEGF-C mRNA and protein expression levels, whereas siRNAs - knocked down MTA1 decreased the VEGF-C expression level. CONCLUSION MTA1, as a regulator of tumor-associated lymphangiogenesis, promotes lymphangiogenesis in CRC by mediating the VEGF-C expression.
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